JP2013203727A - Method for producing granulated material by utilizing crystalline cellulose - Google Patents
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- Medicinal Preparation (AREA)
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Abstract
Description
本発明は結晶セルロースを利用した造粒物の製造方法に関する。 The present invention relates to a method for producing a granulated product using crystalline cellulose.
結晶セルロースは繊維性植物から得られたα-セルロースを酸で部分的に解重合して精製したセルロースであり、化学的に不活性であることから薬物と混合した場合にも変化がなく、医薬品添加物として広く用いられている。打錠機で圧縮すると粒子が絡み合い容易に成型することができ、水分により容易に崩壊することや良好な流動性から錠剤の結合剤や崩壊剤としても優れた機能を有している(薬学用語解説、公益社団法人日本薬学会)。 Crystalline cellulose is cellulose that is purified by partially depolymerizing α-cellulose obtained from fibrous plants with acid, and since it is chemically inert, there is no change even when mixed with drugs. Widely used as an additive. When compressed by a tableting machine, the particles can be easily entangled and easily molded, and it has an excellent function as a binder and disintegrant for tablets due to its easy disintegration due to moisture and good fluidity (pharmaceutical terms Commentary, Japan Pharmaceutical Association).
一方、粉体の造粒により得られる球形に近い粒子を核粒子として用い、この核粒子に有効成分や必要に応じて賦形剤などを被覆することにより顆粒を調製して固形製剤を製造する方法が利用されている。核粒子としてはショ糖又はショ糖とデンプンを含む核粒子などが提案され実用化されており(特開昭61-1614号公報)、低置換度ヒドロキシプロピルセルロースを含む核粒子も提案されている(特開平5-163137号公報)。しかしながら、核としてショ糖あるいはショ糖とデンプンから成る核を用い、該核に結合剤溶液を用いて薬物含有する粉体を被覆する工程を含む製造方法においては、ショ糖の溶解が見られ、顆粒同士の凝集が観察される等の問題が生じる。 On the other hand, particles close to a sphere obtained by granulation of powder are used as core particles, and the core particles are coated with an active ingredient and, if necessary, excipients to prepare granules to produce a solid preparation The method is being used. As the core particles, core particles containing sucrose or sucrose and starch have been proposed and put to practical use (Japanese Patent Laid-Open No. 61-1614), and core particles containing low-substituted hydroxypropylcellulose have also been proposed. (Japanese Patent Laid-Open No. 5-163137). However, in the production method including the step of using sucrose or nuclei consisting of sucrose and starch as a core and coating the core with a drug-containing powder using a binder solution, dissolution of sucrose is seen, Problems such as the aggregation of granules are observed.
この問題を解決するための手段として、例えば特開昭61-213201号に記載された結晶セルロース球形顆粒、及び特定の平均重合度を有する結晶セルロース(平均重合度60〜375の結晶セルロース)を50%以上含有する核粒子を調製する方法が提案されている(特開平7−173050号公報)。また、結晶セルロースと添加物を組み合わせて上記の問題を解決する手段として、平均重合度60〜375の結晶セルロースを10〜70%及び乳糖などの水溶性添加剤を10〜90%含有する核粒子 (特開平4-283520号公報)も提案されている。しかしながら、結晶セルロース球形顆粒は高い吸水能を有していることから、結晶セルロース球形顆粒に対して結合剤溶液を噴霧しながら造粒すると、結合剤の粘性が増し、造粒物同士の凝集や流動層造粒機の機壁への付着など製剤工程において種々の問題が生じる。 As means for solving this problem, for example, crystalline cellulose spherical granules described in JP-A-61-213201, and crystalline cellulose having a specific average degree of polymerization (crystalline cellulose having an average degree of polymerization of 60 to 375) are 50. A method for preparing core particles containing at least% is proposed (Japanese Patent Laid-Open No. 7-173050). Further, as means for solving the above problems by combining crystalline cellulose and additives, core particles containing 10 to 70% crystalline cellulose having an average degree of polymerization of 60 to 375 and 10 to 90% of a water-soluble additive such as lactose (JP-A-4-83520) has also been proposed. However, since the crystalline cellulose spherical granules have a high water absorption capacity, granulation while spraying the binder solution on the crystalline cellulose spherical granules increases the viscosity of the binder, causing aggregation between the granulated products and Various problems occur in the preparation process such as adhesion to the wall of the fluidized bed granulator.
本発明の課題は結晶セルロースを利用した造粒物の製造方法を提供することにある。より具体的には、上記の問題を回避しつつ簡便な方法により結晶セルロースを利用した造粒物を効率的に製造する方法を提供することが本発明の課題である。 The subject of this invention is providing the manufacturing method of the granulated material using crystalline cellulose. More specifically, it is an object of the present invention to provide a method for efficiently producing a granulated product using crystalline cellulose by a simple method while avoiding the above problems.
