JP6073543B2 - Method for producing loratadine-containing orally disintegrating tablet - Google Patents
Method for producing loratadine-containing orally disintegrating tablet Download PDFInfo
- Publication number
- JP6073543B2 JP6073543B2 JP2011111427A JP2011111427A JP6073543B2 JP 6073543 B2 JP6073543 B2 JP 6073543B2 JP 2011111427 A JP2011111427 A JP 2011111427A JP 2011111427 A JP2011111427 A JP 2011111427A JP 6073543 B2 JP6073543 B2 JP 6073543B2
- Authority
- JP
- Japan
- Prior art keywords
- loratadine
- granulation
- powder
- fluidized bed
- orally disintegrating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 title claims description 132
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims description 44
- 238000004519 manufacturing process Methods 0.000 title claims description 38
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Description
本発明は、アレルギー性鼻炎、蕁麻疹等のアレルギー性疾患治療剤として有用なロラタジンを含有する口腔内崩壊錠の製造方法に関する。 The present invention relates to a method for producing an orally disintegrating tablet containing loratadine useful as a therapeutic agent for allergic diseases such as allergic rhinitis and urticaria.
口腔内崩壊錠は、水なしで服用することができ、高齢者、小児、嚥下困難な患者等に、飲みやすい剤形であり、高齢化社会の到来や患者のコンプライアンス向上のため、その意義が重要視されるようになって来た。 Orally disintegrating tablets can be taken without water and are easy to drink for elderly people, children, patients with difficulty swallowing, etc., and their significance is due to the arrival of an aging society and improved patient compliance. It has come to be regarded as important.
従来、ロラタジン含有口腔内崩壊錠としては、ゼラチン等の担体物質の水溶液に薬物を懸濁させ、トレイ等の容器に充填した後、凍結乾燥させて得られる、いわゆるザイディス（Ｚｙｄｉｓ）技術（特許文献１参照）を用いて製造されたクラリチンレディタブ錠が市販されている。しかし、このザイディス技術を商業的に応用するには、特殊な製造設備を要し、製造工程が煩雑で費用がかかるという欠点がある。また、ザイディス型の口腔内崩壊錠は、口腔内での溶解性については極めて優れているものの、錠剤が非常に柔らかく吸湿しやすいために完全防湿性の頑丈な包装形態が必須であることから、自動分包機への適用が不可能なだけでなく、容器から錠剤を取り出す際に壊れたり欠けたりしがちなど、医療現場では使い勝手が悪い。そのため、通常の製造設備により製造可能でかつ医療現場での取扱いが容易なロラタジン含有口腔内崩壊錠の開発が求められている。 Conventionally, as a loratadine-containing orally disintegrating tablet, a so-called Zydis technique obtained by suspending a drug in an aqueous solution of a carrier substance such as gelatin, filling a container such as a tray and then freeze-drying (Patent Document) 1) is commercially available. However, in order to apply this Zaydis technology commercially, special manufacturing equipment is required, and the manufacturing process is complicated and expensive. In addition, Zydis type orally disintegrating tablets are extremely excellent in solubility in the oral cavity, but since tablets are very soft and easy to absorb moisture, a completely moisture-proof and sturdy packaging form is essential. Not only is it impossible to apply it to an automatic packaging machine, but it tends to be broken or chipped when taking out tablets from a container. Therefore, development of a loratadine-containing orally disintegrating tablet that can be produced by ordinary production equipment and can be easily handled in the medical field is demanded.
一般的な錠剤製造用設備および製造方法によって製造しうるロラタジン含有口腔内崩壊錠としては、例えば、ロラタジン粉末に、造粒マンニトール、結晶セルロース、クロスポビドン等を混合、打錠して得られる口腔内崩壊錠（特許文献２参照）、ロラタジン粉末に、コロイド状二酸化ケイ素等を混合後、造粒し、マンニトール等を更に混合後、打錠して得られる口腔内崩壊錠（特許文献３参照）、ロラタジン粉末に、マンニトール、ソルビトール、及びケイ酸カルシウムを混合して複合材とし、更に、デンプン、クロスカルメロースナトリウム、ケイ酸カルシウム等を混合後、打錠して得られる口腔内崩壊錠（特許文献４参照）が提案されている。しかし、これらのロラタジン含有口腔内崩壊錠には、いずれも、ロラタジンの溶出性（即ち薬物放出性）が不十分であるという欠点がある。 As a loratadine-containing orally disintegrating tablet that can be produced by a general tablet production facility and production method, for example, the oral cavity obtained by mixing granulated mannitol, crystalline cellulose, crospovidone, and the like with loratadine powder and tableting Disintegrating tablets (see Patent Document 2), colloidal silicon dioxide and the like mixed with loratadine powder, granulated, further mixed with mannitol and the like, and then orally disintegrating tablets obtained by tableting (see Patent Document 3), Oral disintegrating tablets obtained by mixing loratadine powder with mannitol, sorbitol, and calcium silicate to form a composite material, and further mixing starch, croscarmellose sodium, calcium silicate, etc. (Patent Document) 4) has been proposed. However, all of these loratadine-containing orally disintegrating tablets have a drawback that the dissolution property (that is, drug release property) of loratadine is insufficient.
本発明の目的は、特殊な製造設備を用いることなく、口腔内崩壊性及び薬物放出性のいずれにも優れたロラタジン含有口腔内崩壊錠を得ることができる製造方法、及び該製造方法により得られたロラタジン含有口腔内崩壊錠を提供することにある。 The object of the present invention is obtained by a production method capable of obtaining a loratadine-containing orally disintegrating tablet excellent in both orally disintegrating property and drug releasing property without using a special production facility, and the production method. Another object is to provide an orally disintegrating tablet containing loratadine.
本発明者は、上記目的を達成すべく鋭意研究した結果、ロラタジン含有口腔内崩壊錠を製造するに当たって、ロラタジンを溶液状態乃至は懸濁状態で用い、２段階の造粒工程を行い、且つ１段目の造粒物の割合を錠剤重量の５０重量％以下とする場合には、錠剤からのロラタジンの放出性が向上すること、また得られた錠剤の口腔内崩壊性にも優れることを見出した。本発明者は、かかる知見に基づいて、更に検討を重ねた結果、本発明を完成するに至った。 As a result of intensive studies to achieve the above object, the present inventor conducted loratadine in a solution state or a suspension state to produce a loratadine-containing orally disintegrating tablet, and performed a two-step granulation process. When the ratio of the granulated product at the stage is 50% by weight or less of the tablet weight, it has been found that the release property of loratadine from the tablet is improved and the oral disintegration property of the obtained tablet is also excellent. It was. As a result of further studies based on this knowledge, the present inventor has completed the present invention.
本発明は、以下に示す、ロラタジン含有口腔内崩壊錠の製造方法及び該製造方法により得られたロラタジン含有口腔内崩壊錠を提供するものである。 This invention provides the manufacturing method of the loratadine containing orally disintegrating tablet shown below, and the loratadine containing orally disintegrating tablet obtained by this manufacturing method.
１．ロラタジン含有口腔内崩壊錠を製造する方法であって、ロラタジンを溶液状態乃至は懸濁状態で用いること、２段階の造粒工程を行うこと、及び１段階目の造粒物の割合を錠剤重量の５０重量％以下とすることを特徴とするロラタジン含有口腔内崩壊錠の製造方法。 1. A method for producing a loratadine-containing orally disintegrating tablet, wherein loratadine is used in a solution state or a suspension state, a two-step granulation step is performed, and a ratio of the first-step granulated product is determined as a tablet weight. The manufacturing method of the loratadine containing orally disintegrating tablet characterized by being 50 weight% or less of this.
２．第１段階目の造粒を、流動層造粒により行う上記項１に記載のロラタジン含有口腔内崩壊錠の製造方法。 2. Item 2. The method for producing a loratadine-containing orally disintegrating tablet according to Item 1, wherein the first-stage granulation is performed by fluidized bed granulation.
３．第２段階目の造粒を、流動層造粒により行う上記項１又は２に記載のロラタジン含有口腔内崩壊錠の製造方法。 3. Item 3. The method for producing a loratadine-containing orally disintegrating tablet according to Item 1 or 2, wherein the second-stage granulation is performed by fluidized bed granulation.
４．第２段階目の造粒後に、更に第３段階の造粒を、流動層造粒により行う上記項１〜３のいずれかに記載のロラタジン含有口腔内崩壊錠の製造方法。 4). Item 4. The method for producing an orally disintegrating tablet containing loratadine according to any one of Items 1 to 3, wherein the granulation in the third stage is further performed by fluidized bed granulation after the granulation in the second stage.
