JPH04283520A - Spherical nuclei and spherical granule - Google Patents

Spherical nuclei and spherical granule

Info

Publication number
JPH04283520A
JPH04283520A JP4665491A JP4665491A JPH04283520A JP H04283520 A JPH04283520 A JP H04283520A JP 4665491 A JP4665491 A JP 4665491A JP 4665491 A JP4665491 A JP 4665491A JP H04283520 A JPH04283520 A JP H04283520A
Authority
JP
Japan
Prior art keywords
spherical
coating
nuclei
granules
core
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.)
Pending
Application number
JP4665491A
Other languages
Japanese (ja)
Inventor
Etsuo Kamata
悦雄 鎌田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Asahi Chemical Industry Co Ltd
Original Assignee
Asahi Chemical Industry Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Asahi Chemical Industry Co Ltd filed Critical Asahi Chemical Industry Co Ltd
Priority to JP4665491A priority Critical patent/JPH04283520A/en
Publication of JPH04283520A publication Critical patent/JPH04283520A/en
Pending legal-status Critical Current

Links

Landscapes

  • Medicinal Preparation (AREA)

Abstract

PURPOSE:To provide the subject specified pherical nuclei and the subject spheri cal granule obtained by using the spherical nuclei. CONSTITUTION:A pharmaceutically inactive spherical nuclei containing 10-70wt.% crtstalline cellulose having 60-375 average polymerization degree and 10-90wt.% water-soluble additive ius used and the surface thereof is coated with a drug. The above-treated nuclei is then further film coated to obtain the objective spherical granule. In comparison with the conventional spherical nuclei, the above-obtained spherical nuclei has a proper water absorption capacity and a low abrasion wear and coagulation between granules can be reduce therefor. The efficiency of coating is high and the rate of power coating is also high. In addition, the spherical granule of this invention is resistive to destruction due to intestinal motion in comparison with a phperical granule prepared by using the conventional spherical nuclei and a desired dissolution pattern, therefor, can be readily obtained.

Description

【発明の詳細な説明】[Detailed description of the invention]

【0001】0001

【産業上の利用分野】本発明は、球状核および球状核を
用いて製造される球形顆粒に関する。
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to spherical nuclei and spherical granules produced using spherical nuclei.

【0002】0002

【従来の技術】持効性医薬品の放出制御手段、腸溶化の
手段、薬効成分の安定性改善または味のマスキング手段
として、医薬品はフィルムコ−ティングを施されること
が多い。顆粒にフィルムコ−ティングを施す場合は、コ
−ティング効率を高め、再現性良くコ−ティングするた
めに、形状が球形に近い核に、薬物および賦形剤から成
る粉体を被覆して作った素顆粒を用いることが多い。こ
の場合核として、特開昭61−1614号公報にあるよ
うにノンパレル(商品名、フロイント産業(株)製、成
分;白糖あるいは白糖/デンプン)を用いることが一般
的であった。
BACKGROUND OF THE INVENTION Pharmaceuticals are often coated with a film as a means for controlling the release of long-acting pharmaceuticals, as a means for enteric coating, as a means for improving the stability of active pharmaceutical ingredients, or as a means for masking taste. When applying film coating to granules, in order to increase the coating efficiency and coat with good reproducibility, a powder consisting of drug and excipients is coated on a core that is nearly spherical in shape. Taelin granules are often used. In this case, it has been common to use Nonpareil (trade name, manufactured by Freund Sangyo Co., Ltd., ingredients: white sugar or white sugar/starch) as described in Japanese Patent Application Laid-Open No. 61-1614.

【0003】また特開昭61−213201号公報はコ
−ティング用の核として使用できる結晶セルロ−ス球形
顆粒に関するもので、見掛け密度が0.65g/ml以
上、真球度が0.8以上と規定されている。また特開昭
63−301816号公報には実施例で結晶セルロ−ス
からなる球形核顆粒が使用されているが、粒度範囲が2
0〜32メッシュとあるのみで他に何の記述もない。ま
た、これらには原料としての結晶セルロ−スについて何
の記述もない。また前者に述べられている真球度は短軸
の長さ/長軸の長さとあるのみで、個々の粒子を規定す
るのか、粒子全体として規定するのかあいまいである。 これらには、球状核として重要と考えられる吸水性、磨
損度について何の規定もないし、吸水性については記述
さえない。
[0003] Furthermore, JP-A-61-213201 relates to crystalline cellulose spherical granules that can be used as cores for coating, and has an apparent density of 0.65 g/ml or more and a sphericity of 0.8 or more. It is stipulated that Furthermore, in JP-A-63-301816, spherical core granules made of crystalline cellulose are used in the examples, but the particle size range is 2.
There is no other description other than 0 to 32 mesh. Furthermore, these documents do not contain any description of crystalline cellulose as a raw material. In addition, the sphericity mentioned in the former only refers to the length of the minor axis/length of the major axis, and it is unclear whether it defines individual particles or the entire particle. These have no regulations regarding water absorption and abrasion degree, which are considered important for spherical nuclei, and there is no description of water absorption.

【0004】0004

【発明が解決しようとする課題】しかし、核として白糖
あるいは白糖/デンプンから成る核を用いた場合、該核
に結合液を用いて薬物を含有する粉体を被覆し、さらに
フィルムコ−ティングを施す製剤方法においては、核の
主成分である白糖が結合液に溶解し、表面が粘着性とな
るため、またその核は磨損度が高いため、・顆粒同士の
凝集 ・コ−ティング機の機壁への顆粒の付着・収率、コ−テ
ィング効率の悪化 という問題があった。また、体内に顆粒を投与した場合
、次第に核の主成分である白糖が溶出し、強度が低下す
るため、腸の運動により力が加えられると、溶出をコン
トロ−ルするためのコ−ティング被膜層が壊れ、望まれ
る溶出パタ−ンが得られにくいという問題があった。
However, when a core made of sucrose or sucrose/starch is used as a core, the core is coated with a drug-containing powder using a binding liquid and then coated with a film. In the formulation method used, white sugar, the main component of the core, dissolves in the binding liquid, making the surface sticky, and the core is highly abrasive. There were problems such as adhesion of granules to the wall and deterioration of yield and coating efficiency. In addition, when granules are administered into the body, white sugar, which is the main component of the nucleus, gradually elutes and the strength decreases, so when force is applied due to intestinal movement, a coating is applied to control the elution. There was a problem that the layer was broken and it was difficult to obtain the desired elution pattern.

【0005】また、従来の結晶セルロ−スからなる球状
核は、磨損度が低下し核の強度が向上するメリットはあ
るものの、核の吸水率が大きくなり過ぎ、薬物を含有す
る粉体を被覆する際に、結合液が多量に必要で、粉体被
覆速度が遅くなるという欠点があった。
[0005] Although the conventional spherical core made of crystalline cellulose has the advantage of reducing the degree of abrasion and improving the strength of the core, the water absorption rate of the core is too high and it is difficult to coat the powder containing the drug. However, there are disadvantages in that a large amount of binding liquid is required and the powder coating speed is slow.

【0006】[0006]

【課題を解決するための手段および作用】本発明者は、
鋭意検討の結果、核として、平均重合度が60〜375
である結晶セルロ−スを10〜70%および水溶性添加
剤を10〜90%含有する薬学的に不活性な球状核を用
いることによって、上記における問題を解決し、本発明
を完成した。
[Means and effects for solving the problem] The present inventors
As a result of intensive studies, the average degree of polymerization of the core was 60 to 375.
By using a pharmaceutically inert spherical core containing 10-70% of crystalline cellulose and 10-90% of a water-soluble additive, the above problems were solved and the present invention was completed.

【0007】即ち、本発明は、平均重合度が60〜37
5である結晶セルロ−スを10〜70%および水溶性添
加剤を10〜90%含有する薬学的に不活性な球状核、
および該球状核のまわりに薬物を含有する粉体層があり
、該粉体層のまわりにコ−ティング剤の被膜層を有する
球形顆粒に関する。本発明の球状核は、崩壊せず強度も
高いのでこれを用いた球形顆粒を体内に投与した場合、
顆粒が腸内運動による破壊を受けにくいため、溶出をコ
ントロ−ルするためのコ−ティング被膜層が壊れにくく
、望まれる溶出パタ−ンが得られ易いという利点がある
That is, in the present invention, the average degree of polymerization is 60 to 37.
a pharmaceutically inert spherical core containing 10-70% of crystalline cellulose and 10-90% of a water-soluble additive;
and a spherical granule having a powder layer containing a drug around the spherical core, and a coating layer of a coating agent around the powder layer. The spherical nucleus of the present invention does not disintegrate and has high strength, so when spherical granules using this are administered into the body,
Since the granules are less likely to be destroyed by intestinal movements, there is an advantage that the coating layer for controlling elution is less likely to be destroyed, making it easier to obtain a desired elution pattern.