本発明者らは上記の課題を解決すべく鋭意研究を行った結果、吸湿した結晶セルロース（以下、吸湿結晶セルロースと記載）を用いて結合剤溶液を噴霧しながら造粒を行うと、造粒物同士の凝集やコーティング機の機壁への付着などがなく、極めて簡便かつ効率的に所望の造粒物を製造できることを見出した。本発明は上記の知見を基にして完成されたものである。 As a result of diligent research to solve the above problems, the present inventors conducted granulation while spraying a binder solution using hygroscopic crystalline cellulose (hereinafter referred to as hygroscopic crystalline cellulose). It has been found that the desired granulated product can be produced very easily and efficiently without aggregation of materials and adhesion to the wall of the coating machine. The present invention has been completed based on the above findings.
すなわち、本発明により、吸湿結晶セルロースに結合剤溶液を噴霧して造粒を行う工程
を含む造粒物の製造方法が提供される。
上記の発明の好ましい態様によれば、吸湿結晶セルロースが吸湿前の結晶セルロース1質量部に対して1/8〜1/2質量部の水分を含む吸湿結晶セルロースである上記の方法；吸湿結晶セルロースに噴霧する結合剤溶液が薬物を含む上記の方法；吸湿結晶セルロースに噴霧する結合剤溶液が水及びエタノールを含む上記の方法：結合剤溶液におけるエタノールの含有量が0〜80%(w/w)である上記の方法；及び結合剤がヒドロキシプロピルセルロースである上記の方法が提供される。
That is, according to the present invention, a method for producing a granulated product is provided which includes a step of granulating by spraying a binder solution onto hygroscopic crystalline cellulose.
According to a preferred embodiment of the above invention, the above-mentioned method, wherein the hygroscopic crystalline cellulose is a hygroscopic crystalline cellulose containing 1/8 to 1/2 part by mass of water relative to 1 part by mass of the crystalline cellulose before moisture absorption; The above-mentioned method in which the binder solution to be sprayed contains a drug; the above-mentioned method in which the binder solution to be sprayed on hygroscopic crystalline cellulose contains water and ethanol: the content of ethanol in the binder solution is 0 to 80% (w / w And the above method wherein the binder is hydroxypropylcellulose.
本発明のさらに好ましい態様によれば、乾燥状態の結晶セルロースに水を噴霧して吸湿結晶セルロースを調製する工程を含む上記の方法；造粒を流動層造粒機を用いて行う上記の方法；1分間あたり吸湿前の結晶セルロース質量の1/100質量部以下の結合剤溶液を吸湿結晶セルロースに対して噴霧する上記の方法；ロキサチジン酢酸エステル塩酸塩を含む結合剤溶液を吸湿結晶セルロースに噴霧する工程を含む上記の方法；ロキサチジン酢酸エステル塩酸塩及びエタノールを含むヒドロキシプロピルセルロース水溶液を吸湿結晶セルロースに噴霧する工程を含む上記の方法；並びに吸湿前の結晶セルロースとしてセルフィアCP-203を用いる上記の方法が提供される。 According to a further preferred embodiment of the present invention, the above method comprising the step of preparing moisture-absorbing crystalline cellulose by spraying water on dry crystalline cellulose; the above method wherein granulation is performed using a fluidized bed granulator; The above-mentioned method of spraying a binder solution of 1/100 parts by mass or less of crystalline cellulose before moisture absorption per minute on moisture-absorbing crystalline cellulose; spraying a binder solution containing roxatidine acetate hydrochloride on moisture-absorbing crystalline cellulose The above-mentioned method comprising the steps; the above-mentioned method comprising the step of spraying a hydroxypropylcellulose aqueous solution containing roxatidine acetate hydrochloride and ethanol onto the hygroscopic crystalline cellulose; and the above-mentioned method using SELFIA CP-203 as the crystalline cellulose before moisture absorption Is provided.
別の観点からは、本発明により、吸湿結晶セルロースに結合剤溶液を噴霧して造粒を行う工程により製造することができる造粒物；吸湿結晶セルロースに薬剤を含む結合剤溶液を噴霧して造粒を行う工程により製造することができる造粒物；該造粒物を含む固形製剤；該造粒物を用いて製造することができる固形製剤；及び固形製剤の製造のための該造粒物の使用が提供される。 From another point of view, according to the present invention, a granulated product that can be produced by spraying a binder solution onto the hygroscopic crystalline cellulose and granulating; spraying the binder solution containing the drug on the hygroscopic crystalline cellulose; A granulated product that can be produced by a granulating step; a solid preparation containing the granulated product; a solid preparation that can be produced using the granulated product; and the granulated product for producing a solid preparation Use of objects is provided.