５．第１段階目の造粒物の割合が、錠剤重量の３０〜４５重量％である上記項１〜４のいずれかに記載のロラタジン含有口腔内崩壊錠の製造方法。 5. Item 5. The method for producing a loratadine-containing orally disintegrating tablet according to any one of Items 1 to 4, wherein the ratio of the first-stage granulated product is 30 to 45% by weight of the tablet weight.
６．上記項１〜５のいずれかに記載の製造方法によって得られたロラタジン含有口腔内崩壊錠。 6). The loratadine containing orally disintegrating tablet obtained by the manufacturing method in any one of said items 1-5.
本発明のロラタジン含有口腔内崩壊錠の製造方法によれば、以下の如き格別顕著な効果を得ることができる。 According to the method for producing a loratadine-containing orally disintegrating tablet of the present invention, the following remarkable effects can be obtained.
（１）本発明の製造方法においては、ロラタジン、賦形剤等を含む製剤原料を用いて、ロラタジン含有口腔内崩壊錠を製造するに当たって、ロラタジンを溶液状態乃至は懸濁状態で用い、少なくとも２段階の造粒工程を行い、且つ１段目の造粒物の割合を錠剤重量の５０重量％以下としたことによって、ロラタジンの口腔内崩壊錠からの放出性が著しく向上している。 (1) In the production method of the present invention, at the time of producing a loratadine-containing orally disintegrating tablet using a pharmaceutical raw material containing loratadine, excipients and the like, loratadine is used in a solution state or a suspended state, and at least 2 By performing the step granulation step and setting the ratio of the first step granulated product to 50% by weight or less of the tablet weight, the release of loratadine from the orally disintegrating tablet is remarkably improved.
（２）また、得られたロラタジン含有口腔内崩壊錠は、口腔内崩壊時間が通常３０秒以内程度であり、口腔内崩壊性にも優れている。また、優れた口腔内崩壊性を有していながら、自動分包機にも適用可能な錠剤硬度を有している。 (2) In addition, the obtained loratadine-containing orally disintegrating tablet usually has an oral disintegration time of about 30 seconds or less and is excellent in oral disintegration. Moreover, it has a tablet hardness applicable to an automatic packaging machine while having excellent oral disintegration properties.
（３）従って、本発明の製造方法によれば、特殊な製造設備を用いることなく、口腔内崩壊性及び薬物放出性のいずれにも優れたロラタジン含有口腔内崩壊錠を得ることができる。 (3) Therefore, according to the production method of the present invention, a loratadine-containing orally disintegrating tablet excellent in both orally disintegrating property and drug releasing property can be obtained without using special production equipment.
ロラタジン含有口腔内崩壊錠の製造方法
本発明のロラタジン含有口腔内崩壊錠の製造方法は、ロラタジンを溶液状態乃至は懸濁状態で用いること、２段階の造粒工程を行うこと、及び１段階目の造粒物の割合を錠剤重量の５０重量％以下とすることを特徴とするものである。
Method for producing loratadine-containing orally disintegrating tablet The method for producing the loratadine-containing orally disintegrating tablet of the present invention comprises using loratadine in a solution state or in a suspended state, performing a two-step granulation step, and the first step. The ratio of the granulated product is 50% by weight or less of the tablet weight.
本発明のロラタジン含有口腔内崩壊錠の製造方法においては、通常、ロラタジンと、賦形剤、結合剤及び崩壊剤である添加剤とを含み、更に必要に応じて、滑沢剤、矯味剤等のその他の添加剤を含む製剤原料を用いて、第１造粒工程、第２造粒工程を行った後、打錠工程を行うことによって、ロラタジン含有口腔内崩壊錠を調製する。ここで、ロラタジン以外の賦形剤、結合剤、崩壊剤、及び必要に応じて用いられるその他の添加剤の添加時期は、特に限定されず、任意の工程で添加することができ、またこれらのいずれかの添加剤を１の工程または複数の工程において複数回添加することもできる。 In the method for producing a loratadine-containing orally disintegrating tablet of the present invention, it usually contains loratadine and an additive that is an excipient, a binder and a disintegrant, and if necessary, a lubricant, a corrigent and the like. A loratadine-containing orally disintegrating tablet is prepared by performing a tableting step after performing a first granulation step and a second granulation step using a pharmaceutical raw material containing other additives. Here, the addition timing of excipients other than loratadine, binders, disintegrants, and other additives used as necessary is not particularly limited, and can be added in any step. Any additive may be added multiple times in one step or multiple steps.
ロラタジン
ロラタジンは、本発明口腔内崩壊錠の薬効成分であり、化学名がエチル ４−（８−クロロ−５，６−ジヒドロ−１１Ｈ−ベンゾ[５，６]シクロヘプタ[１，２−ｂ]ピリジン−1１−イリデン）−１−ピペリジンカルボキシレートである。ロラタジンは、持続性選択Ｈ１受容体拮抗作用を有しており、アレルギー性疾患治療剤として有用である。
Loratadine loratadine is a medicinal component of the orally disintegrating tablet of the present invention, and its chemical name is ethyl 4- (8-chloro-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridine. -11-ylidene) -1-piperidinecarboxylate. Loratadine has a persistent selective H 1 receptor antagonistic action and is useful as a therapeutic agent for allergic diseases.
添加剤
本発明のロラタジン含有口腔内崩壊錠の製造方法においては、ロラタジン以外の製剤原料として、製薬分野において通常使用される薬理学的に許容される各種添加剤、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、矯味剤等の添加剤を、適宜組み合わせて、用いることができる。
Additives In the process for producing the loratadine-containing orally disintegrating tablet of the present invention, various pharmacologically acceptable additives usually used in the pharmaceutical field, such as excipients and binders, as pharmaceutical raw materials other than loratadine. Additives such as disintegrants, lubricants, and flavoring agents can be used in appropriate combinations.
賦形剤としては、例えば、デキストリン、白糖、果糖、乳糖、トウモロコシデンプン、デンプン、カルボキシメチルスターチナトリウム、部分アルファー化デンプン、ヒドロキシプロピルスターチ、マンニトール、エリスリトール、ソルビトール、キシリトール、トレハロース、マルチトール、ラクチトール、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、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポピドン、軽質無水ケイ酸、酸化マグネシウム、炭酸マグネシウム、炭酸カルシウム、クエン酸カルシウム、合成ケイ酸アルミニウムなどが挙げられる。これらの賦形剤は、単独でまたは二種以上組み合わせて使用できる。 Examples of the excipient include dextrin, sucrose, fructose, lactose, corn starch, starch, sodium carboxymethyl starch, partially pregelatinized starch, hydroxypropyl starch, mannitol, erythritol, sorbitol, xylitol, trehalose, maltitol, lactitol, Low substituted hydroxypropyl cellulose, crystalline cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, light anhydrous silicic acid, magnesium oxide, magnesium carbonate, calcium carbonate, calcium citrate, synthetic aluminum silicate, etc. . These excipients can be used alone or in combination of two or more.
崩壊剤としては、例えば、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、架橋化ポリビニルピロリドン、低置換度ヒドロキシプロピルセルロース、各種デンプン類などが挙げられる。これらの崩壊剤は、単独でまたは二種以上組み合わせて使用できる。 Examples of the disintegrant include carmellose calcium, carmellose sodium, croscarmellose sodium, cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, and various starches. These disintegrants can be used alone or in combination of two or more.
結合剤としては、例えば、ショ糖等の糖類、ゼラチン、アラビアゴム末、メチルセルロース、エチルセルロース、ヒプロメロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、カルボキシメチルセルロース（カルメロース）、結晶セルロース・カルボキシメチルセルロースナトリウム、ポリビニルピロリドン、ポリビニルアルコール、マクロゴール、プルラン、デキストリン、トラガント、アルギン酸ナトリウム、キサンタンガム、部分α化デンプン、寒天などが挙げられる。これらの結合剤は、単独でまたは二種以上組み合わせて使用できる。 Examples of the binder include saccharides such as sucrose, gelatin, gum arabic powder, methyl cellulose, ethyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose (carmellose), crystalline cellulose / sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol , Macrogol, pullulan, dextrin, tragacanth, sodium alginate, xanthan gum, partially pregelatinized starch, agar and the like. These binders can be used alone or in combination of two or more.
これらの添加剤の割合は、ロラタジン１００重量部に対して、１００〜１２０００重量部程度の範囲から選択でき、通常、３００〜１００００重量部程度、好ましくは５００〜８０００重量部程度である。 The ratio of these additives can be selected from the range of about 100 to 12000 parts by weight with respect to 100 parts by weight of loratadine, and is usually about 300 to 10000 parts by weight, preferably about 500 to 8000 parts by weight.