【0008】本発明は、核として平均重合度が60〜3
75である結晶セルロ−ス(以下、結晶セルロ−スと略
記する)を10〜70%および水溶性添加剤を10〜9
0%含有する薬学的に不活性な球状核を用いているので
、球状核に適度な吸水性があるために、従来の白糖およ
び白糖/デンプンからなる核と比べて、顆粒同士の凝集
が1/10以下と少なく、また機壁への顆粒の付着が防
止できるので、結合液噴霧速度、粉体供給速度などの条
件の厳密なコントロ−ルは不要となる利点がある。また
、コ−ティング時の磨損がほとんどないため、コ−ティ
ング効率も高いという利点がある。また、従来の結晶セ
ルロ−スからなる球状核と比べ、本発明の球状核は水溶
性成分を含み、かつ適度な吸水性を持つので、結合液の
消費が少なく、粉体被覆速度が速いという利点がある。
[0008] In the present invention, the core has an average degree of polymerization of 60 to 3.
75% crystalline cellulose (hereinafter abbreviated as crystalline cellulose) and 10% to 70% water-soluble additives.
Since we use a pharmaceutically inactive spherical core containing 0%, the spherical core has moderate water absorption, so compared to conventional sucrose and sucrose/starch cores, the aggregation of granules is 1. /10 or less, and since adhesion of granules to the machine wall can be prevented, there is an advantage that strict control of conditions such as binding liquid spray rate and powder supply rate is not necessary. Furthermore, since there is almost no wear and tear during coating, there is an advantage that coating efficiency is high. In addition, compared to conventional spherical cores made of crystalline cellulose, the spherical cores of the present invention contain water-soluble components and have appropriate water absorption properties, resulting in less consumption of binding liquid and faster powder coating speed. There are advantages.

【0009】以下本発明について詳細に説明する。本発
明でいう球状核は、平均重合度が60〜375である結
晶セルロ−スを10〜70%、好ましくは10〜50%
、水溶性添加剤を10〜90%含有し、薬学的に不活性
であることが必要である。ここでいう薬学的に不活性と
は薬効成分を含まないことをいう。また、好ましくはそ
の平均粒径は100〜1000μm、好ましくは100
〜700μm、特に好ましくは150〜500μm、タ
ッピング見掛け密度は0.65g/ml以上、好ましく
は0.75g/ml以上、真球度は0.7以上、好まし
くは0.8以上の球状であって、かつその吸水率は5〜
15%、磨損度は1%以下、好ましくは0.8%以下で
あって、水中において実質的に崩壊しないことである。 結晶セルロ−スを70%以上含有すると、核の吸水率が
大きくなりすぎ、薬物を含有する粉体を被覆する際に結
合液が多量に必要となる。また、核への粉体の付着力も
弱くなる。また、結晶セルロ−スの含有量が10%以下
では、核の磨損度が大きくなり、また、吸水率も小さく
なりすぎ、好ましくない。水溶性添加剤は、球状核に結
合液を噴霧して粉体を被覆する場合に、核の吸水率を抑
え、かつ核への粉体の付着性を増すために必要であるが
、10〜90%が適当である。水溶性添加剤の含有量が
90%以上では核の磨損度が大きくなり、また、吸水率
も小さくなりすぎる。また、10%以下では核の吸水率
が大きくなり、かつ核に結合液を噴霧した時に粘着性が
低くなるため、粉体の付着性が弱くなり好ましくない。
The present invention will be explained in detail below. The spherical core in the present invention is composed of 10 to 70%, preferably 10 to 50%, of crystalline cellulose having an average degree of polymerization of 60 to 375.
, must contain 10-90% water-soluble additives and be pharmaceutically inert. The term "pharmaceutically inactive" as used herein means that it does not contain any medicinal ingredients. Further, preferably the average particle size is 100 to 1000 μm, preferably 100 μm.
~700 μm, particularly preferably 150 to 500 μm, apparent tapping density is 0.65 g/ml or more, preferably 0.75 g/ml or more, and sphericity is 0.7 or more, preferably 0.8 or more. , and its water absorption rate is 5~
15%, the degree of abrasion is 1% or less, preferably 0.8% or less, and substantially does not disintegrate in water. If the crystalline cellulose content is 70% or more, the water absorption rate of the core becomes too high, and a large amount of binding liquid is required when coating the drug-containing powder. Furthermore, the adhesion of the powder to the core becomes weaker. Furthermore, if the content of crystalline cellulose is less than 10%, the degree of abrasion of the core becomes large and the water absorption rate becomes too low, which is not preferable. Water-soluble additives are necessary to suppress the water absorption rate of the cores and increase the adhesion of the powder to the cores when the binding liquid is sprayed onto the spherical cores to coat the powder. 90% is appropriate. If the content of the water-soluble additive is 90% or more, the degree of abrasion of the core becomes large and the water absorption rate becomes too low. Further, if it is less than 10%, the water absorption rate of the core becomes large and the adhesion becomes low when the binding liquid is sprayed onto the core, which is not preferable because the adhesion of the powder becomes weak.

【0010】また、球状核の平均粒径は、薬物を含む粉
体の量や、被膜量、目標とする球形顆粒の粒径により決
まるが、100μm以下では粉体のコ−ティングが困難
で顆粒同士の凝集が起こり易くなり、1000μm以上
では被覆させる薬物の量が制限され好ましくない。好ま
しくは100μm〜700μm、特に好ましくは150
μm〜500μmである。また、タッピング見掛け密度
は0.65g/ml以上であることが好ましく、それ以
下では粉体のコ−ティング時に核の流動性が悪くなり、
均一なコ−ティングが困難である。また、顆粒同士の凝
集も多くなる。特に好ましくは0.75g/ml以上で
ある。また、真球度が0.7以下では、それを用いて作
った球形顆粒の真球度が悪くなり、製品美観上あるいは
薬物溶出速度のコントロ−ルの点で好ましくない。特に
好ましくは0.8以上である。また、球状核の吸水率が
5%未満では結合液やコ−ティング液を噴霧した場合に
、顆粒の凝集・機壁への顆粒の付着が多くなり、また、
吸水率が15%より大きいと、核が吸収する液量が多く
なるので粉体の被覆速度が遅くなるという欠点がある。 また磨損度が1%より大きいとコ−ティング時に摩耗が
起こり、収率・コ−ティング効率が悪くなる。また水中
で実質的に崩壊しないことにより強度を保ち、体内に投
与した場合、球形顆粒の破壊を防ぎ薬物溶出が終了する
まで、望まれる溶出パタ−ンを維持できる。
[0010] The average particle diameter of the spherical core is determined by the amount of drug-containing powder, the amount of coating, and the target particle size of the spherical granules, but if it is less than 100 μm, it is difficult to coat the powder and the granules are If the diameter is 1000 μm or more, the amount of drug to be coated will be limited, which is not preferable. Preferably 100 μm to 700 μm, particularly preferably 150 μm
It is μm to 500 μm. In addition, the tapping apparent density is preferably 0.65 g/ml or more; if it is less than that, the fluidity of the core will be poor during powder coating.
Uniform coating is difficult. In addition, aggregation of granules increases. Particularly preferably, it is 0.75 g/ml or more. Furthermore, if the sphericity is less than 0.7, the sphericity of the spherical granules made using it will be poor, which is not preferable in terms of product aesthetics or control of drug elution rate. Particularly preferably, it is 0.8 or more. In addition, if the water absorption rate of the spherical core is less than 5%, when the binding liquid or coating liquid is sprayed, the granules will agglomerate and adhere to the machine wall.
When the water absorption rate is greater than 15%, the amount of liquid absorbed by the core increases, resulting in a disadvantage that the coating speed of the powder becomes slow. Furthermore, if the degree of abrasion is greater than 1%, abrasion occurs during coating, resulting in poor yield and coating efficiency. In addition, it maintains its strength by not substantially disintegrating in water, and when administered into the body, it prevents the destruction of the spherical granules and maintains the desired elution pattern until drug elution is completed.