さらに別の観点からは、本発明により、吸湿結晶セルロースに結合剤溶液を噴霧して造粒を行う工程を含む造粒物の製造方法に用いるための吸湿前の結晶セルロース；吸湿結晶セルロースに結合剤溶液を噴霧して造粒を行う工程を含む造粒物の製造方法に用いるための吸湿結晶セルロース；及び該造粒物の製造のための吸湿前の結晶セルロース又は吸湿結晶セルロースの使用が提供される。 From another aspect, according to the present invention, crystalline cellulose before moisture absorption for use in a method for producing a granulated product comprising a step of granulating by spraying a binder solution onto moisture-absorbing crystalline cellulose; binding to moisture-absorbing crystalline cellulose A hygroscopic crystalline cellulose for use in a method for producing a granulated product comprising a step of granulating by spraying an agent solution; and use of the crystalline cellulose before moisture absorption or the hygroscopic crystalline cellulose for producing the granulated product Is done.
本発明の方法によれば、結晶セルロースを用いて造粒物を製造する際に造粒物同士の凝集や流動層造粒機の機壁への付着などがなく、極めて簡便かつ効率的に所望の造粒物を製造することができ、多様な薬剤を有効成分として含む造粒物の製造に利用することができるので、徐放製剤や錠剤などの固形製剤の製造に極めて有用な方法である。 According to the method of the present invention, when producing a granulated product using crystalline cellulose, there is no aggregation between the granulated products and adhesion to the wall of the fluidized bed granulator, which is extremely simple and efficient. This is a very useful method for the production of solid preparations such as sustained-release preparations and tablets because it can be used for the production of granulated substances containing various drugs as active ingredients. .
本発明の方法は、結晶セルロースを用いて造粒物を製造するにあたり、吸湿結晶セルロースに結合剤溶液を噴霧して造粒を行う工程を含むことを特徴としている。 The method of the present invention is characterized in that, in producing a granulated product using crystalline cellulose, a step of granulating by spraying a binder solution onto hygroscopic crystalline cellulose is performed.
本発明の方法に使用する吸湿結晶セルロースを調製するために用いる吸湿前の結晶セルロース(乾燥状態の結晶セルロース：以下、吸湿前の結晶セルロースを「乾燥状態の結晶セルロース」と呼ぶことがある)の種類は特に限定されず、任意の結晶セルロースを使用することができるが、好ましくは医薬品添加物として提供されている結晶セルロースを使用することができる。一般的に結晶セルロースは乾燥減量(1g, 105℃、3時間)が7.0%以下の規格を満足しており、水分含量は7.0%以下程度と推定されるが、本発明の方法における吸湿結晶セルロースを調製するための乾燥状態の結晶セルロースとして水分含量が7.0%以下の結晶セルロースを使用することが好ましい。 Crystalline cellulose before moisture absorption used for preparing the moisture-absorbing crystalline cellulose used in the method of the present invention (dried crystalline cellulose: hereinafter, crystalline cellulose before moisture absorption may be referred to as “dried crystalline cellulose”) The type is not particularly limited, and any crystalline cellulose can be used, but crystalline cellulose provided as a pharmaceutical additive can be preferably used. In general, crystalline cellulose satisfies the standard of loss on drying (1 g, 105 ° C., 3 hours) of 7.0% or less, and the water content is estimated to be about 7.0% or less, but the moisture-absorbing crystalline cellulose in the method of the present invention It is preferable to use a crystalline cellulose having a water content of 7.0% or less as the crystalline cellulose in a dry state for preparing the liquid.
乾燥状態の結晶セルロースの結晶化度は特に限定されないが、X線回折法により求められる結晶化度が10%以上であることが好ましく、さらに好ましくは40%以上である。また、乾燥状態の結晶セルロースの平均粒子径は40〜750μm程度であることが好ましい。乾燥状態の結晶セルロースの平均重合度も特に限定されないが、一般的には平均重合度60〜375の範囲の結晶セルロースを用いることが好ましい場合がある。水などで造粒された結晶セルロース造粒物を乾燥状態の結晶セルロースとして使用してもよい。例えば、造粒された市販の結晶セルロースとしてセルフィア(登録商標、旭化成ケミカルズ株式会社)などを用いることができ、CP-203、CP-305、又はCP-507などを用いることができるが、好ましくはセルフィアCP-203を用いることができる。 The crystallinity of the dry crystalline cellulose is not particularly limited, but the crystallinity obtained by the X-ray diffraction method is preferably 10% or more, and more preferably 40% or more. The average particle size of the crystalline cellulose in the dry state is preferably about 40 to 750 μm. The average degree of polymerization of the crystalline cellulose in the dry state is not particularly limited, but it is generally preferable to use crystalline cellulose having an average degree of polymerization of 60 to 375. A crystalline cellulose granulated product granulated with water or the like may be used as dry crystalline cellulose. For example, SELPHYR (registered trademark, Asahi Kasei Chemicals Co., Ltd.) can be used as the granulated commercially available crystalline cellulose, CP-203, CP-305, CP-507, etc. can be used, preferably SELPHY CP-203 can be used.