本発明において、賦形剤、崩壊剤及び結合剤以外に、必要に応じて用いられるその他の添加剤としては、例えば、滑沢剤、矯味剤、流動化剤、帯電防止剤、着色剤、香料、界面活性剤、湿潤剤、充填剤、増量剤、吸着剤、保存剤（例えば防腐剤など）、緩衝剤などを挙げることができる。 In the present invention, in addition to the excipient, the disintegrant, and the binder, other additives used as necessary include, for example, a lubricant, a corrigent, a fluidizing agent, an antistatic agent, a colorant, and a fragrance. , Surfactants, wetting agents, fillers, extenders, adsorbents, preservatives (for example, preservatives), buffers and the like.
上記滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、軽質無水ケイ酸、フマル酸ステアリルナトリウム、タルク、ラウリル硫酸ナトリウム、水素添加植物油、マイクロクリスタリンワックス、ショ糖脂肪酸エステル、ポリエチレングリコールなどを挙げることができる。矯味剤としては、例えば、クエン酸、無水クエン酸、クエン酸ナトリウム、酒石酸、リンゴ酸、グリシン、アラニン、ショ糖、乳糖、マンニトール、キシリトール、サッカリン、サッカリンナトリウム、アスパルテーム、ステビオシドなどを挙げることができる。流動化剤としては、例えば、含水二酸化ケイ素、軽質無水ケイ酸、合成ケイ酸アルミニウム、合成ヒドロタルサイト、乾燥水酸化アルミニウムゲル、カオリン、ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウム、タルクなどが挙げられる。帯電防止剤としては、例えば、軽質無水ケイ酸などを挙げることができる。着色剤としては、例えば、タール色素、酸化鉄、カラメル、ベンガラ、酸化チタン、天然色素などを挙げることができる。香料としては、例えば、ストロベリーフレーバー、レモンフレーバー、レモンライムフレーバー、オレンジフレーバー、ｌ−メントール、ハッカ油などが挙げられる。 Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearyl fumarate, talc, sodium lauryl sulfate, hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acid ester, polyethylene glycol And so on. Examples of the corrigent include citric acid, anhydrous citric acid, sodium citrate, tartaric acid, malic acid, glycine, alanine, sucrose, lactose, mannitol, xylitol, saccharin, sodium saccharin, aspartame, stevioside and the like. Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, synthetic hydrotalcite, dry aluminum hydroxide gel, kaolin, calcium silicate, magnesium metasilicate aluminate, and talc. . Examples of the antistatic agent include light anhydrous silicic acid. Examples of the colorant include tar dye, iron oxide, caramel, bengara, titanium oxide, and natural dye. Examples of the fragrances include strawberry flavor, lemon flavor, lemon lime flavor, orange flavor, l-menthol and peppermint oil.
これらその他の添加剤は、単独でまたは二種以上組み合わせて使用できる。これらのその他の添加剤は、特に、最終製剤中の含量に制限はない。 These other additives can be used alone or in combination of two or more. These other additives are not particularly limited in content in the final formulation.
第１造粒工程
本発明のロラタジン含有口腔内崩壊錠の製造方法においては、先ず、第１造粒工程として、ロラタジンと、結合剤、賦形剤、崩壊剤等の少なくとも１種の添加剤とを、造粒する。ここで、ロラタジンは、溶液状態乃至は懸濁状態で用いることが必須である。ロラタジンは、溶液状態、懸濁状態、及び一部溶液状態で残部懸濁状態（外観上は懸濁状態）のいずれであってもよい。ロラタジンを、粉末等の固形状態で用いた場合には、薬物放出性が大きく低下する。通常、ロラタジンは、エタノール溶液乃至はエタノール懸濁液として用いることが、好ましい。エタノールの使用量は、ロラタジンが溶液状態乃至は懸濁状態となる量であればよく、適宜、決定することができる。また、結合剤は、水溶液等の溶液状態で用いることが、このことにより、薬物放出性が向上する傾向にある点から、好ましい。
First granulation step In the method for producing a loratadine-containing orally disintegrating tablet of the present invention, first, as the first granulation step, loratadine and at least one additive such as a binder, an excipient, and a disintegrant are added. Granulate. Here, it is essential to use loratadine in a solution state or a suspension state. Loratadine may be in a solution state, a suspension state, or a partial solution state and a remaining suspension state (in a suspended state in appearance). When loratadine is used in a solid state such as a powder, drug releasability is greatly reduced. Usually, loratadine is preferably used as an ethanol solution or ethanol suspension. The amount of ethanol used may be determined as appropriate as long as loratadine is in a solution state or a suspension state. In addition, it is preferable to use the binder in a solution state such as an aqueous solution because this tends to improve the drug release property.
第１造粒工程は、流動層造粒、撹拌造粒等により行うことができるが、特に、流動層造粒により、造粒を行うのが好ましい。第１造粒工程は、例えば、流動層造粒装置を用いて、ロラタジンのエタノール溶液と結合剤及び添加物の一部を含む水溶液との混合液を、粉末状の賦形剤等にスプレーしながら、混合し、造粒することが好ましい。流動層造粒の温度条件、スプレー速度等は、適宜決定すればよい。流動層造粒装置としては、「ＭＰ−１」（パウレック社製）、「ＦＬＯ−５」（フロイント社製）等の市販品を用いることができる。 The first granulation step can be performed by fluidized bed granulation, stirring granulation or the like, but it is particularly preferable to perform granulation by fluidized bed granulation. In the first granulation step, for example, using a fluidized bed granulator, a mixed liquid of an ethanol solution of loratadine and an aqueous solution containing a part of the binder and additives is sprayed on a powdery excipient or the like. However, it is preferable to mix and granulate. What is necessary is just to determine suitably the temperature conditions, spray speed, etc. of fluid bed granulation. As the fluidized bed granulator, commercially available products such as “MP-1” (manufactured by POWREC) and “FLO-5” (manufactured by Freund) can be used.
第１造粒工程で得られた造粒物は、乾燥後、整粒機を用いて整粒するのが好ましい。整粒に使用する装置としては、特に制限はないが、例えば、「パワーミル」（不二パウダル（株）製）、「コーミル」（パウレック社製）、「ロールグラニュレーター」（日本グラニュレーター（株）製）等の整粒機が挙げられる。また、篩などを使用して整粒してもよい。 The granulated product obtained in the first granulation step is preferably sized using a sizing machine after drying. There are no particular restrictions on the apparatus used for sizing, but for example, “Power Mill” (produced by Fuji Paudal Co., Ltd.), “Komil” (produced by Powrec), “Roll Granulator” (Nippon Granulator Co., Ltd.) )) And the like. Moreover, you may size-size using a sieve etc.
第２造粒工程
次に、第２造粒工程において、第１造粒工程において得られた造粒物を、賦形剤、結合剤、崩壊剤、矯味剤等の少なくとも１種の添加剤と共に、更に造粒する。また、第１造粒工程の造粒物の使用量は、最終的に得られる錠剤重量の５０重量％以程度となるように調節することが必要である。第１造粒工程の造粒物が錠剤重量の５０重量％を超えるとロラタジンの錠剤からの放出性が低下するので好ましくない。第１造粒工程の造粒物の使用量は、錠剤重量の３０〜４５重量％程度となるように調節するのが好ましい。
Second granulation step Next, in the second granulation step, the granulated product obtained in the first granulation step is combined with at least one additive such as an excipient, a binder, a disintegrant, and a corrigent. Then granulate further. Moreover, it is necessary to adjust the usage-amount of the granulated material of a 1st granulation process so that it may become about 50 weight% or more of the tablet weight finally obtained. If the granulated product in the first granulation step exceeds 50% by weight of the tablet weight, it is not preferable because the release of loratadine from the tablet decreases. The amount of the granulated product used in the first granulation step is preferably adjusted to be about 30 to 45% by weight of the tablet weight.
第２造粒工程は、流動層造粒、撹拌造粒等により行うことができるが、特に、流動層造粒により、造粒を行うのが製造効率の向上の点から好ましい。第２造粒工程は、例えば、流動層造粒装置を用いて、結合剤と添加剤の一部を含む水溶液との混合液を、第１造粒工程の造粒物と賦形剤等の添加剤との粉末状混合物にスプレーしながら、混合し、造粒することが好ましい。流動層造粒の温度条件、スプレー速度等や、流動層造粒装置は、第１造粒工程の場合と同様に、適宜決定することができる。 The second granulation step can be performed by fluidized bed granulation, stirring granulation, or the like. In particular, it is preferable to perform granulation by fluidized bed granulation from the viewpoint of improving production efficiency. In the second granulation step, for example, using a fluidized bed granulator, a mixed solution of a binder and an aqueous solution containing a part of the additive is used as a granulated product and an excipient in the first granulation step. It is preferable to mix and granulate while spraying the powder mixture with the additive. The temperature conditions of the fluidized bed granulation, the spray speed, etc., and the fluidized bed granulator can be appropriately determined as in the case of the first granulating step.