【0011】本発明の球状核の成分について述べるが、
用いる結晶セルロ−スは、リンタ−、パルプ、再生繊維
等のセルロ−ス質を酸加水分解あるいはアルカリ酸化分
解あるいは両者を組み合わせる、あるいは上記の化学的
処理の後に粉砕などの機械的処理を施すなどして得られ
るものであって、平均重合度は60〜375である必要
がある。好ましくは100〜300である。ここでいう
結晶セルロ−スとは、X線回折法により求められる結晶
化度が10%以上であるセルロ−スをいう。好ましくは
40%以上である。また、吸水量が1.0〜2.8ml
/g、200メッシュ留分が80%以下であることが好
ましい。平均重合度が60未満ではセルロ−ス分子の絡
み合いが少なくなるため球状核の磨損度が大きくなり、
また375より大きいと繊維性が現れるため球状になり
にくく好ましくない。ここでいう水溶性添加剤とは、水
100gに対しておおよそ1g以上溶解し得る薬学的に
不活性な添加剤であり、乳糖、白糖、D−マンニト−ル
、ブドウ糖などの糖類、デキストリン、アルファ−化デ
ンプンなどのデンプン加工品、ポリビニルピロリドン、
ポリエチレングリコ−ルなどの合成高分子、メチルセル
ロ−ス、ヒドロキシプロピルセルロ−ス、ヒドロキシプ
ロピルメチルセルロ−スなどのセルロ−ス誘導体などで
ある。結晶セルロ−ス、水溶性添加剤以外の添加剤とし
ては、薬学的に不活性であれば良く、それらはコ−ンス
タ−チ、ポテトスタ−チなどのデンプン類、あるいは第
二リン酸カルシウム、ケイ酸アルミニウムなどの無機物
類、あるいはステアリン酸マグネシウムなどの脂肪酸類
などである。
The components of the spherical nucleus of the present invention will be described.
The crystalline cellulose used can be obtained by acid hydrolysis, alkaline oxidative decomposition, or a combination of both, or by mechanical treatment such as crushing after the above chemical treatment. The average degree of polymerization must be from 60 to 375. Preferably it is 100-300. The term "crystalline cellulose" as used herein refers to cellulose having a crystallinity of 10% or more as determined by X-ray diffraction. Preferably it is 40% or more. In addition, the water absorption amount is 1.0 to 2.8ml.
/g, the 200 mesh fraction is preferably 80% or less. When the average degree of polymerization is less than 60, the degree of wear of the spherical core increases because the entanglement of cellulose molecules decreases.
On the other hand, if it is larger than 375, fibrous properties appear, making it difficult to form a sphere, which is not preferable. The water-soluble additives referred to here are pharmaceutically inert additives that can dissolve approximately 1 g or more in 100 g of water, including sugars such as lactose, sucrose, D-mannitol, and glucose, dextrin, and alpha - Processed starch products such as converted starch, polyvinylpyrrolidone,
These include synthetic polymers such as polyethylene glycol, and cellulose derivatives such as methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Additives other than crystalline cellulose and water-soluble additives may be pharmaceutically inert, such as starches such as cornstarch, potato starch, dicalcium phosphate, aluminum silicate, etc. and fatty acids such as magnesium stearate.

【0012】本発明の球状核は、例えば以下の方法によ
り製造する。結晶セルロ−スを10〜70%、水溶性添
加剤10〜90%含有する粉体を混合攪拌造粒機にいれ
、蒸留水を加え練合する。蒸留水の代わりに、ヒドロキ
シプロピルセルロ−ス、デンプン糊、ポリビニルピロリ
ドンなどの水溶液を結合液として用いても良い。その後
、押し出し造粒機を用いて混練物の押し出し造粒を行う
。その後、押し出し物を転動型コ−ティング装置へ移し
、球形化を行った後、乾燥し、必要に応じて篩分し、球
状核を得る。この方法では、押し出し造粒時に混練物が
強く圧密化されるので、結晶セルロ−スの含有量が少な
い場合でも、磨損度の小さい球状核が製造できる利点が
ある。水溶性添加剤は、押し出し造粒時に押し出しをス
ム−ズに行うための潤滑剤としても働く。このように本
発明の球状核は高価な機器を使用せずとも、従来より使
用されてきた安価な機器を組み合わせて製造することが
できるという利点がある。
The spherical core of the present invention is produced, for example, by the following method. A powder containing 10 to 70% crystalline cellulose and 10 to 90% water-soluble additives is placed in a mixing agitation granulator, and distilled water is added and kneaded. Instead of distilled water, an aqueous solution of hydroxypropylcellulose, starch paste, polyvinylpyrrolidone, etc. may be used as the binding liquid. Thereafter, the kneaded product is extruded and granulated using an extrusion granulator. Thereafter, the extrudate is transferred to a rolling coating device, spheroidized, dried and, if necessary, sieved to obtain spherical cores. In this method, the kneaded material is strongly consolidated during extrusion granulation, so even when the content of crystalline cellulose is small, it has the advantage that spherical nuclei with a low degree of wear can be produced. The water-soluble additive also acts as a lubricant for smooth extrusion during extrusion granulation. As described above, the spherical core of the present invention has the advantage that it can be manufactured by combining conventionally used inexpensive equipment without using expensive equipment.

【0013】本発明の球形顆粒の製造方法について述べ
る。従来、薬物を含む粉体層の被覆、フィルムコ−ティ
ングは有機溶媒系で行われることが多かったが、環境・
コスト・残留などの問題のため、徐々に有機溶媒系から
水溶液系、水性懸濁液系へと転換が図られている。従っ
て、以下のように水溶液系あるいは水性懸濁液系で行う
ことが好ましく、また水系で行うほうが本発明の球状核
の効果がより顕著になる利点もある。球状核を転動型コ
−ティング装置中で転動させながら、結合剤含有水溶液
を連続的に噴霧し、同時に薬物と必要ならば賦形剤とか
ら成る粉体を供給し、球状核に粉体を被覆して素顆粒と
する、あるいは球状核を流動層コ−ティング機中で流動
させながら、結合剤水溶液中に薬物を溶解あるいは懸濁
させた液を噴霧し、球状核に薬物を含む粉体を被覆し、
素顆粒とする。必要があれば素顆粒を乾燥後、コ−ティ
ング剤の水溶液またはコ−ティング剤の水性懸濁液を噴
霧し、乾燥させて防湿、苦味マスキング、腸溶性、持効
性などを目的とした被膜層を形成させ、球形顆粒とする
。また、薬物を含む粉体を被覆する際、コ−ティング剤
の水溶液あるいはコ−ティング剤の水性懸濁液を同時に
噴霧してもかまわない。
The method for producing spherical granules of the present invention will be described. Conventionally, coating of powder layers containing drugs and film coating were often performed using organic solvents, but due to environmental and
Due to issues such as cost and residue, attempts are being made to gradually switch from organic solvent systems to aqueous solutions and aqueous suspension systems. Therefore, it is preferable to use an aqueous solution system or an aqueous suspension system as described below, and there is also the advantage that the effect of the spherical nuclei of the present invention is more pronounced when carried out in an aqueous system. While rolling the spherical core in a rolling coating device, an aqueous binder-containing solution is continuously sprayed, and at the same time, a powder consisting of a drug and, if necessary, an excipient is supplied to the spherical core. Coating the body to form elementary granules, or spraying a solution in which the drug is dissolved or suspended in an aqueous binder solution while fluidizing the spherical core in a fluidized bed coating machine to contain the drug in the spherical core. coated with powder,
Let it be an elementary granule. If necessary, after drying the elementary granules, an aqueous solution of a coating agent or an aqueous suspension of a coating agent is sprayed and dried to form a coating for moisture-proofing, bitterness masking, enteric properties, long-acting properties, etc. Form layers to form spherical granules. Furthermore, when coating the powder containing the drug, an aqueous solution or suspension of the coating agent may be simultaneously sprayed.