本発明の方法に用いる吸湿結晶セルロースに含まれる水分量は特に限定されないが、例えば乾燥状態の結晶セルロースの1質量部に対して約1/20〜3/4質量部、好ましくは約1/10〜3/5質量部、さらに好ましくは1/8〜1/2質量部程度の水分量を選択することができる。結晶セルロースに含まれる水分は、例えばカールフィッシャー法などにより適宜決定することが可能である。吸湿結晶セルロースには水分のほかエタノールやアセトンなどの揮発性の水溶性有機溶媒が含まれていてもよい。例えば乾燥状態の結晶セルロースの1質量部に対して約1/20〜1/10質量部程度の範囲で上記有機溶媒を含んでいてもよい。 The amount of water contained in the hygroscopic crystalline cellulose used in the method of the present invention is not particularly limited. For example, it is about 1/20 to 3/4 part by mass, preferably about 1/10 to 1 part by mass of the dry crystalline cellulose. A water content of about 3/5 parts by mass, more preferably about 1 / 8-1 / 2 parts by mass can be selected. The moisture contained in the crystalline cellulose can be appropriately determined by, for example, the Karl Fischer method. Hygroscopic crystalline cellulose may contain volatile water-soluble organic solvents such as ethanol and acetone in addition to moisture. For example, the organic solvent may be contained in a range of about 1/20 to 1/10 parts by mass with respect to 1 part by mass of crystalline cellulose in a dry state.
本発明の方法に用いる吸湿結晶セルロースの調製方法は特に限定されず、上記の範囲で水分を吸収させることができる方法であれば任意の方法を採用することができる。例えば、乾燥状態の結晶セルロースを高湿環境下に静置する方法、又は乾燥状態の結晶セルロースを高湿環境下で攪拌する方法などにより、数時間から数日間で吸湿させる方法を採用することができる。加湿の際にエタノールやアセトンなどの蒸気を導入してもよい。あるいは乾燥状態の結晶セルロースに対して撹拌下で水を噴霧する方法を採用してもよい。この方法は例えば攪拌が可能な造粒装置中で行うことができ、例えば流動層造粒機、転動造粒機、又は攪拌造粒機など、好ましくは流動層造粒機などを用いて行うことができる。噴霧する水にエタノールやアセトンなどの水溶性有機溶媒を添加しておいてもよい。 The method for preparing the hygroscopic crystalline cellulose used in the method of the present invention is not particularly limited, and any method can be adopted as long as it can absorb moisture within the above range. For example, it is possible to adopt a method of absorbing moisture in a few hours to several days by a method of standing dry crystalline cellulose in a high humidity environment or a method of stirring dry crystalline cellulose in a high humidity environment. it can. You may introduce vapor | steams, such as ethanol and acetone, in the case of humidification. Or you may employ | adopt the method of spraying water with stirring with respect to dry crystalline cellulose. This method can be performed, for example, in a granulator capable of stirring, for example, using a fluidized bed granulator, a rolling granulator, or a stirred granulator, preferably using a fluidized bed granulator. be able to. A water-soluble organic solvent such as ethanol or acetone may be added to the water to be sprayed.
例えば流動層造粒機を用いて乾燥状態の結晶セルロースから吸湿結晶セルロースを水の噴霧により調製する場合には、風量を約0.2〜25m3/分程度として給気温度20〜40℃、好ましくは30℃程度として噴霧を行い、回転数を20〜400 rpm程度として、乾燥状態の結晶セルロース1質量部に対して約1/20〜3/4質量部、好ましくは約1/10〜3/5質量部、さらに好ましくは1/8〜1/2質量部程度の水又はエタノール若しくはアセトンなどの水溶性有機溶媒を含む水を30分から数時間かけて噴霧すればよい。もっとも、本発明の方法は上記の特定の態様に限定されることはない。例えば上記の方法で乾燥状態の結晶セルロースから調製した吸湿結晶セルロースは特に整粒することなく結合剤溶液の噴霧による造粒工程に使用することができる。 For example, when a hygroscopic crystalline cellulose is prepared by spraying water from dried crystalline cellulose using a fluidized bed granulator, the air flow is about 0.2 to 25 m 3 / min, and the supply temperature is 20 to 40 ° C., preferably Spraying is performed at about 30 ° C., and the rotation speed is about 20 to 400 rpm. About 1/20 to 3/4 parts by mass, preferably about 1/10 to 3/5 with respect to 1 part by mass of dry crystalline cellulose. What is necessary is just to spray water containing water-soluble organic solvents, such as ethanol or acetone about 30 mass parts, more preferably about 1 / 8-1 / 2 mass part water. However, the method of the present invention is not limited to the specific embodiment described above. For example, moisture-absorbing crystalline cellulose prepared from dried crystalline cellulose by the above method can be used in a granulating step by spraying a binder solution without any particular size adjustment.