第２造粒工程で得られた造粒物は、乾燥後、整粒機を用いて整粒することが好ましい。整粒に使用する装置等は、第１造粒工程の場合と同様でよく、又篩により整粒してもよい。 The granulated product obtained in the second granulation step is preferably sized using a granulator after drying. The apparatus used for sizing may be the same as in the first granulation step, or may be sized by a sieve.
本発明のロラタジン口腔内崩壊錠の製造方法では、第１造粒工程及び第２造粒工程の２段階の造粒工程を行うことを必須とし、１段階の造粒のみでは錠剤からのロラタジンの放出性の向上は殆ど認められない。 In the production method of the loratadine orally disintegrating tablet of the present invention, it is essential to perform the two-stage granulation process of the first granulation process and the second granulation process, and the loratadine from the tablet can be obtained only by one-stage granulation. There is almost no improvement in release.
第３造粒工程等
本発明のロラタジン口腔内崩壊錠の製造方法では、第１造粒工程及び第２造粒工程の２段の造粒工程に加えて、更に必要に応じて、３段階目以上の造粒工程を行ってもよい。第３造粒工程及びそれ以降の造粒工程は、第２造粒工程と同様に、通常、添加剤を用いて、流動層造粒、撹拌造粒等により行うことができるが、特に、流動層造粒により、造粒を行うのが製造効率の向上の点から好ましい。
In the method for producing the loratadine orally disintegrating tablet of the present invention such as the third granulation step, in addition to the two-step granulation step of the first granulation step and the second granulation step, the third step is further performed as necessary. You may perform the above granulation process. The third granulation step and the subsequent granulation step can be performed by fluidized bed granulation, stirring granulation, etc., usually using additives, as in the second granulation step. Granulation is preferably performed by layer granulation from the viewpoint of improving production efficiency.
打錠工程
次いで、少なくとも２段階の造粒工程によって得られた造粒物に、通常、滑沢剤、崩壊剤等の添加剤の少なくとも１種を混合した後、常法により、打錠を行う。打錠機としては、医薬品の製造に使用しうるものであれば特に制限はなく、例えばロータリー式打錠機や単発打錠機などが使用される。
Tableting Step Next, the granulated product obtained by at least two granulation steps is usually mixed with at least one additive such as a lubricant and a disintegrant, and then tableted by a conventional method. . The tableting machine is not particularly limited as long as it can be used for the production of pharmaceuticals. For example, a rotary tableting machine or a single-shot tableting machine is used.
かくして得られる本発明のロラタジン含有口腔内崩壊錠を使用する場合には、ヒトに、アレルギー性鼻炎、蕁麻疹等のアレルギー性疾患に対する治療有効量を投与すればよい。患者の年令、体重、症状、性別などにより投与量は変わりうるが、通常、１日当たり、１回または数回に分けて、ロラタジンに換算して、例えば５〜２０ｍｇ程度を、水無しで、唾液のみで経口的に投与することができる。この場合において、本発明のロラタジン口腔内崩壊錠は、口腔内崩壊性が、通常３０秒以内程度と良好であり、また優れた口腔内崩壊性を有していながら、ＰＴＰ包装からの押し出しに耐える硬度を有している。 When the thus obtained loratadine-containing orally disintegrating tablet of the present invention is used, a therapeutically effective amount for allergic diseases such as allergic rhinitis and urticaria may be administered to humans. The dose may vary depending on the patient's age, body weight, symptoms, sex, etc., but is usually divided into one or several times per day, and converted to loratadine, for example, about 5 to 20 mg without water, It can be administered orally with saliva alone. In this case, the loratadine orally disintegrating tablet of the present invention has good orally disintegrating properties, usually within about 30 seconds, and withstands extrusion from PTP packaging while having excellent orally disintegrating properties. Has hardness.
本発明のロラタジン口腔内崩壊錠は、通常、ＰＴＰ包装またはボトル包装（例：プラスチック瓶、ガラス瓶、アルミニウム缶）されていてもよい。また、それらの包装された錠剤は、さらにピロー包装等の二次包装されていてもよい。包装中には脱臭剤、乾燥剤、脱酸素剤等を同封しても良い。 The loratadine orally disintegrating tablet of the present invention may be usually packaged in PTP or bottle (eg, plastic bottle, glass bottle, aluminum can). Moreover, those packaged tablets may be further subjected to secondary packaging such as pillow packaging. A deodorant, a desiccant, an oxygen scavenger and the like may be enclosed during packaging.
以下、実施例及び比較例を挙げて、本発明を更に具体的に説明するが、本発明はこれらの実施例によって何ら制限されるものではない。 EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated further more concretely, this invention is not restrict | limited at all by these Examples.
各実施例及び比較例において、溶出率は、下記溶出試験によって求めた。
溶出試験
第十五改正日本薬局方の溶出試験法第２法（パドル法）に準じて試験を実施し、１５分後及び３０分後の溶出率（％）を、ＨＰＬＣ法を用いて測定した。
各検体量：１錠。
試験液：McIlvaineの緩衝液（３７℃、ｐＨ４．０）９００ｍＬ
パドル回転数：５０ｒｐｍ
試験は、３回行い、その平均値を示した。
In each example and comparative example, the dissolution rate was determined by the following dissolution test.
Dissolution test Fifteenth revision Japanese Pharmacopoeia dissolution test was conducted in accordance with Method 2 (Paddle Method), and dissolution rate (%) after 15 minutes and 30 minutes was measured using HPLC method. .
Sample volume: 1 tablet.
Test solution: McIlvaine buffer (37 ° C, pH 4.0) 900 mL
Paddle rotation speed: 50rpm
The test was performed 3 times and the average value was shown.
実施例１
ロラタジン（９０．０ｇ）のエタノール溶液１０８０ｇに、Ｄ−マンニトール（９．０ｇ）およびヒドロキシプロピルセルロース（１２．６ｇ）の水溶液５４０ｇを加えて混合した。得られた混合液の一部（１４４０ｇ）を、Ｄ−マンニトール（３２３．２ｇ）および低置換度ヒドロキシプロピルセルロース（５７．６ｇ）の混合物に、スプレーすることによって、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末を、２２号篩によって整粒し、整粒末Ａを得た。
Example 1
540 g of an aqueous solution of D-mannitol (9.0 g) and hydroxypropylcellulose (12.6 g) was added to 1080 g of an ethanol solution of loratadine (90.0 g) and mixed. A part of the obtained mixture (1440 g) was sprayed onto a mixture of D-mannitol (323.2 g) and low-substituted hydroxypropylcellulose (57.6 g) to perform fluidized bed granulation ( Fluidized bed granulator: model “MP-01” manufactured by Paulec. The obtained granulated powder was sized using a No. 22 sieve to obtain sized powder A.
整粒末Ａ（１６８．０ｇ）、Ｄ−マンニトール（１８６．１ｇ）、低置換度ヒドロキシプロピルセルロース（３０．２ｇ）およびアスパルテーム（８．４ｇ）の混合物に、ヒドロキシプロピルセルロース（１．３ｇ）およびクエン酸水和物（０．８ｇ）の水溶液１４０ｇを、スプレーすることによって、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を、２２号篩によって整粒し、整粒末を得た。得られた整粒末の一部（４７．０ｇ）に、クロスポビドン（１．５ｇ）、軽質無水ケイ酸（０．５ｇ）およびフマル酸ステアリルナトリウム（１．０ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、単発打錠機（株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１５０ｍｇの錠剤を得た。 A mixture of sized powder A (168.0 g), D-mannitol (186.1 g), low-substituted hydroxypropyl cellulose (30.2 g) and aspartame (8.4 g) was added to hydroxypropyl cellulose (1.3 g) and Fluidized bed granulation was performed by spraying 140 g of an aqueous solution of citric acid hydrate (0.8 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized using a No. 22 sieve to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.