【0014】被覆に用いる粉体の量は、投与すべき薬物
量や最終顆粒の大きさなどによって異なるが、球状核に
対しておおよそ5〜300%程度である。しかし、必要
によってはもっと多くても構わない。また、薬物の種類
は問わないが、水溶性薬物のほうが結合剤水溶液に溶解
して粘着性を帯び、顆粒同士の付着凝集を起こし易くな
るので、本発明の球状核を用いる効果がより顕著となる
The amount of powder used for coating varies depending on the amount of drug to be administered and the size of the final granules, but is approximately 5 to 300% of the spherical core. However, it may be more if necessary. In addition, although the type of drug does not matter, water-soluble drugs dissolve in an aqueous binder solution and become sticky, making it easier for granules to adhere to each other and agglomerate, so the effect of using the spherical core of the present invention is more pronounced. Become.

【0015】結合剤としては、ヒドロキシプロピルセル
ロ−ス(HPC)、ヒドロキシプロピルメチルセルロ−
ス(HPMC)、メチルセルロ−ス、カルボキシメチル
セルロ−ス・ナトリウムなどのセルロ−ス誘導体、デン
プン糊、アルファ−化デンプンなどのデンプン加工品、
アラビアガム、プルランなどの多糖類、ポリビニルピロ
リドン(PVP)などの合成高分子、糖シロップなどの
糖類などの水溶液が好ましい。薬物が水溶性の場合、薬
物水溶液自体を結合剤水溶液として用いても良い。また
、有機溶媒を用いる場合は、PVP、HPCなどを有機
溶媒に溶解させて用いれば良い。
As a binder, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose
cellulose derivatives such as cellulose (HPMC), methylcellulose, sodium carboxymethylcellulose, starch pastes, pregelatinized starch and other processed starch products,
Preferred are aqueous solutions of polysaccharides such as gum arabic and pullulan, synthetic polymers such as polyvinylpyrrolidone (PVP), and saccharides such as sugar syrup. When the drug is water-soluble, the aqueous drug solution itself may be used as the aqueous binder solution. Further, when using an organic solvent, PVP, HPC, etc. may be dissolved in the organic solvent.

【0016】賦形剤としては、結晶セルロ−ス、低置換
度ヒドロキシプロピルセルロ−スなどのセルロ−ス類、
コ−ンスタ−チ(CS)、アルファ−化デンプン、部分
アルファ−化デンプンなどのデンプン類、乳糖、白糖、
D−マンニト−ルなどの糖類、タルク、無水ケイ酸、ケ
イ酸アルミニウムなどの無機物類などがあげられる。コ
−ティング機としては、遠心流動型コ−ティング機、流
動層コ−ティング機、転動型流動層コ−ティング機、パ
ン型コ−ティング機など通常のコ−ティング機が使用で
きる。
Examples of excipients include celluloses such as crystalline cellulose and low-substituted hydroxypropyl cellulose;
Starches such as corn starch (CS), pregelatinized starch, partially pregelatinized starch, lactose, sucrose,
Examples include sugars such as D-mannitol, and inorganic substances such as talc, silicic anhydride, and aluminum silicate. As the coating machine, a conventional coating machine such as a centrifugal fluid coating machine, a fluidized bed coating machine, a rolling fluidized bed coating machine, or a pan type coating machine can be used.

【0017】コ−ティング剤の水溶液としては、HPM
C、HPC、PVP、ポリビニルアルコ−ル、ポリエチ
レングリコ−ルなどの水溶液があげられる。コ−ティン
グ剤の水性懸濁剤としては、水不溶性のコ−ティング剤
を懸濁液状としたものであって、エチルセルロ−ス(E
C)、ヒドロキシプロピルメチルセルロ−スフタレ−ト
、セルロ−スアセテ−トフタレ−ト、カルボキシメチル
エチルセルロ−ス、セルロ−スアセテ−ト、セルロ−ス
アセテ−トブチレ−ト、ヒドロキシプロピルメチルセル
ロ−スアセテ−トサクシネ−トなどのセルロ−ス類、ア
クリル系共重合体類、ビニル系共重合体類、シェラック
、シリコン樹脂類などの水性懸濁液があげられる。市販
品としては例えば、TC−5(HPMC、信越化学(株
)製)、EC−N−10F(EC、信越化学(株)製)
、Aquacoat(ECの水性懸濁液、米国FMC社
製)、オイドラギットL−30D−55、同NE30D
(両者ともアクリル系共重合体の水性懸濁液、独レ−ム
・ファ−マ社製)などがある。これらコ−ティング剤は
単独で用いても、2つ以上組み合わせて用いても良い。 また、有機溶媒を用いる場合は、上記のコ−ティング剤
が溶解する溶媒系を用いて行う。エタノ−ルあるいはア
セトンなどのような水と混和し得る有機溶媒と水の混液
を用いても良い。また、溶出速度調節のための水溶性物
質、可塑剤、安定化剤、着色料、薬物等を必要に応じて
加えても良い。被膜層の量はコ−ティングの目的によっ
ても異なるが、素顆粒に対して1〜50%程度、好まし
くは2〜30%程度である。
[0017] As the aqueous solution of the coating agent, HPM
Examples include aqueous solutions of C, HPC, PVP, polyvinyl alcohol, polyethylene glycol, and the like. The aqueous suspension of the coating agent is a suspension of a water-insoluble coating agent, such as ethyl cellulose (E
C), hydroxypropyl methyl cellulose sphthalate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methyl cellulose acetate succinate Examples include aqueous suspensions of celluloses such as carbonate, acrylic copolymers, vinyl copolymers, shellac, silicone resins, and the like. Commercially available products include, for example, TC-5 (HPMC, manufactured by Shin-Etsu Chemical Co., Ltd.) and EC-N-10F (EC, manufactured by Shin-Etsu Chemical Co., Ltd.).
, Aquacoat (EC aqueous suspension, manufactured by FMC, USA), Eudragit L-30D-55, Eudragit NE30D
(Both are aqueous suspensions of acrylic copolymers, manufactured by Rehm Pharma, Germany). These coating agents may be used alone or in combination of two or more. Furthermore, when an organic solvent is used, a solvent system in which the above-mentioned coating agent is dissolved is used. A mixture of water and an organic solvent miscible with water such as ethanol or acetone may also be used. Further, water-soluble substances, plasticizers, stabilizers, colorants, drugs, etc. for controlling the elution rate may be added as necessary. Although the amount of the coating layer varies depending on the purpose of coating, it is about 1 to 50%, preferably about 2 to 30%, based on the elementary particles.

【0018】得られた球形顆粒にさらに粉体層およびコ
−ティング剤の被膜層を形成させても良い。得られた球
形顆粒は、公知の方法によりカプセルに充填しても良く
、あるいは適当な賦形剤と混合後圧縮し、錠剤としても
良い。
A powder layer and a coating layer of a coating agent may be further formed on the obtained spherical granules. The obtained spherical granules may be filled into capsules by a known method, or mixed with appropriate excipients and compressed to form tablets.

【0019】[0019]

【実施例】以下、実施例により本発明を説明する。なお
、結晶セルロ−スと球状核と球形顆粒の物性評価方法は
下記の通りである。ここで結晶セルロ−スは結晶化度が
10%以上のものを用いた。 結晶セルロ−ス ・平均重合度 Industrial  and  Engineer
ing  Chemistry;vol.42,p50
2(1950)に記載された銅安溶液粘度法による。 ・吸水量(ml/g) JIS  K5101に記載の吸油量の測定法に準じ、
油の代わりに蒸留水を用いる。終点は全体が一つの塊上
となった後、離水し始める点とする。 ・200メッシュ留分(%) 柳本製作所製ロ−タップ式篩振盪機により、目開き75
μm(200メッシュ)のJIS標準篩を用いて試料3
0gを30分間篩分した後の、篩上の残留分である。
[Examples] The present invention will be explained below with reference to Examples. The methods for evaluating the physical properties of crystalline cellulose, spherical nuclei, and spherical granules are as follows. The crystalline cellulose used here had a crystallinity of 10% or more. Crystalline Cellulose/Average Degree of Polymerization Industrial and Engineer
ing Chemistry; vol. 42, p50
2 (1950) according to the copper ammonium solution viscosity method.・Water absorption (ml/g) According to the oil absorption measurement method described in JIS K5101,
Use distilled water instead of oil. The end point is the point at which the water begins to separate from the water after the whole becomes a single lump.・200 mesh fraction (%) A mesh size of 75 was obtained using a low-tap sieve shaker made by Yanagimoto Seisakusho.
Sample 3 using a μm (200 mesh) JIS standard sieve.
This is the residue on the sieve after sieving 0g for 30 minutes.