吸湿結晶セルロースに対して結合剤溶液を噴霧することにより造粒物を製造することができる。吸湿結晶セルロースに噴霧する結合剤溶液としては、例えば結合剤の水溶液を用いることができるが、結合剤溶液は有機溶媒の溶液であってもよい。また結合剤の水溶液はエタノールやアセトンなどの水溶性有機溶媒を含んでいてもよい。本発明の方法の好ましい態様では噴霧する結合剤溶液は溶媒として水及びエタノールなどの水溶性有機溶媒を含んでいる。この場合には、結合剤溶液における該有機溶媒の含有量として例えば0〜80%(w/w)程度、好ましくはエタノールを0〜80%(w/w)程度含有することが好ましい。 The granulated product can be produced by spraying the binder solution onto the hygroscopic crystalline cellulose. As the binder solution sprayed onto the hygroscopic crystalline cellulose, for example, an aqueous solution of a binder can be used, but the binder solution may be a solution of an organic solvent. The aqueous solution of the binder may contain a water-soluble organic solvent such as ethanol or acetone. In a preferred embodiment of the method of the present invention, the binder solution to be sprayed contains water and a water-soluble organic solvent such as ethanol as a solvent. In this case, the content of the organic solvent in the binder solution is, for example, about 0 to 80% (w / w), preferably about 0 to 80% (w / w) of ethanol.
造粒は一般的には結合剤溶液を噴霧可能な通常の造粒機を用いて行うことができるが、例えば流動層造粒機などを用いることができる。結合剤溶液の噴霧量は造粒機の種類や吸湿結晶セルロースの水分量、あるいは結合剤の種類などに応じて適宜選択することができるが、一般的には1分間あたり吸湿前の結晶セルロース1質量部に対して1/50質量部以下、好ましくは1/80質量部以下、さらに好ましくは1/100質量部以下の結合剤溶液を吸湿結晶セルロースに対して噴霧することが好ましい。噴霧する際の液滴の直径は特に限定されないが、例えば10〜100μm程度である。結合剤溶液の噴霧に際しては造粒物が凝集塊を形成することなく、造粒機の内壁に付着することがないように流動条件や噴霧条件を適宜決定することができる。 In general, granulation can be performed using an ordinary granulator capable of spraying the binder solution. For example, a fluidized bed granulator can be used. The amount of the binder solution sprayed can be appropriately selected according to the type of granulator, the moisture content of the hygroscopic crystalline cellulose, or the type of the binder, but in general, the crystalline cellulose before moisture absorption per minute 1 It is preferable to spray the hygroscopic crystalline cellulose with a binder solution of 1/50 parts by mass or less, preferably 1/80 parts by mass or less, more preferably 1/100 parts by mass or less with respect to parts by mass. Although the diameter of the droplet at the time of spraying is not specifically limited, For example, it is about 10-100 micrometers. When spraying the binder solution, the flow conditions and spraying conditions can be appropriately determined so that the granulated material does not form aggregates and does not adhere to the inner wall of the granulator.
結合剤の種類は特に限定されず、結合剤溶液の噴霧量、造粒機の種類、又は吸湿結晶セルロースの水分量などに応じて当業者が適宜選択可能であるが、例えば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、又はポリビニルアルコールなどを用いることができる。これらのうちヒドロキシプロピルセルロースが好ましい。結合剤溶液における結合剤の濃度も特に限定されず、結合剤溶液の噴霧量、造粒機の種類、又は吸湿結晶セルロースの水分量などに応じて当業者が適宜選択可能であるが、例えば1〜5質量％程度である。 The type of the binder is not particularly limited and can be appropriately selected by those skilled in the art according to the spray amount of the binder solution, the type of granulator, the moisture content of the hygroscopic crystalline cellulose, and the like, for example, hydroxypropylcellulose, methylcellulose Polyvinyl pyrrolidone, polyvinyl alcohol, or the like can be used. Of these, hydroxypropylcellulose is preferred. The concentration of the binder in the binder solution is not particularly limited and can be appropriately selected by those skilled in the art depending on the amount of the binder solution sprayed, the type of granulator, the moisture content of the hygroscopic crystalline cellulose, etc. About 5% by mass.
造粒にあたり、1種又は2種以上の製剤用添加物を使用してもよい。例えば安定化剤、界面活性剤、緩衝剤、抗酸化剤、着色剤、賦形剤、崩壊剤、保存剤、又は溶解補助剤などの製剤用添加物を1種又は2種以上を用いることができ、好ましくは崩壊剤などを適宜使用することができる。製剤用添加物は造粒に際して吸湿結晶セルロースに固体状態で混合添加することもできるが、例えば賦形剤などの製剤用添加物を結合剤溶液に溶解又は分散して噴霧することも可能である。造粒のために使用する1種又は2種以上の製剤用添加物の種類は限定されず、造粒にあたって添加する方法も限定されることはない。 In granulation, one or more additives for preparation may be used. For example, one or more preparation additives such as stabilizers, surfactants, buffers, antioxidants, colorants, excipients, disintegrants, preservatives, or solubilizers may be used. Preferably, a disintegrant or the like can be used as appropriate. The formulation additive can be mixed and added to the hygroscopic crystalline cellulose in the solid state at the time of granulation. For example, the formulation additive such as an excipient can be dissolved or dispersed in the binder solution and sprayed. . The kind of the additive for 1 type (s) or 2 or more types used for granulation is not limited, The method to add in granulation is not limited, either.