実施例２
ロラタジン（６０．０ｇ）のエタノール溶液７２０ｇに、Ｄ−マンニトール（６．０ｇ）およびヒドロキシプロピルセルロース（８．４ｇ）の水溶液３６０ｇを加えて混合した。得られた混合液（１０８０ｇ）を、Ｄ−マンニトール（３４８．０ｇ）および低置換度ヒドロキシプロピルセルロース（５７．６ｇ）の混合物にスプレーすることによって、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末Ｂを得た。
Example 2
To 720 g of an ethanol solution of loratadine (60.0 g), 360 g of an aqueous solution of D-mannitol (6.0 g) and hydroxypropyl cellulose (8.4 g) was added and mixed. The obtained mixed liquid (1080 g) was sprayed onto a mixture of D-mannitol (348.0 g) and low-substituted hydroxypropylcellulose (57.6 g) to perform fluidized bed granulation (fluidized bed granulation). (Apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain sized powder B.
整粒末Ｂ（１６０．０ｇ）、Ｄ−マンニトール（１７７．２ｇ）、低置換度ヒドロキシプロピルセルロース（２８．８ｇ）およびアスパルテーム（８．０ｇ）の混合物に、ヒドロキシプロピルセルロース（１．４ｇ）およびクエン酸水和物（０．６ｇ）の水溶液１００ｇをスプレーして、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（３５８．１ｇ）に、クロスポビドン（１１．４ｇ）、軽質無水ケイ酸（３．８ｇ）およびフマル酸ステアリルナトリウム（７．６ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、単発打錠機（株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量２００ｍｇの錠剤を得た。 To a mixture of sized powder B (160.0 g), D-mannitol (177.2 g), low-substituted hydroxypropylcellulose (28.8 g) and aspartame (8.0 g), hydroxypropylcellulose (1.4 g) and Fluidized bed granulation was performed by spraying 100 g of an aqueous solution of citric acid hydrate (0.6 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC, Inc.). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (11.4 g), light anhydrous silicic acid (3.8 g) and sodium stearyl fumarate (7.6 g) were added to and mixed with a portion (358.1 g) of the obtained sized powder, and loratadine was mixed. A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 200 mg per tablet.
実施例３
整粒末Ｂ（１６０．０ｇ）、Ｄ−マンニトール（２３７．８ｇ）、低置換度ヒドロキシプロピルセルロース（３８．４ｇ）およびアスパルテーム（９．６ｇ）の混合物に、ヒドロキシプロピルセルロース（４．８ｇ）およびクエン酸水和物（０．６ｇ）の水溶液１００ｇをスプレーして、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（５６．４ｇ）に、クロスポビドン（１．８ｇ）、軽質無水ケイ酸（０．６ｇ）およびフマル酸ステアリルナトリウム（１．２ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、単発打錠機（株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量２４０ｍｇの錠剤を得た。
Example 3
To a mixture of sized powder B (160.0 g), D-mannitol (237.8 g), low-substituted hydroxypropyl cellulose (38.4 g) and aspartame (9.6 g), hydroxypropyl cellulose (4.8 g) and Fluidized bed granulation was performed by spraying 100 g of an aqueous solution of citric acid hydrate (0.6 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC, Inc.). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.8 g), light anhydrous silicic acid (0.6 g) and sodium stearyl fumarate (1.2 g) were added to and mixed with a part (56.4 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets having a loratadine content of 10 mg and a tablet weight of 240 mg per tablet.
実施例４
ロラタジン（８５．０ｇ）のエタノール溶液１０２０ｇに、Ｄ−マンニトール（１７．０ｇ）およびヒドロキシプロピルセルロース（２３．８ｇ）の水溶液５１０ｇを加えて混合した。得られた混合液１５３０ｇを、Ｄ−マンニトール（３２３．０ｇ）および低置換度ヒドロキシプロピルセルロース（６１．２ｇ）の混合物にスプレーすることによって、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末Ｃを得た。
Example 4
To 1020 g of an ethanol solution of loratadine (85.0 g), 510 g of an aqueous solution of D-mannitol (17.0 g) and hydroxypropylcellulose (23.8 g) was added and mixed. Fluidized-bed granulation was performed by spraying 1530 g of the obtained mixed liquid onto a mixture of D-mannitol (323.0 g) and low-substituted hydroxypropylcellulose (61.2 g) (fluidized-bed granulator: (Pauleck, model “MP-01”). Part of the resulting granulated powder was sized to obtain sized powder C.
ヒドロキシプロピルセルロース（４．４ｇ）およびクエン酸水和物（２．９ｇ）の水溶液４９０ｇの一部（１４０ｇ）を整粒末Ｃ（１６８．０ｇ）、Ｄ−マンニトール（１８６．１ｇ）、低置換度ヒドロキシプロピルセルロース（３０．２ｇ）およびアスパルテーム（８．４ｇ）の混合物にスプレーして、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（４７．０ｇ）に、クロスポビドン（１．５ｇ）、軽質無水ケイ酸（０．５ｇ）およびフマル酸ステアリルナトリウム（１．０ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、単発打錠機（株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１５０ｍｇの錠剤を得た。 A portion (140 g) of an aqueous solution of hydroxypropylcellulose (4.4 g) and citric acid hydrate (2.9 g) was adjusted to a sized powder C (168.0 g), D-mannitol (186.1 g), low substitution The mixture was sprayed onto a mixture of hydroxypropylcellulose (30.2 g) and aspartame (8.4 g) to perform fluidized bed granulation (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.
実施例５
ロラタジン（９０．０ｇ）のエタノール溶液１０８０ｇに、Ｄ−マンニトール（２７．０ｇ）およびヒドロキシプロピルセルロース（３７．８ｇ）の水溶液５４０ｇを加えて混合した。得られた混合液１６２０ｇを、Ｄ−マンニトール（３２０．４ｇ）および低置換度ヒドロキシプロピルセルロース（６４．８ｇ）の混合物にスプレーすることによって、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末Ｄを得た。
Example 5
540 g of an aqueous solution of D-mannitol (27.0 g) and hydroxypropylcellulose (37.8 g) was added to 1080 g of an ethanol solution of loratadine (90.0 g) and mixed. Fluidized bed granulation was performed by spraying 1620 g of the obtained mixed liquid onto a mixture of D-mannitol (320.4 g) and low-substituted hydroxypropylcellulose (64.8 g) (fluidized bed granulating apparatus: (Pauleck, model “MP-01”). Part of the resulting granulated powder was sized to obtain sized powder D.
ヒドロキシプロピルセルロース（４．４ｇ）およびクエン酸水和物（２．９ｇ）の水溶液４９０ｇの一部（１４０ｇ）を、整粒末Ｄ（１６８．０ｇ）、Ｄ−マンニトール（１８６．１ｇ）、低置換度ヒドロキシプロピルセルロース（３０．２ｇ）およびアスパルテーム（８．４ｇ）の混合物にスプレーして、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（４７．０ｇ）に、クロスポビドン（１．５ｇ）、軽質無水ケイ酸（０．５ｇ）およびフマル酸ステアリルナトリウム（１．０ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、単発打錠機（株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１５０ｍｇの錠剤を得た。 A portion (140 g) of an aqueous solution of hydroxypropylcellulose (4.4 g) and citric acid hydrate (2.9 g) was mixed with sized powder D (168.0 g), D-mannitol (186.1 g), low Fluidized bed granulation was carried out by spraying onto a mixture of substituted hydroxypropylcellulose (30.2 g) and aspartame (8.4 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.
実施例６
ロラタジン（６０．０ｇ）のエタノール溶液７２０ｇに、Ｄ−マンニトール（３．０ｇ）およびヒドロキシプロピルセルロース（４．２ｇ）の水溶液３６０ｇを加えて混合した。得られた混合液１０８０ｇを、Ｄ−マンニトール（３５５．２ｇ）および低置換度ヒドロキシプロピルセルロース（５７．６ｇ）の混合物にスプレーすることによって、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末Ｅを得た。
Example 6
To 720 g of an ethanol solution of loratadine (60.0 g), 360 g of an aqueous solution of D-mannitol (3.0 g) and hydroxypropyl cellulose (4.2 g) was added and mixed. By spraying 1080 g of the obtained mixed liquid onto a mixture of D-mannitol (355.2 g) and low-substituted hydroxypropylcellulose (57.6 g), fluidized bed granulation was performed (fluidized bed granulating apparatus: (Pauleck, model “MP-01”). Part of the resulting granulated powder was sized to obtain sized powder E.