【0020】球状核 ・平均粒径(μm) 柳本製作所製ロ−タップ式篩振盪機により、JIS標準
篩を用いて試料30gを10分間篩分し、累積50重量
%の粒度を平均粒径とする。 ・タッピング見掛け密度(g/ml) 試料30gを100mlメスシリンダ−に充填し、30
回程度タッピングし、求める。繰り返し数は3で、その
平均値をとる。 ・真球度 100個の粒子について顕微鏡写真を撮り、それぞれの
短径/長径比を求め、その平均値をとる。 ・吸水率(%) 球状核400g(固形分換算)を遠心流動型コ−ティン
グ装置〔フロイント産業(株)製、CF−360〕中で
回転させながら、3%HPC(低粘度タイプ)水溶液を
6g/minの速度で噴霧する。核同士が付着し始める
まで行って終点とし、要した液重量(g)を求める。吸
水率は以下の式で表される。なお式中の含水率は、球状
核がもともと含んでいる水分率である。
Spherical core/average particle size (μm) Using a low-tap sieve shaker manufactured by Yanagimoto Seisakusho, 30 g of sample was sieved for 10 minutes using a JIS standard sieve, and the cumulative particle size of 50% by weight was determined as the average particle size. do.・Tapping apparent density (g/ml) Fill a 100ml measuring cylinder with 30g of sample,
Tap about a few times and ask. The number of repetitions is 3, and the average value is taken. - Take microscopic photographs of 100 particles with sphericity, determine the short axis/long axis ratio of each, and take the average value.・Water absorption rate (%) While rotating 400 g of spherical cores (solid content equivalent) in a centrifugal fluid coating device [CF-360, manufactured by Freund Sangyo Co., Ltd.], a 3% HPC (low viscosity type) aqueous solution was added. Spray at a rate of 6 g/min. The process is continued until the nuclei begin to adhere to each other, which is defined as the end point, and the required liquid weight (g) is determined. The water absorption rate is expressed by the following formula. Note that the water content in the formula is the water content originally contained in the spherical core.

【0021】[0021]

【数1】[Math 1]

【0022】・磨損度(%) 萱垣式磨損度測定機に試料10gを仕込み、25rpm
で15分間回転させ、粉化による重量減少を表す。繰り
返し数は3で、その平均値をとる。 球形顆粒 ・コ−ティング効率(%) 球形顆粒の回収量を、用いた原料の総量で除す。 ・凝集度(%) 球形顆粒を紙上に分散させ、凝集している顆粒の個数を
数え、総個数で除す。 n=1,000で行う。
・Abrasion degree (%) 10g of sample was placed in the Kayagaki type abrasion measurement machine, and the rotation speed was 25 rpm.
Rotate for 15 minutes to represent weight loss due to powdering. The number of repetitions is 3, and the average value is taken. Spherical granules/coating efficiency (%) Divide the amount of spherical granules recovered by the total amount of raw materials used.・Degree of agglomeration (%) Disperse spherical granules on paper, count the number of agglomerated granules, and divide by the total number. Performed with n=1,000.

【0023】[0023]

【実施例1】表1に示す結晶セルロ−ス(a)400g
、200メッシュ乳糖(DMV社製)600gをポリ袋
中で混合した後、プラネタリ−ミキサ−5DM−R(品
川製作所製)に入れ、蒸留水0.7kgを加え、5分間
練合する。その後、押し出し造粒機RG−5型(菊水製
作所製、スクリ−ン口径0.5mmφ)を用いて押し出
す。押し出し物0.6kgをとり、マルメライザ−Q−
230(不二パウダル(株)製)へ移し、蒸留水を少量
ずつ噴霧させながら、500rpmで20分間転動させ
、球形化する。湿球状物を流動層造粒機UNI−GLA
TT(大川原化工機(株)製)へ仕込み、入口温度60
℃で乾燥し、16メッシュ(目開き1mm)でふるい球
状核(A)を得た。得られた球状核(A)の物性を表2
に示す。
[Example 1] 400 g of crystalline cellulose (a) shown in Table 1
, 600 g of 200 mesh lactose (manufactured by DMV) were mixed in a plastic bag, placed in a planetary mixer 5DM-R (manufactured by Shinagawa Seisakusho), added with 0.7 kg of distilled water, and kneaded for 5 minutes. Thereafter, it is extruded using an extrusion granulator RG-5 type (manufactured by Kikusui Seisakusho, screen diameter: 0.5 mm). Take 0.6 kg of extrudate and use Marmerizer-Q-
230 (manufactured by Fuji Paudal Co., Ltd.), and rolled at 500 rpm for 20 minutes while spraying distilled water little by little to form spheres. Fluidized bed granulator UNI-GLA for wet spheres
Pour into TT (manufactured by Okawara Kakoki Co., Ltd.) at an inlet temperature of 60
It was dried at °C and sieved with 16 mesh (1 mm opening) to obtain a spherical core (A). Table 2 shows the physical properties of the obtained spherical nucleus (A).
Shown below.

【0024】[0024]

【実施例2】表1に示す結晶セルロ−ス(b)を用い、
水の添加量を減量する以外は実施例1と同様の方法で球
状核(B)を得た。得られた球状核(B)の物性を表2
に示す。
[Example 2] Using crystalline cellulose (b) shown in Table 1,
A spherical core (B) was obtained in the same manner as in Example 1 except that the amount of water added was reduced. Table 2 shows the physical properties of the obtained spherical nucleus (B).
Shown below.

【0025】[0025]

【実施例3】表1に示す結晶セルロ−ス(c)を用い、
水の添加量を減量する以外は実施例1と同様の方法で球
状核(C)を得た。得られた球状核(C)の物性を表2
に示す。
[Example 3] Using crystalline cellulose (c) shown in Table 1,
A spherical core (C) was obtained in the same manner as in Example 1 except that the amount of water added was reduced. Table 2 shows the physical properties of the obtained spherical nucleus (C).
Shown below.

【0026】[0026]

【実施例4】表1に示す結晶セルロ−ス(d)を用い、
水の添加量を増量する以外は実施例1と同様の方法で球
状核(D)を得た。得られた球状核(D)の物性を表2
に示す。
[Example 4] Using crystalline cellulose (d) shown in Table 1,
A spherical core (D) was obtained in the same manner as in Example 1 except that the amount of water added was increased. Table 2 shows the physical properties of the obtained spherical nucleus (D).
Shown below.

【0027】[0027]

【比較例1】表1に示す結晶セルロ−ス(e)を用い、
水の添加量を減量する以外は実施例1と同様の方法で球
状核(E)を得た。得られた球状核(E)の物性を表2
に示す。
[Comparative Example 1] Using crystalline cellulose (e) shown in Table 1,
A spherical core (E) was obtained in the same manner as in Example 1 except that the amount of water added was reduced. Table 2 shows the physical properties of the obtained spherical nucleus (E).
Shown below.

【0028】[0028]

【比較例2】表1に示す結晶セルロ−ス(f)を用い、
水の添加量を増量する以外は実施例1と同様の方法で球
状核(F)を得た。得られた球状核(F)の物性を表2
に示す。
[Comparative Example 2] Using crystalline cellulose (f) shown in Table 1,
A spherical core (F) was obtained in the same manner as in Example 1 except that the amount of water added was increased. Table 2 shows the physical properties of the obtained spherical nucleus (F).
Shown below.

【0029】[0029]

【実施例5】実施例1の球状核(A)400gを遠心流
動型コ−ティング装置〔フロイント産業(株)製、CF
−360〕に入れ、エア温度40℃、ロ−タ−回転数1
60rpmとし、HPC(低粘度タイプ)水溶液(3%
W/V)を10ml/minの速度で噴霧しながら、下
記組成粉体を造粒状態を見ながら供給し、粉体被覆を行
う。その後、顆粒を取り出し、40℃で16時間乾燥さ
せる。次に、目開き106μmの篩を通して微粉をカッ
トし、素顆粒を得た。
[Example 5] 400 g of the spherical core (A) of Example 1 was coated with a centrifugal fluid coating device [manufactured by Freund Sangyo Co., Ltd., CF
-360], air temperature 40℃, rotor rotation speed 1
60 rpm, HPC (low viscosity type) aqueous solution (3%
W/V) was sprayed at a rate of 10 ml/min, a powder having the following composition was supplied while monitoring the granulation state, and powder coating was performed. The granules are then removed and dried at 40° C. for 16 hours. Next, the fine powder was cut through a sieve with an opening of 106 μm to obtain elementary granules.