本発明の方法において結合剤溶液に薬剤を溶解しておくことは本発明の特に好ましい態様である。薬剤の種類は特に限定されず、2種以上の薬剤を組み合わせて用いてもよい。2種以上の薬剤を用いる場合には、2種以上の薬剤を含む結合剤溶液を調製して噴霧してもよいが、異なる2種の薬剤を含む結合剤溶液をそれぞれ調製し、それらを同時に、段階的に、又は交互に吸湿結晶セルロースに噴霧して造粒を行うこともできる。薬剤としては、例えば、解熱鎮痛剤、向精神薬、抗不安薬、抗うつ薬、催眠鎮静薬、鎮痙薬、中枢神経作用薬、脳代謝改善剤、脳循環改剤、抗てんかん剤、交感神経興奮剤、抗痴呆薬、制酸剤、抗潰瘍剤、鎮咳去痰剤、鎮吐剤、気管支拡張剤、抗アレルギー薬、抗ヒスタミン剤、強心剤、不整脈用剤、利尿薬、血圧降下剤、血管収縮薬、冠血管拡張剤、末梢血管拡張薬、抗高脂血症用剤、利胆剤、抗生物質、合成抗菌剤、糖尿病治療薬、骨粗鬆症用剤、抗リウマチ薬、骨格筋弛緩薬、鎮痙剤、ホルモン剤、アルカロイド系麻薬、サルファ剤、痛風治療薬、血液凝固阻止剤、又は抗悪性腫瘍剤などに包含される各種の薬剤を用いることができるが、これらに限定されるわけではない。本発明の方法に特に好適に使用できる薬剤群として、例えば実施例に示したロキサチジン酢酸エステル塩酸塩などの胃酸分泌抑制作用を有するヒスタミン受容体拮抗薬を挙げることができるが、本発明の方法はこの特定の薬剤に限定されるわけではない。 Dissolving the drug in the binder solution in the method of the present invention is a particularly preferred embodiment of the present invention. The type of drug is not particularly limited, and two or more drugs may be used in combination. When two or more drugs are used, a binder solution containing two or more drugs may be prepared and sprayed, but a binder solution containing two different drugs may be prepared and used simultaneously. Alternatively, granulation can be performed by spraying the hygroscopic crystalline cellulose stepwise or alternately. Examples of drugs include antipyretic analgesics, psychotropic drugs, anxiolytics, antidepressants, hypnotic sedatives, antispasmodic drugs, central nervous system agonists, cerebral metabolism improvers, cerebral circulation modifiers, antiepileptics, sympathetic nerves Stimulants, anti-dementia drugs, antacids, anti-ulcer agents, antitussives, antiemetics, antiemetics, bronchodilators, antiallergic agents, antihistamines, cardiotonic agents, arrhythmic agents, diuretics, antihypertensive agents, vasoconstrictors, coronary drugs Vasodilator, peripheral vasodilator, antihyperlipidemic agent, antibacterial agent, antibiotic, synthetic antibacterial agent, antidiabetic agent, osteoporosis agent, antirheumatic agent, skeletal muscle relaxant, antispasmodic agent, hormone agent, Various drugs included in alkaloid narcotics, sulfa drugs, anti-gout drugs, blood coagulation inhibitors, or antineoplastic agents can be used, but are not limited thereto. As a group of drugs that can be used particularly preferably in the method of the present invention, for example, histamine receptor antagonists having gastric acid secretion inhibitory action such as loxathidine acetate hydrochloride shown in the Examples can be mentioned. You are not limited to this particular drug.