ヒドロキシプロピルセルロース（６．８ｇ）およびクエン酸水和物（１．２ｇ）の水溶液２００ｇの一部（１００ｇ）を、整粒末Ｅ（１６０．０ｇ）、Ｄ−マンニトール（２３９．２ｇ）、低置換度ヒドロキシプロピルセルロース（３８．４ｇ）およびアスパルテーム（９．６ｇ）の混合物にスプレーして、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（５６．４ｇ）に、クロスポビドン（１．８ｇ）、軽質無水ケイ酸（０．６ｇ）およびフマル酸ステアリルナトリウム（１．２ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、単発打錠機（株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量２４０ｍｇの錠剤を得た。 A part (100 g) of an aqueous solution of hydroxypropylcellulose (6.8 g) and citric acid hydrate (1.2 g) (100 g) was mixed with sized powder E (160.0 g), D-mannitol (239.2 g), low Fluidized bed granulation was carried out by spraying a mixture of substituted hydroxypropylcellulose (38.4 g) and aspartame (9.6 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.8 g), light anhydrous silicic acid (0.6 g) and sodium stearyl fumarate (1.2 g) were added to and mixed with a part (56.4 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets having a loratadine content of 10 mg and a tablet weight of 240 mg per tablet.
実施例７
ロラタジン（６６０．０ｇ）のエタノール溶液７９２０ｇに、Ｄ−マンニトール（６６．０ｇ）およびヒドロキシプロピルセルロース（３３．０ｇ）の水溶液３９６０ｇを加えて混合した。得られた混合液１１８８０ｇの一部（１０８００ｇ）を、Ｄ−マンニトール（２４７８．０ｇ）および低置換度ヒドロキシプロピルセルロース（４３２．０ｇ）の混合物にスプレーすることによって、流動層造粒を行った（流動層造粒装置：フロイント社製、機種「ＦＬＯ−５」）。得られた造粒末の一部を整粒し、整粒末Ｆを得た。
Example 7
To 9920 g of an ethanol solution of loratadine (660.0 g), 3960 g of an aqueous solution of D-mannitol (66.0 g) and hydroxypropylcellulose (33.0 g) was added and mixed. By spraying a part (10800 g) of the resulting mixed solution 11880 g onto a mixture of D-mannitol (2478.0 g) and low-substituted hydroxypropylcellulose (432.0 g), fluidized bed granulation was performed ( Fluidized bed granulator: model “FLO-5” manufactured by Freund Corporation. Part of the resulting granulated powder was sized to obtain sized powder F.
ヒドロキシプロピルセルロース（３９．０ｇ）およびクエン酸水和物（９．０ｇ）の水溶液１５００ｇの一部（１２５０ｇ）を、整粒末Ｆ（１５００．０ｇ）、Ｄ−マンニトール（２２４０．０ｇ）、低置換度ヒドロキシプロピルセルロース（３６０．０ｇ）およびアスパルテーム（９０．０ｇ）の混合物にスプレーして、流動層造粒を行った（流動層造粒装置：フロイント社製、機種「ＦＬＯ−５」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（３８０７．０ｇ）に、クロスポビドン（１２１．５ｇ）、軽質無水ケイ酸（４０．５ｇ）およびフマル酸ステアリルナトリウム（８１．０ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、ロータリー打錠機（商品名「ＶＩＲＧＯ−５１２」、株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１８０ｍｇの錠剤を得た。 A portion (1250 g) of an aqueous solution of hydroxypropylcellulose (39.0 g) and citric acid hydrate (9.0 g) was mixed with sized powder F (1500.0 g), D-mannitol (2240.0 g), low Fluidized bed granulation was performed by spraying onto a mixture of hydroxypropylcellulose (360.0 g) and aspartame (90.0 g) (fluidized bed granulating apparatus: model “FLO-5” manufactured by Freund Corporation). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (121.5 g), light anhydrous silicic acid (40.5 g) and sodium stearyl fumarate (81.0 g) were added to and mixed with a part (3807.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a rotary tableting machine (trade name “VIRGO-512”, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a tablet with a loratadine content of 10 mg and a tablet weight of 180 mg per tablet. It was.
実施例８
ロラタジン（８０．０ｇ）のエタノール溶液９６０ｇに、Ｄ−マンニトール（８．０ｇ）の水溶液４８０ｇを加えて混合した。得られた混合液１４４０ｇを、Ｄ−マンニトール（３２３．２ｇ）、低置換度ヒドロキシプロピルセルロース（５７．６ｇ）およびヒドロキシプロピルセルロース（１１．２ｇ）の混合物にスプレーすることによって、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末Ｇを得た。
Example 8
480 g of an aqueous solution of D-mannitol (8.0 g) was added to 960 g of an ethanol solution of loratadine (80.0 g) and mixed. By spraying 1440 g of the resulting mixture to a mixture of D-mannitol (323.2 g), low substituted hydroxypropylcellulose (57.6 g) and hydroxypropylcellulose (11.2 g), fluid bed granulation (Fluidized bed granulator: manufactured by Paulek, model “MP-01”). Part of the resulting granulated powder was sized to obtain sized powder G.
ヒドロキシプロピルセルロース（４．５ｇ）およびクエン酸水和物（３．０ｇ）の水溶液５００ｇの一部（１５０ｇ）を整粒末Ｇ（１８０．０ｇ）、Ｄ−マンニトール（１９９．４ｇ）、低置換度ヒドロキシプロピルセルロース（３２．４ｇ）およびアスパルテーム（９．０ｇ）の混合物にスプレーして、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（４７．０ｇ）に、クロスポビドン（１．５ｇ）、軽質無水ケイ酸（０．５ｇ）およびフマル酸ステアリルナトリウム（１．０ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、単発打錠機（株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１５０ｍｇの錠剤を得た。 Part (150 g) of 500 g of an aqueous solution of hydroxypropylcellulose (4.5 g) and citric acid hydrate (3.0 g) was sized powder G (180.0 g), D-mannitol (199.4 g), low substitution The mixture was sprayed onto a mixture of hydroxypropylcellulose (32.4 g) and aspartame (9.0 g) to perform fluidized bed granulation (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.
比較例１
ロラタジン（４２．０ｇ）のエタノール溶液５０４ｇに、Ｄ−マンニトール（４．２ｇ）、ヒドロキシプロピルセルロース（５．９ｇ）およびクエン酸水和物（１．３ｇ）の水溶液２５２ｇを加えて混合した。得られた混合液の一部（６３０ｇ）を、Ｄ−マンニトール（３７５．６ｇ）、低置換度ヒドロキシプロピルセルロース（６３．０ｇ）およびアスパルテーム（１０．５ｇ）の混合物にスプレーすることによって、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（４７．０ｇ）に、クロスポビドン（１．５ｇ）、軽質無水ケイ酸（０．５ｇ）およびフマル酸ステアリルナトリウム（１．０ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、単発打錠機（株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１５０ｍｇの錠剤を得た。
Comparative Example 1
To 504 g of an ethanol solution of loratadine (42.0 g), 252 g of an aqueous solution of D-mannitol (4.2 g), hydroxypropylcellulose (5.9 g) and citric acid hydrate (1.3 g) was added and mixed. By spraying a portion (630 g) of the resulting mixture onto a mixture of D-mannitol (375.6 g), low substituted hydroxypropylcellulose (63.0 g) and aspartame (10.5 g), a fluidized bed. Granulation was performed (fluidized bed granulator: manufactured by Paulek, model “MP-01”). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.
比較例２
整粒末Ｂ（２４０．０ｇ）、Ｄ−マンニトール（１４６．４ｇ）、低置換度ヒドロキシプロピルセルロース（２５．２ｇ）およびアスパルテーム（９．０ｇ）の混合物に、ヒドロキシプロピルセルロース（１．５ｇ）およびクエン酸水和物（０．９ｇ）の水溶液１５０ｇをスプレーして、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（５６．４ｇ）に、クロスポビドン（１．８ｇ）、軽質無水ケイ酸（０．６ｇ）およびフマル酸ステアリルナトリウム（１．２ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、単発打錠機（株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１５０ｍｇの錠剤を得た。
Comparative Example 2
To a mixture of sized powder B (240.0 g), D-mannitol (146.4 g), low-substituted hydroxypropyl cellulose (25.2 g) and aspartame (9.0 g), hydroxypropyl cellulose (1.5 g) and Fluidized bed granulation was performed by spraying 150 g of an aqueous solution of citric acid hydrate (0.9 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC, Inc.). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.8 g), light anhydrous silicic acid (0.6 g) and sodium stearyl fumarate (1.2 g) were added to and mixed with a part (56.4 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.
比較例３
ヒドロキシプロピルセルロース（９．８ｇ）およびＤ−マンニトール（７．０ｇ）の水溶液１９６．０ｇを、ロラタジン（７０．０ｇ）、Ｄ−マンニトール（２８２．８ｇ）および低置換度ヒドロキシプロピルセルロース（５０．４ｇ）の混合物にスプレーすることによって、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末Ｈを得た。
Comparative Example 3
196.0 g of an aqueous solution of hydroxypropylcellulose (9.8 g) and D-mannitol (7.0 g) was added to loratadine (70.0 g), D-mannitol (282.8 g) and low-substituted hydroxypropylcellulose (50.4 g). ) Was sprayed onto the mixture to obtain fluidized bed granulation (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC, Inc.). Part of the obtained granulated powder was sized to obtain sized powder H.