【0030】粉体組成 テオフィリン(和光純薬(株)製)  50g白   
     糖(九州製糖(株)製)100gC    
    S(日澱化学(株)製)  50gついで、素
顆粒をCF−360装置に入れ、エア温度60℃、ロ−
タ−回転数200rpmとし、下記組成の水性懸濁液を
20ml/minの速度で噴霧し、徐放性コ−ティング
を行った。
Powder composition Theophylline (manufactured by Wako Pure Chemical Industries, Ltd.) 50g white
Sugar (manufactured by Kyushu Sugar Co., Ltd.) 100gC
S (manufactured by Nippon Star Chemical Co., Ltd.) 50g, the elementary granules were placed in a CF-360 device, and the air temperature was 60°C.
The aqueous suspension having the following composition was sprayed at a rate of 20 ml/min at a rotational speed of 200 rpm to form a sustained release coating.

【0031】水性懸濁液 Aquacoat    400g (EC水性懸濁液、30%W/V、米国FMC社製)ク
エン酸トリエチル  (和光純薬(株)製)  25g
コ−ティング終了後、60℃の乾燥機に1時間入れて、
球形顆粒を得た。結合液供給開始から粉体被覆終了まで
に要した時間(T(分))、得られた球形顆粒の凝集度
、コ−ティング効率の測定結果を表3に示す。
Aqueous suspension Aquacoat 400g (EC aqueous suspension, 30% W/V, manufactured by FMC, USA) Triethyl citrate (manufactured by Wako Pure Chemical Industries, Ltd.) 25g
After coating, put it in a dryer at 60℃ for 1 hour.
Spherical granules were obtained. Table 3 shows the measurement results of the time (T (minutes)) required from the start of supply of the binding liquid to the end of powder coating, the degree of aggregation of the obtained spherical granules, and the coating efficiency.

【0032】[0032]

【実施例6〜8】球状核(B)、(C)、(D)を用い
る以外は、実施例5と同様に操作し、球形顆粒を得た。 T(分)、球形顆粒の凝集度、コ−ティング効率の測定
結果を表3に示す。
Examples 6 to 8 Spherical granules were obtained in the same manner as in Example 5, except that spherical nuclei (B), (C), and (D) were used. Table 3 shows the measurement results of T (min), degree of agglomeration of spherical granules, and coating efficiency.

【0033】[0033]

【比較例3〜4】球状核(E)、(F)を用いる以外は
、実施例5と同様に操作し、球形顆粒を得た。T(分)
、球形顆粒の凝集度、コ−ティング効率の測定結果を表
3に示す。
Comparative Examples 3 and 4 Spherical granules were obtained in the same manner as in Example 5, except that spherical nuclei (E) and (F) were used. T (minutes)
Table 3 shows the measurement results of the degree of agglomeration and coating efficiency of the spherical granules.

【0034】[0034]

【実施例9】表4に示す処方(g)を用い、水の添加量
を増量する以外は、実施例1と同様の方法で球状核(G
)を得た。得られた球状核(G)の物性を表5に示す。
[Example 9] A spherical nucleus (G
) was obtained. Table 5 shows the physical properties of the obtained spherical nucleus (G).

【0035】[0035]

【実施例10】表4に示す処方(h)を用い、水の添加
量を減量する以外は、実施例1と同様の方法で球状核(
H)を得た。得られた球状核(H)の物性を表5に示す
[Example 10] Spherical nuclei (
H) was obtained. Table 5 shows the physical properties of the obtained spherical nucleus (H).

【0036】[0036]

【実施例11】表4に示す処方(i)を用い、水の添加
量を増量する以外は、実施例1と同様の方法で球状核(
I)を得た。得られた球状核(I)の物性を表5に示す
[Example 11] Spherical nuclei (
I) was obtained. Table 5 shows the physical properties of the obtained spherical core (I).

【0037】[0037]

【比較例5】表4に示す処方(j)を用い、水の添加量
を減量する以外は、実施例1と同様の方法で球状核(J
)を得た。得られた球状核(J)の物性を表5に示す。
[Comparative Example 5] Using the formulation (j) shown in Table 4, spherical nuclei (J
) was obtained. Table 5 shows the physical properties of the obtained spherical nucleus (J).

【0038】[0038]

【比較例6】表4に示す処方(k)を用い、水の添加量
を増量する以外は、実施例1と同様の方法で球状核(K
)を得た。得られた球状核(K)の物性を表5に示す。
[Comparative Example 6] Using the recipe (k) shown in Table 4, the spherical nuclei (K
) was obtained. Table 5 shows the physical properties of the obtained spherical nucleus (K).

【0039】[0039]

【比較例7】ノンパレル−101(市販品、フロイント
産業(株)製、商品名)42メッシュ〜32メッシュを
球状核(L)とする。該球状核(L)の組成を表4(l
)に、物性を表5に示す。
[Comparative Example 7] Nonpareil-101 (commercial product, manufactured by Freund Sangyo Co., Ltd., trade name) 42 mesh to 32 mesh was used as the spherical core (L). The composition of the spherical nucleus (L) is shown in Table 4 (l
), and the physical properties are shown in Table 5.

【0040】[0040]

【比較例8】ノンパレル−103(市販品、フロイント
産業(株)製、商品名)42メッシュ〜32メッシュを
球状核(M)とする。該球状核(M)の組成を表4(m
)に、物性を表5に示す。
[Comparative Example 8] Nonpareil-103 (commercial product, manufactured by Freund Sangyo Co., Ltd., trade name) 42 mesh to 32 mesh was used as the spherical core (M). The composition of the spherical nucleus (M) is shown in Table 4 (m
), and the physical properties are shown in Table 5.

【0041】[0041]

【実施例12〜14】表5に示す球状核(G)、(H)
、(I)を用いる以外は、実施例5と同様に操作して球
形顆粒を得た。T(分)、球形顆粒の凝集度、コ−ティ
ング効率の測定結果を表6に示す。
[Examples 12 to 14] Spherical nuclei (G) and (H) shown in Table 5
, (I) was used in the same manner as in Example 5 to obtain spherical granules. Table 6 shows the measurement results of T (min), degree of agglomeration of spherical granules, and coating efficiency.

【0042】[0042]

【比較例9〜12】表5に示す球状核(J)、(K)、
(L)、(M)を用いる以外は、実施例5と同様に操作
して球形顆粒を得た。T(分)、球形顆粒の凝集度、コ
−ティング効率の測定結果を表6に示す。
[Comparative Examples 9 to 12] Spherical nuclei (J), (K) shown in Table 5,
Spherical granules were obtained in the same manner as in Example 5 except for using (L) and (M). Table 6 shows the measurement results of T (min), degree of agglomeration of spherical granules, and coating efficiency.

【0043】[0043]

【実施例15】表2に示す球状核(A)500gを流動
層コ−ティング機(大河原化工機(株)製、UNI  
GLATT)に仕込み、入口温度を60℃として流動さ
せながら、下記の薬物水溶液を10ml/minの速度
で噴霧し、薬物を被覆する。 薬物溶液組成 スルピリン(保栄薬工(株)製)  100gHPC(
低粘度タイプ)              5g蒸留
水                        
  145gつぎに苦味マスキングのため、TC−5(
信越化学(株)製)水溶液(10%W/V)150ml
を10ml/minの速度で噴霧する。その後、顆粒を
取り出し、40℃で16時間乾燥させる。次に、目開き
106μmの篩を通して微粉をカットし、球形顆粒を得
た。球形顆粒の凝集度、コ−ティング効率の測定結果を
表7に示す。
[Example 15] 500 g of the spherical cores (A) shown in Table 2 were coated in a fluidized bed coating machine (manufactured by Okawara Kakoki Co., Ltd., UNI
GLATT), and the following drug aqueous solution was sprayed at a rate of 10 ml/min to coat the drug while the inlet temperature was set to 60° C. and the solution was allowed to flow. Drug solution composition Sulpirin (manufactured by Hoei Yakuko Co., Ltd.) 100g HPC (
Low viscosity type) 5g distilled water
145g Next, for bitterness masking, add TC-5 (
Shin-Etsu Chemical Co., Ltd.) aqueous solution (10% W/V) 150ml
Spray at a rate of 10 ml/min. The granules are then removed and dried at 40° C. for 16 hours. Next, the fine powder was cut through a sieve with an opening of 106 μm to obtain spherical granules. Table 7 shows the measurement results of the degree of agglomeration and coating efficiency of the spherical granules.