造粒条件は適宜選択可能で特に限定されることはないが、例えば流動層造粒機を用いて結合剤溶液の噴霧により造粒を行う場合には、風量を約0.2〜25m3/分程度とし、給気温度を30〜80℃として噴霧を行い、回転数を20〜400 rpm程度として、吸湿結晶セルロースに結合剤溶液を30分から数時間かけて噴霧すればよい。造粒物の粒径は特に限定されないが、例えば100〜800μm程度とすることができ、必要に応じて造粒後に整粒を行い所望の粒度分布の造粒物を製造することができる。篩のサイズは特に限定されないが、例えば目開き500μm程度の篩で整粒することが好ましい。また、造粒物は必要に応じて乾燥工程に付してもよい。乾燥は当業者に周知の方法で行うことができ、所望の水分値まで乾燥した造粒物を容易に調製することができる。さらに造粒物に対して溶出制御や安定性改善のために皮膜をコーティングすることもできる。 The granulation conditions can be appropriately selected and are not particularly limited. For example, when granulating by spraying a binder solution using a fluidized bed granulator, the air volume is about 0.2 to 25 m 3 / min. Then, spraying is performed at an air supply temperature of 30 to 80 ° C., a rotation speed is set to about 20 to 400 rpm, and the binder solution may be sprayed on the hygroscopic crystalline cellulose over 30 minutes to several hours. The particle size of the granulated product is not particularly limited, but can be, for example, about 100 to 800 μm. If necessary, granulation can be performed after granulation to produce a granulated product having a desired particle size distribution. The size of the sieve is not particularly limited, but for example, it is preferable to adjust the size with a sieve having an opening of about 500 μm. Moreover, you may attach | subject a granulated material to a drying process as needed. Drying can be performed by a method well known to those skilled in the art, and a granulated product dried to a desired moisture value can be easily prepared. Further, the granulated product can be coated with a film for elution control and stability improvement.
上記の工程で得られた造粒物が薬剤を含まない場合には、この造粒物を核粒子として用いてコーティングなどの汎用の手法により1種又は2種以上の薬剤を造粒物に担持させることができ、その後に常法により錠剤、顆粒剤、細粒剤、カプセル剤などの固形製剤を製造することができる。本発明の工程により薬剤を含む造粒物を製造する場合には、その造粒物を用いて錠剤、顆粒剤、細粒剤、カプセル剤などの固形製剤を製造することができる。固形製剤の製造にあたっては、例えば上記の工程で得られた造粒物と適宜の賦形剤を混合し、必要に応じて結合剤や崩壊剤とともに圧縮成型することにより錠剤を製造することができ、さらに錠剤に対して必要に応じて腸溶コーティングなどのフィルムコーティングや糖衣を施すことができる。また、上記の工程で得られた造粒物を必要に応じて結合剤や崩壊剤と混合してさらに造粒することにより顆粒剤などを製造することができる。これらの方法は当業者に周知かつ汎用されており、当業者に利用可能な適宜の方法により所望の固形製剤を製造することができる。 When the granulated product obtained in the above process does not contain a drug, this granulated product is used as a core particle and one or more drugs are supported on the granulated product by a general technique such as coating. Thereafter, solid preparations such as tablets, granules, fine granules and capsules can be produced by a conventional method. When a granulated product containing a drug is produced by the process of the present invention, a solid preparation such as a tablet, granule, fine granule or capsule can be produced using the granulated product. In the production of a solid preparation, for example, a tablet can be produced by mixing the granulated product obtained in the above step and an appropriate excipient and, if necessary, compression molding together with a binder and a disintegrant. Furthermore, film coating such as enteric coating and sugar coating can be applied to the tablets as necessary. Moreover, a granule etc. can be manufactured by mixing the granulated material obtained by said process with a binder and a disintegrating agent as needed, and further granulating. These methods are well known and widely used by those skilled in the art, and a desired solid preparation can be produced by an appropriate method available to those skilled in the art.
以下、実施例により本発明をさらに具体的に説明するが、本発明の範囲は下記の実施例に限定されることはない。
例1
結晶セルロース(水で造粒された結晶セルロース粒、セルフィア(登録商標)CP-203、旭化成ケミカルズ株式会社）300 gを流動層造粒機(SFC-LABO)に投入し、風量を約0.4 m3/分として給気温度を30℃、回転数を300 rpmにて流動させた。はじめに水75 gを2 g/分の速度で噴霧した。次いでロキサチジン酢酸エステル塩酸塩(Roxa)120 g、ヒドロキシプロピルセルロース(HPC) 9 gを含む薬剤水溶液を同条件で流動させながら噴霧して造粒した。造粒物を給気温度(30℃)で乾燥した。上記操作にて得られた乾燥品を篩過器に投入し、JP30号篩(目開き:500μm)で整粒した。篩を通過した顆粒：413.7 g(100%)、篩上に残った顆粒は0.1 g(0.0%)であった。同様に例2〜5を行いそれぞれの製造例について収率及び団粒率を求めた。
収率(%)=(篩上に残存した粒子質量(B)＋篩を通過した粒子質量(C))/原材料質量(A)×100
団粒率(%)=(B)/(B+C)×100
EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example.
Example 1
300 g of crystalline cellulose (crystalline cellulose granulated with water, SELFIA (registered trademark) CP-203, Asahi Kasei Chemicals Co., Ltd.) is put into a fluidized bed granulator (SFC-LABO), and the air volume is about 0.4 m 3 As a result, the air supply temperature was made to flow at 30 ° C. and the rotation speed at 300 rpm. First, 75 g of water was sprayed at a rate of 2 g / min. Next, an aqueous drug solution containing 120 g of roxatidine acetate hydrochloride (Roxa) and 9 g of hydroxypropyl cellulose (HPC) was sprayed and granulated while flowing under the same conditions. The granulated product was dried at the supply temperature (30 ° C.). The dried product obtained by the above operation was put into a sieving machine and sized with a JP30 sieve (aperture: 500 μm). Granules passed through the sieve: 413.7 g (100%), and the granules remaining on the sieve were 0.1 g (0.0%). Similarly, Examples 2 to 5 were performed, and the yield and the aggregate rate were determined for each of the production examples.