ヒドロキシプロピルセルロース（４．５ｇ）およびクエン酸水和物（３．０ｇ）の水溶液５００ｇの一部（１５０ｇ）を、整粒末Ｈ（１８０．０ｇ）、Ｄ−マンニトール（１９９．４ｇ）、低置換度ヒドロキシプロピルセルロース（３２．４ｇ）およびアスパルテーム（９．０ｇ）の混合物にスプレーして、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（４７．０ｇ）に、クロスポビドン（１．５ｇ）、軽質無水ケイ酸（０．５ｇ）およびフマル酸ステアリルナトリウム（１．０ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、ロータリー打錠機（商品名「ＶＩＲＧＯ−５１２」、株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１５０ｍｇの錠剤を得た。 Part (150 g) of 500 g of an aqueous solution of hydroxypropylcellulose (4.5 g) and citric acid hydrate (3.0 g) was mixed with sized powder H (180.0 g), D-mannitol (199.4 g), low Fluidized bed granulation was performed by spraying onto a mixture of substituted hydroxypropylcellulose (32.4 g) and aspartame (9.0 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder is tableted using a rotary tableting machine (trade name “VIRGO-512”, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a tablet having a loratadine content of 10 mg and a tablet weight of 150 mg per tablet. It was.
比較例４
Ｄ−マンニトール（７．０ｇ）の水溶液１４０．０ｇを、ロラタジン（７０．０ｇ）、Ｄ−マンニトール（２８２．８ｇ）、低置換度ヒドロキシプロピルセルロース（５０．４ｇ）およびヒドロキシプロピルセルロース（９．８ｇ）の混合物にスプレーすることによって、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末Ｉを得た。
Comparative Example 4
140.0 g of an aqueous solution of D-mannitol (7.0 g) was added to loratadine (70.0 g), D-mannitol (282.8 g), low-substituted hydroxypropylcellulose (50.4 g) and hydroxypropylcellulose (9.8 g). ) Was sprayed onto the mixture to obtain fluidized bed granulation (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC, Inc.). Part of the resulting granulated powder was sized to obtain sized powder I.
ヒドロキシプロピルセルロース（４．５ｇ）およびクエン酸水和物（３．０ｇ）の水溶液５００ｇの一部（１５０ｇ）を、整粒末Ｉ（１８０．０ｇ）、Ｄ−マンニトール（１９９．４ｇ）、低置換度ヒドロキシプロピルセルロース（３２．４ｇ）およびアスパルテーム（９．０ｇ）の混合物にスプレーして、流動層造粒を行った（流動層造粒装置：パウレック社製、機種「ＭＰ−０１」）。得られた造粒末の一部を整粒し、整粒末を得た。得られた整粒末の一部（４７．０ｇ）に、クロスポビドン（１．５ｇ）、軽質無水ケイ酸（０．５ｇ）およびフマル酸ステアリルナトリウム（１．０ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、単発打錠機（株式会社菊水製作所製）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１５０ｍｇの錠剤を得た。 A portion (150 g) of an aqueous solution of hydroxypropylcellulose (4.5 g) and citric acid hydrate (3.0 g) (150 g) was mixed with sized powder I (180.0 g), D-mannitol (199.4 g), low Fluidized bed granulation was performed by spraying onto a mixture of substituted hydroxypropylcellulose (32.4 g) and aspartame (9.0 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.
表１及び表２に、各実施例及び比較例における第1造粒工程（表中「造粒工程１」という）におけるロラタジン及び結合剤（ヒドロキシプロピルセルロース）の添加状態、第1造粒工程の造粒物（表中「整粒末１」という）の１錠当たりの重量（mg）（ア）、１錠の錠剤重量（mg）（イ）及びこれら重量の割合〔（ア）／（イ）〕、造粒方法、造粒回数、並びに溶出率を示した。 Tables 1 and 2 show the addition state of loratadine and a binder (hydroxypropylcellulose) in the first granulation step (referred to as “granulation step 1” in the table) in each Example and Comparative Example, the first granulation step Weight per tablet (mg) (A), tablet weight (mg) (A) and ratio of these weights [(A) / (I ]], Granulation method, number of granulations, and dissolution rate.
表１及び表２から明らかなように、各実施例の錠剤は、比較例１（造粒回数１回）及び比較例２〔（ア）／（イ）が０．５を超える〕の錠剤と比較して、ロラタジンの溶出性に優れる。即ち、ロラタジン及び結合剤（ヒドロキシプロピルセルロース）をそれぞれ溶液として使用し、また２段階の造粒工程を実施し、且つ１段階目の造粒工程が錠剤重量の５０重量％以下である錠剤ではロラタジンの溶出性が顕著に高められた。 As is clear from Tables 1 and 2, the tablets of each Example were the tablets of Comparative Example 1 (number of granulation times 1) and Comparative Example 2 [(A) / (I) exceeds 0.5]. In comparison, the dissolution of loratadine is excellent. That is, loratadine and a binder (hydroxypropylcellulose) are each used as a solution, a two-step granulation process is performed, and a loratadine is used in a tablet in which the first-stage granulation process is 50% by weight or less of the tablet weight. Was significantly improved.
また、ロラタジン及び結合剤（ヒドロキシプロピルセルロース）をともに粉末状態で添加した場合（比較例４）の溶出率は、３０分で実質的に許容可能な下限の８５％を満たさず、又結合剤（ヒドロキシプロピルセルロース）のみを溶液状態で添加した場合（比較例３）においても溶出率の上昇は３０分で９０％程度に留まり、不十分であった。一方、ロラタジンと結合剤（ヒドロキシプロピルセルロース）をともに溶液状態で添加した実施例１〜７の溶出性は非常に速やかであり、１５分間の溶出率は９２．５％以上、３０分間の溶出率は９７．６％以上と非常に高い値であった。また、ロラタジンを溶液状態で添加し、結合剤（ヒドロキシプロピルセルロース）を粉末状態で添加した場合（実施例８）の溶出率は、１５分で９０．７％と若干低いものの、３０分で９６．７％であり、実用上十分な溶出率を示した。 In addition, when both loratadine and a binder (hydroxypropylcellulose) were added in a powder state (Comparative Example 4), the dissolution rate did not satisfy 85% of the lower limit substantially acceptable in 30 minutes, and the binder ( Even when only hydroxypropylcellulose) was added in the solution state (Comparative Example 3), the increase in elution rate was only about 90% in 30 minutes, which was insufficient. On the other hand, the dissolution properties of Examples 1 to 7 in which both loratadine and a binder (hydroxypropylcellulose) were added in a solution state were very rapid. The dissolution rate for 15 minutes was 92.5% or more, and the dissolution rate for 30 minutes. Was a very high value of 97.6% or more. Further, when loratadine was added in a solution state and a binder (hydroxypropylcellulose) was added in a powder state (Example 8), the elution rate was slightly low at 90.7% in 15 minutes, but 96 in 30 minutes. 0.7%, indicating a practically sufficient elution rate.
実施例９
ロラタジン（５００．０ｇ）のエタノール溶液６０００ｇに、Ｄ−マンニトール（５０．０ｇ）およびヒドロキシプロピルセルロース（３５．０ｇ）の水溶液３０００ｇを加えて混合した。得られた溶液９０００ｇをＤ−マンニトール（２９３５ｇ）および低置換度ヒドロキシプロピルセルロース（４８０．０ｇ）の混合物にスプレーすることによって流動層造粒（流動層造粒装置：フロイント社製、機種：「ＦＬＯ−５」）した。得られた造粒末を整粒し、整粒末Ｊを得た。
Example 9
To 6000 g of ethanol solution of loratadine (500.0 g), 3000 g of an aqueous solution of D-mannitol (50.0 g) and hydroxypropyl cellulose (35.0 g) was added and mixed. By spraying 9000 g of the resulting solution onto a mixture of D-mannitol (2935 g) and low-substituted hydroxypropylcellulose (480.0 g), fluidized bed granulation (fluidized bed granulator: manufactured by Freund Corporation, model: “FLO” −5 ”). The obtained granulated powder was sized to obtain sized powder J.