【0044】[0044]

【比較例13】球状核(L)を用いる以外は、実施例1
5と同様に操作し、球形顆粒を得た。球形顆粒の凝集度
、コ−ティング効率の測定結果を表7に示す。
[Comparative Example 13] Example 1 except for using a spherical nucleus (L)
The procedure was repeated in the same manner as in 5 to obtain spherical granules. Table 7 shows the measurement results of the degree of agglomeration and coating efficiency of the spherical granules.

【0045】[0045]

【実施例16】表5に示す球状核(I)400gを遠心
流動型コ−ティング装置〔フロイント産業(株)製、C
F−360〕に入れ、エア温度40℃、ロ−タ−回転数
160rpmとし、ポリビニルピロリドン(BASF社
製、K−30)水溶液(6%W/V)100mlを噴霧
しながら、下記組成の粉体を供給し、粉体コ−ティング
を行う。その後、顆粒を取り出し、40℃で16時間乾
燥させる。次に、目開き106μmの篩を通して微粉を
カットし、素顆粒を得た。
[Example 16] 400 g of the spherical nucleus (I) shown in Table 5 was coated with a centrifugal fluid coating device [manufactured by Freund Sangyo Co., Ltd., C
F-360], the air temperature was set to 40°C, the rotor rotation speed was set to 160 rpm, and while spraying 100 ml of polyvinylpyrrolidone (manufactured by BASF, K-30) aqueous solution (6% W/V), powder having the following composition was added. powder coating. The granules are then removed and dried at 40° C. for 16 hours. Next, the fine powder was cut through a sieve with an opening of 106 μm to obtain elementary granules.

【0046】粉体組成 リボフラビン  (和光純薬(株))        
        20g 乳糖          (DMV社製、200メッシ
ュ)   60g C    S      (日澱化学(株)製)   
        20g 次に、素顆粒をCF−360装置に入れ、エア温度60
℃、ロ−タ−回転数200rpmとし、下記組成の水性
懸濁液を15ml/minの速度で噴霧し、コ−ティン
グを行う。
Powder composition Riboflavin (Wako Pure Chemical Industries, Ltd.)
20g Lactose (manufactured by DMV, 200 mesh) 60g C S (manufactured by Nippon Deka Chemical Co., Ltd.)
20g Next, put the elementary granules into a CF-360 device and set the air temperature to 60.
℃, the rotor rotation speed is 200 rpm, and an aqueous suspension having the following composition is sprayed at a rate of 15 ml/min to perform coating.

【0047】水性懸濁液組成 オイドラギットL−30D−55    300g(3
0%W/V、独レ−ム・ファルマ社製)タルク(和光純
薬(株)製)          15gクエン酸トリ
エチル(和光純薬(株)製)9g蒸留水    136
g コ−ティング終了後、40℃で16時間乾燥し、腸溶性
球形顆粒を得た。得られた腸溶性球形顆粒の凝集度、コ
−ティング効率の測定結果を表8に示す。
Aqueous suspension composition Eudragit L-30D-55 300g (3
0% W/V, manufactured by Lehm Pharma, Germany) Talc (manufactured by Wako Pure Chemical Industries, Ltd.) 15 g Triethyl citrate (manufactured by Wako Pure Chemical Industries, Ltd.) 9 g Distilled water 136
g After coating, it was dried at 40°C for 16 hours to obtain enteric coated spherical granules. Table 8 shows the measurement results of the degree of aggregation and coating efficiency of the enteric coated spherical granules obtained.

【0048】[0048]

【比較例14】球状核(M)を用いる以外は、実施例1
6と同様に操作し、球形顆粒を得た。球形顆粒の凝集度
、コ−ティング効率の測定結果を表8に示す。
[Comparative Example 14] Example 1 except for using a spherical nucleus (M)
The procedure was repeated in the same manner as in 6 to obtain spherical granules. Table 8 shows the measurement results of the degree of agglomeration and coating efficiency of the spherical granules.

【0049】[0049]

【実施例17】実施例16と同様に素顆粒を製した後、
素顆粒をCF−360装置に入れ、エア温度60℃、ロ
−タ−回転数200rpmとし、下記組成の水性懸濁液
を15ml/minの速度で噴霧し、徐放性コ−ティン
グを行う。 水性懸濁液 Aquacoat    300g (EC水性懸濁液、30%W/V、米国FMC社製)マ
イバセット9−40  25g (グリセリン酢酸脂肪酸エステル、光洋商会(株)製)
コ−ティング終了後、60℃の乾燥機に1時間入れて、
球形顆粒を得る。
[Example 17] After producing elementary granules in the same manner as in Example 16,
The elementary granules are placed in a CF-360 apparatus, the air temperature is set to 60 DEG C., the rotor rotation speed is set to 200 rpm, and an aqueous suspension having the following composition is sprayed at a rate of 15 ml/min to form a sustained release coating. Aqueous suspension Aquacoat 300g (EC aqueous suspension, 30% W/V, manufactured by FMC, USA) Mybaset 9-40 25g (glycerin acetic acid fatty acid ester, manufactured by Koyo Shokai Co., Ltd.)
After coating, put it in a dryer at 60℃ for 1 hour.
Obtain spherical granules.

【0050】[0050]

【比較例15】比較例14と同様に素顆粒を製する。以
後、実施例17と同様に操作し、球形顆粒を得る。
[Comparative Example 15] Elementary granules were produced in the same manner as in Comparative Example 14. Thereafter, the same procedure as in Example 17 is carried out to obtain spherical granules.

【0051】[0051]

【試験例1】実施例17で得た徐放性球形顆粒約300
mg(リボフラビン10mgに相当)を軽食摂取後に、
水100mlとともに投与し、各時間毎に尿を採取して
高速液体クロマトグラフィ法により、リボフラビンを定
量し、経時的に尿中排出速度を求める(n=5)。結果
を表9に示す。
[Test Example 1] Approximately 300 sustained-release spherical granules obtained in Example 17
mg (equivalent to 10 mg of riboflavin) after a light meal,
The drug is administered with 100 ml of water, and urine is collected every hour to quantify riboflavin by high-performance liquid chromatography to determine the urinary excretion rate over time (n=5). The results are shown in Table 9.

【0052】[0052]

【試験例2】試験例1と同様に、比較例15で得た球形
顆粒について試験した結果を表9に示す。試験例1と比
べて、試験例2では排出速度のピ−クが速く、高くなっ
ており、また、消失も速い。このことは、腸内運動によ
り体内で顆粒が破壊されるため、薬物が速く溶出してし
まい、徐放性が保ちにくいことを意味している。これに
対して試験例1では徐放性を示した。なお、日本薬局方
(11局)のパドルを用いた溶出試験では、実施例17
と比較例15の球形顆粒の溶出速度にはほとんど差がな
かった。
[Test Example 2] Similar to Test Example 1, the spherical granules obtained in Comparative Example 15 were tested and the results are shown in Table 9. Compared to Test Example 1, in Test Example 2, the peak of the discharge rate was faster and higher, and the disappearance was also faster. This means that because the granules are destroyed in the body by intestinal movements, the drug dissolves quickly, making it difficult to maintain sustained release. In contrast, Test Example 1 exhibited sustained release properties. In addition, in the dissolution test using the paddle of the Japanese Pharmacopoeia (11 stations), Example 17
There was almost no difference in the elution rate of the spherical granules of Comparative Example 15 and Comparative Example 15.