Yield (%) = (Particle mass remaining on sieve (B) + Particle mass passed through sieve (C)) / Raw material mass (A) × 100
Aggregate rate (%) = (B) / (B + C) × 100
比較例
結晶セルロース(水で造粒された結晶セルロース粒、セルフィア(登録商標)CP-203、旭化成ケミカルズ株式会社)300 gを流動層造粒機(SFC-LABO)に投入し、風量を約0.4 m3/分として給気温度を30℃、回転数を300 rpmにて流動させた。次いでロキサチジン酢酸エステル塩酸塩120 g、HPC 9 gを含む薬剤水溶液を同条件で流動させながら噴霧して造粒を試みたところ、顆粒同士の凝集が多数発生して流動層造粒機の攪拌が困難な状態になった。得られた顆粒凝集塊は整粒操作を行うことができなかった。
Comparative Example Crystalline cellulose (crystalline cellulose granules granulated with water, SELFIA (registered trademark) CP-203, Asahi Kasei Chemicals Corporation) 300 g was charged into a fluidized bed granulator (SFC-LABO), and the air volume was about 0.4. The supply air temperature was 30 ° C. and the rotation speed was 300 rpm as m 3 / min. Next, when granulation was attempted by spraying a drug aqueous solution containing 120 g of roxatidine acetate hydrochloride and 9 g of HPC while flowing under the same conditions, agglomeration of granules occurred, and the fluidized bed granulator was stirred. It became difficult. The resulting granule aggregate could not be sized.
例6
結晶セルロース(セルフィア(登録商標)CP-203、旭化成ケミカルズ株式会社)32.7 kgを流動層造粒機(SFC-50)に投入し、給気風量を流動約12 m3/分、スリット約10 m3/分として給気温度を30℃、回転数をローター50 rpm、アジテーター150 rpmにて流動させた。はじめに精製水8.18 kgを300 g/分の速度で噴霧した。次いで、給気温度を約45℃に上げた後、Roxa16.8 kg、HPC 1.335 kgを含む薬剤水溶液を噴霧して造粒物を製造した。造粒物を給気温度(60℃)で乾燥した。上記操作にて得られた乾燥品を篩過器に投入し、JP30号篩(目開き:500μm)で整粒した。篩を通過した顆粒：49.85kg(100%)、篩上に残った顆粒は0.02 kg(0.0%)であった。
Example 6
32.7 kg of crystalline cellulose (Selfia (registered trademark) CP-203, Asahi Kasei Chemicals Corporation) is charged into a fluidized bed granulator (SFC-50), the supply air volume is about 12 m 3 / min, and the slit is about 10 m. The supply air temperature was 30 ° C., the rotation speed was 50 rpm, and the agitator was 150 rpm. First, 8.18 kg of purified water was sprayed at a rate of 300 g / min. Next, after raising the supply air temperature to about 45 ° C., a drug aqueous solution containing 16.8 kg of Roxa and 1.335 kg of HPC was sprayed to produce a granulated product. The granulated product was dried at the supply air temperature (60 ° C.). The dried product obtained by the above operation was put into a sieving machine and sized with a JP30 sieve (aperture: 500 μm). Granules passed through the sieve: 49.85 kg (100%), and the granules remaining on the sieve were 0.02 kg (0.0%).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07173050A (en) * | 1990-04-18 | 1995-07-11 | Asahi Chem Ind Co Ltd | Spherical nucleus, spherical granule and their production |
| US20020028248A1 (en) * | 1996-03-14 | 2002-03-07 | Takayuki Tsukada | Rapid-release microdispersible ecadotril preparation |
| CN1795858A (en) * | 2004-12-30 | 2006-07-05 | 北京德众万全医药科技有限公司 | Oral taking tablets of Roxatidine Acetate Hydrochloride |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07173050A (en) * | 1990-04-18 | 1995-07-11 | Asahi Chem Ind Co Ltd | Spherical nucleus, spherical granule and their production |
| US20020028248A1 (en) * | 1996-03-14 | 2002-03-07 | Takayuki Tsukada | Rapid-release microdispersible ecadotril preparation |
| CN1795858A (en) * | 2004-12-30 | 2006-07-05 | 北京德众万全医药科技有限公司 | Oral taking tablets of Roxatidine Acetate Hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| JPN6016001347; Ｉｎｔ． Ｊ． Ｃｈｅｍ． Ｓｃｉ． Ｖｏｌ．７ Ｎｏ．３, 2009, ｐｐ．１９１５-１９２０ * |
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