ヒドロキシプロピルセルロース（６．０ｇ）およびＤ−マンニトール（１４４．０ｇ）の水溶液１４４０ｇを整粒末Ｊ（４８０．０ｇ）にスプレーすることによって流動層造粒（流動層造粒装置：パウレック社製、機種：「ＭＰ−０１」）し、ついで流動層造粒機（流動層造粒装置：パウレック社製、機種：「ＭＰ−０１」）中でＤ−マンニトール（１３８．４ｇ）、低置換度ヒドロキシプロピルセルロース（３３．０ｇ）およびアスパルテーム（９．５ｇ）とともに混合した後、ヒドロキシプロピルセルロース（２．５ｇ）およびクエン酸水和物（０．５ｇ）の水溶液１２５ｇをスプレーして流動層造粒（流動層造粒装置：パウレック社製、機種：「ＭＰ−０１」）することにより、造粒末を得た。得られた造粒末の一部を整粒した後、得られる整粒末の一部（３５７．１ｇ）に、クロスポビドン（１１．４ｇ）、軽質無水ケイ酸（３．８ｇ）、ステアリン酸マグネシウム（０．１ｇ）およびフマル酸ステアリルナトリウム（７．６ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、打錠機（菊水製作所）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１９０ｍｇの錠剤を得た。 By spraying 1440 g of an aqueous solution of hydroxypropylcellulose (6.0 g) and D-mannitol (144.0 g) onto the sized powder J (480.0 g), fluidized bed granulation (fluidized bed granulator: manufactured by POWREC, Model: “MP-01”), then D-mannitol (138.4 g), low-substituted hydroxy in a fluidized bed granulator (fluidized bed granulator: manufactured by Paulek, model: “MP-01”) After mixing with propylcellulose (33.0 g) and aspartame (9.5 g), 125 g of an aqueous solution of hydroxypropylcellulose (2.5 g) and citric acid hydrate (0.5 g) was sprayed to produce fluidized bed granulation ( Fluidized bed granulator: manufactured by POWREC Co., Ltd., model: “MP-01”), a granulated powder was obtained. After sizing part of the obtained granulated powder, crospovidone (11.4 g), light anhydrous silicic acid (3.8 g), stearic acid is added to a part (357.1 g) of the obtained sized powder. Magnesium (0.1 g) and sodium stearyl fumarate (7.6 g) were added and mixed to obtain a loratadine-containing mixed powder. This loratadine-containing mixed powder was tableted using a tableting machine (Kikusui Seisakusho) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 190 mg per tablet.
実施例１０
ロラタジン（６０．０ｇ）のエタノール懸濁液３００ｇに、Ｄ−マンニトール（６．０ｇ）およびヒドロキシプロピルセルロース（４．２ｇ）の水溶液６００ｇを加えて混合した。得られた溶液９００ｇをＤ−マンニトール（３５２．５ｇ）および低置換度ヒドロキシプロピルセルロース（５７．６ｇ）の混合物にスプレーすることによって流動層造粒（流動層造粒装置：パウレック社製、機種：「ＭＰ−０１」）した。得られた造粒末を整粒し、整粒末Ｋを得た。
Example 10
To 300 g of an ethanol suspension of loratadine (60.0 g), 600 g of an aqueous solution of D-mannitol (6.0 g) and hydroxypropylcellulose (4.2 g) was added and mixed. By spraying 900 g of the obtained solution onto a mixture of D-mannitol (352.5 g) and low-substituted hydroxypropylcellulose (57.6 g), fluidized bed granulation (fluidized bed granulating apparatus: manufactured by POWREC, model: "MP-01"). The obtained granulated powder was sized to obtain sized powder K.
ヒドロキシプロピルセルロース（６．０ｇ）およびＤ−マンニトール（１４４．０ｇ）の水溶液１４４０ｇを整粒末Ｋ（４８０．０ｇ）にスプレーすることによって流動層造粒（流動層造粒装置：パウレック社製、機種：「ＭＰ−０１」）し、ついで流動層造粒機（流動層造粒装置：パウレック社製、機種：「ＭＰ−０１」）中でＤ−マンニトール（１３８．４ｇ）、低置換度ヒドロキシプロピルセルロース（３３．０ｇ）およびアスパルテーム（９．５ｇ）とともに混合した後、ヒドロキシプロピルセルロース（２．５ｇ）およびクエン酸水和物（０．５ｇ）の水溶液１２５ｇをスプレーして流動層造粒（流動層造粒装置：パウレック社製、機種：「ＭＰ−０１」）することにより、造粒末を得た。得られた造粒末の一部を整粒した後、得られる整粒末の一部（３５７．１ｇ）に、クロスポビドン（１１．４ｇ）、軽質無水ケイ酸（３．８ｇ）、ステアリン酸マグネシウム（０．１ｇ）およびフマル酸ステアリルナトリウム（７．６ｇ）を加えて混合し、ロラタジン含有混合末を得た。このロラタジン含有混合末を、打錠機（菊水製作所）を用いて打錠し、１錠当たりのロラタジン含有量１０ｍｇ、１錠重量１９０ｍｇの錠剤を得た。 By spraying 1440 g of an aqueous solution of hydroxypropylcellulose (6.0 g) and D-mannitol (144.0 g) onto the sized powder K (480.0 g), fluidized bed granulation (fluidized bed granulator: manufactured by POWREC, Model: “MP-01”), then D-mannitol (138.4 g), low-substituted hydroxy in a fluidized bed granulator (fluidized bed granulator: manufactured by Paulek, model: “MP-01”) After mixing with propylcellulose (33.0 g) and aspartame (9.5 g), 125 g of an aqueous solution of hydroxypropylcellulose (2.5 g) and citric acid hydrate (0.5 g) was sprayed to produce fluidized bed granulation ( Fluidized bed granulator: manufactured by POWREC Co., Ltd., model: “MP-01”), a granulated powder was obtained. After sizing part of the obtained granulated powder, crospovidone (11.4 g), light anhydrous silicic acid (3.8 g), stearic acid is added to a part (357.1 g) of the obtained sized powder. Magnesium (0.1 g) and sodium stearyl fumarate (7.6 g) were added and mixed to obtain a loratadine-containing mixed powder. This loratadine-containing mixed powder was tableted using a tableting machine (Kikusui Seisakusho) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 190 mg per tablet.
表３に、実施例９及び１０における第１造粒工程（表中「造粒工程１」という）におけるロラタジン及び結合剤（ヒドロキシプロピルセルロース）の添加状態、第1造粒工程の造粒物（表中「整粒末１」という）の１錠当たりの重量（ｍｇ）（ア）、１錠の錠剤重量（ｍｇ）（イ）及びこれら重量の割合〔（ア）／（イ）〕、造粒方法、造粒回数、並びに溶出率を示した。 In Table 3, the addition state of loratadine and a binder (hydroxypropylcellulose) in the first granulation step (referred to as “granulation step 1” in the table) in Examples 9 and 10, the granulation product in the first granulation step ( Weight per tablet (mg) (A) in the table (mg) (A), tablet weight (mg) (A) and ratio of these weights [(A) / (I)] The grain method, the number of granulations, and the dissolution rate were shown.
表３から明らかな様に、ロラタジンを懸濁状態で添加した場合の溶出性は溶液状態で添加した場合と同様に非常に速やかであり、１５分間の溶出率は９６．７％と非常に高い値であった。 As is apparent from Table 3, the dissolution when loratadine is added in a suspended state is very rapid, similar to the case where loratadine is added in a solution state, and the dissolution rate for 15 minutes is as high as 96.7%. Value.
本発明の製造方法により得られるロラタジン口腔内崩壊錠は、口腔内崩壊性及び薬物放出性のいずれにも優れており、アレルギー性疾患治療剤として有用であり、本発明は製薬業分野において有効に利用される。
The loratadine orally disintegrating tablet obtained by the production method of the present invention is excellent in both orally disintegrating property and drug releasing property, and is useful as a therapeutic agent for allergic diseases, and the present invention is effective in the pharmaceutical industry. Used.
Claims (4)
ロラタジンを溶液状態乃至は懸濁状態で用いて第１段階目の造粒を行うこと、
該第１段階目の造粒によって得られた造粒物を、少なくとも１種の添加剤と共に、更に第２段階目の造粒を行うこと、及び
該第１段階目の造粒によって得られた造粒物の割合を錠剤重量の３０〜４５重量％とすることを特徴とするロラタジン含有口腔内崩壊錠の製造方法。 A method for producing a loratadine-containing orally disintegrating tablet comprising:
Granulating the first stage using loratadine in solution or suspension,
The granulated product obtained by the first stage granulation was further granulated in the second stage together with at least one additive, and obtained by the first stage granulation. A method for producing a loratadine-containing orally disintegrating tablet, wherein the ratio of the granulated product is 30 to 45% by weight of the tablet weight.
The method for producing a loratadine-containing orally disintegrating tablet according to any one of claims 1 to 3, wherein the granulation in the third stage is further performed by fluidized bed granulation after the granulation in the second stage.
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