【0053】[0053]

【表1】[Table 1]

【0054】[0054]

【表2】[Table 2]

【0055】[0055]

【表3】[Table 3]

【0056】[0056]

【表4】[Table 4]

【0057】[0057]

【表5】[Table 5]

【0058】[0058]

【表6】[Table 6]

【0059】[0059]

【表7】[Table 7]

【0060】[0060]

【表8】[Table 8]

【0061】[0061]

【表9】[Table 9]

【0062】[0062]

【発明の効果】適度な吸水率と高い強度を持つという特
徴を有する本発明の球状核を用いることによって、核に
薬物を含有する粉体を被覆し、さらにコ−ティング剤を
被覆して球形顆粒を作る場合において、従来の白糖を主
体とする核と比べて、顆粒同士の凝集が1/10程度に
減少し、コ−ティング効率が5%程度高い、商品価値の
高い球形顆粒を容易に製造できる。また、本発明の球状
核は、水溶性添加剤を10〜90%含有するため、従来
の結晶セルロ−スを主体とする球状核と比べて、吸水率
が抑えられ、かつ核への粉体の付着力が強いため、粉体
被覆速度が速く、また結合液量も少なくて良い。また、
本発明の球状核は崩壊せず、強度も高いので、体内に球
形顆粒を投与した場合、腸内運動による破壊を受けにく
いため、望む溶出パタ−ンが得やすい。
Effects of the Invention: By using the spherical core of the present invention, which has the characteristics of moderate water absorption and high strength, the core is coated with drug-containing powder and further coated with a coating agent to form a spherical core. When making granules, the aggregation of granules is reduced to about 1/10 compared to conventional cores made mainly of white sugar, and the coating efficiency is about 5% higher, making it easy to produce spherical granules with high commercial value. Can be manufactured. In addition, since the spherical core of the present invention contains 10 to 90% of water-soluble additives, its water absorption rate is suppressed compared to conventional spherical cores mainly made of crystalline cellulose, and the powder content of the core is reduced. Because of its strong adhesion, the powder coating speed is fast and the amount of binding liquid can be small. Also,
Since the spherical core of the present invention does not disintegrate and has high strength, when the spherical granules are administered into the body, they are less likely to be destroyed by intestinal movements, making it easier to obtain the desired elution pattern.

Claims (2)

【特許請求の範囲】[Claims] 【請求項1】  平均重合度が60〜375である結晶
セルロ−スを10〜70%および水溶性添加剤を10〜
90%含有する薬学的に不活性な球状核。
Claim 1: 10 to 70% crystalline cellulose having an average degree of polymerization of 60 to 375 and 10 to 70% of a water-soluble additive.
Pharmaceutically inactive spherical core containing 90%.
【請求項2】  請求項1の球状核、該球状核のまわり
に薬物を含有する粉体層、該粉体層のまわりに被膜層を
有する球形顆粒。
2. A spherical granule comprising a spherical core according to claim 1, a powder layer containing a drug around the spherical core, and a coating layer around the powder layer.
JP4665491A 1991-03-12 1991-03-12 Spherical nuclei and spherical granule Pending JPH04283520A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4665491A JPH04283520A (en) 1991-03-12 1991-03-12 Spherical nuclei and spherical granule

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP4665491A JPH04283520A (en) 1991-03-12 1991-03-12 Spherical nuclei and spherical granule

Publications (1)

Publication Number Publication Date
JPH04283520A true JPH04283520A (en) 1992-10-08

Family

ID=12753311

Family Applications (1)

Application Number Title Priority Date Filing Date
JP4665491A Pending JPH04283520A (en) 1991-03-12 1991-03-12 Spherical nuclei and spherical granule

Country Status (1)

Country Link
JP (1) JPH04283520A (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995034291A1 (en) * 1994-06-15 1995-12-21 Dumex-Alpharma A/S Pellets
US5618562A (en) * 1993-01-12 1997-04-08 Freund Industrial Co., Ltd. Spherical granule, production method thereof and medicinal preparation using said granule
US6171619B1 (en) * 1996-09-10 2001-01-09 Freund Industrial Co., Ltd. Spherical granule, process for producing the same, and spherical granule preparations using the same
JP2001172430A (en) * 1999-12-21 2001-06-26 Asahi Kasei Corp Spherical granule
JP2006290903A (en) * 2000-04-28 2006-10-26 Glaxo Smith Kline Kk Pharmaceutical formulation comprising carrier beads coated with a layer of valaciclovir
WO2006115198A1 (en) 2005-04-22 2006-11-02 Asahi Kasei Chemicals Corporation Porous cellulose aggregate and molding composition thereof
JP2008050284A (en) * 2006-08-23 2008-03-06 Asahi Kasei Chemicals Corp Spherical nuclear particle and method for producing spherical raw granule
WO2009066644A1 (en) * 2007-11-19 2009-05-28 Freund Corporation Spherical particle and method for producing the same
JP2009120476A (en) * 2007-10-23 2009-06-04 Fuji Chem Ind Co Ltd Spherical particle comprising calcium hydrogen phosphate
US8597686B2 (en) 2004-01-30 2013-12-03 Asahi Kasei Chemicals Corporation Porous cellulose aggregate and formed product composition comprising the same

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5618562A (en) * 1993-01-12 1997-04-08 Freund Industrial Co., Ltd. Spherical granule, production method thereof and medicinal preparation using said granule
WO1995034291A1 (en) * 1994-06-15 1995-12-21 Dumex-Alpharma A/S Pellets
US6171619B1 (en) * 1996-09-10 2001-01-09 Freund Industrial Co., Ltd. Spherical granule, process for producing the same, and spherical granule preparations using the same
JP2001172430A (en) * 1999-12-21 2001-06-26 Asahi Kasei Corp Spherical granule
JP2006290903A (en) * 2000-04-28 2006-10-26 Glaxo Smith Kline Kk Pharmaceutical formulation comprising carrier beads coated with a layer of valaciclovir
US8597686B2 (en) 2004-01-30 2013-12-03 Asahi Kasei Chemicals Corporation Porous cellulose aggregate and formed product composition comprising the same
WO2006115198A1 (en) 2005-04-22 2006-11-02 Asahi Kasei Chemicals Corporation Porous cellulose aggregate and molding composition thereof
JP2008050284A (en) * 2006-08-23 2008-03-06 Asahi Kasei Chemicals Corp Spherical nuclear particle and method for producing spherical raw granule
JP2009120476A (en) * 2007-10-23 2009-06-04 Fuji Chem Ind Co Ltd Spherical particle comprising calcium hydrogen phosphate
WO2009066644A1 (en) * 2007-11-19 2009-05-28 Freund Corporation Spherical particle and method for producing the same

Similar Documents

Publication Publication Date Title
JP2542122B2 (en) Spherical nucleus, spherical granule and method for producing the same
KR930005322B1 (en) Spherical seed cores spherical granules and process for production thereof
JP3015105B2 (en) Powder coated oral dosage form
US8709996B2 (en) Pharmaceutical treatment process using chitosan or derivative thereof
JP2002523443A (en) Omeprazole preparation
PT92616B (en) PROCESS FOR THE PREPARATION OF GRANULATES FOR MULTIPLE PARTICLES ORAL COMPOSITIONS OF CONTROLLED LIBERATION
WO1991018590A1 (en) Process for the manufacture of porous cellulose matrices
JPH0592918A (en) Nucleated powder and its production
JP3987282B2 (en) Particles coated with granulated crystalline ibuprofen
EP0625353B1 (en) Slow-release pharmaceutical composition containing a bile acid as an active ingredient
JPS6248618A (en) Slow-releasing drug preparation and production thereof
JPH04283520A (en) Spherical nuclei and spherical granule
CN1882321B (en) Pellets containing venlafaxine hydrochloride
JP2000500477A (en) Immediate release pharmaceutical composition
CA2634006C (en) Pharmaceutical sustained release compositions comprising liothyronine or the sodium salt of liothyronine
JP2000103730A (en) Medicine composition having improved feeling of administration
JP3219787B2 (en) Method for producing spherical particles
JP2007515456A (en) Coating method
CN102552190A (en) Ilaprazole enteric coated tablet and preparation method thereof
JPH05339151A (en) Sustained release oxybutynin hydrochloride preparation
JP4493769B2 (en) Spherical granules
EP0283442A1 (en) Process for the manufacture of gastro-resistant and enterosoluble small spheres of digestive enzyme and pharmaceutical preparation so obtained
JP3034592B2 (en) Oral solid preparation and production method thereof
GB2256587A (en) Acetazolamide in sustained release form
WO1999042087A2 (en) Controlled release potassium chloride pellet based pharmaceutical compositions having a high active ingredient content

Legal Events

Date Code Title Description
A02 Decision of refusal

Free format text: JAPANESE INTERMEDIATE CODE: A02

Effective date: 20020326