JPH0920689A - Granular agent and its production - Google Patents

Granular agent and its production

Info

Publication number
JPH0920689A
JPH0920689A JP19574595A JP19574595A JPH0920689A JP H0920689 A JPH0920689 A JP H0920689A JP 19574595 A JP19574595 A JP 19574595A JP 19574595 A JP19574595 A JP 19574595A JP H0920689 A JPH0920689 A JP H0920689A
Authority
JP
Japan
Prior art keywords
crystalline cellulose
granules
particle size
granular
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
JP19574595A
Other languages
Japanese (ja)
Other versions
JP4100723B2 (en
Inventor
Kazuhiro Daibu
和博 大生
Yoshihito Yaginuma
義仁 柳沼
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 JP19574595A priority Critical patent/JP4100723B2/en
Publication of JPH0920689A publication Critical patent/JPH0920689A/en
Application granted granted Critical
Publication of JP4100723B2 publication Critical patent/JP4100723B2/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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  • Biological Depolymerization Polymers (AREA)
  • Medicinal Preparation (AREA)

Abstract

PROBLEM TO BE SOLVED: To obtain granular agent having high hardness, excellent disintegrating property and extremely fine particles in a good balance, and capable of practically and efficiently producing, containing crystalline cellulose having a specific granular diameter. SOLUTION: This granular agent contains crystalline cellulose having <=10μm granular diameter in 50% integrate volume and granules having <=500μm granular diameter are made to be >=90wt.% based on whole granules. To obtain the objective granule, crystalline cellulose or a mixture of raw material powder with crystalline cellulose is mechanically ground by a method of kneading with water or a water-soluble binding solution in a planetary mixer to make a granular diameter of the crystalline cellulose having 50% integrate volume <=10μm and the resultant mixture is granulated by extrusion. As the extrusion granulating apparatus, a screw-type extruding granulator having a flat or a semi-spherical die having many holes of 0.2-0.4mmϕ hole diameter at a front face is preferable. The granular agent is preferably a fine granule. The raw material powder is a principal agent of an active component powder of a medicine and/or an auxiliary.

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、医薬品、食品、化粧
品、塗料、セラミックス、樹脂、触媒、その他の工業用
品等の分野における粒剤及びその製法に関する。より詳
しくは、本発明は、積算体積50%の粒径を10μm以
下の結晶セルロース押出造粒時に用いているので、粒剤
の硬度が高く崩壊性の良いため押出造粒しても500μ
m未満の粒子が90重量%以下と極めて微細な粒子をバ
ランス良く有する粒剤を提供できる。
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to granules in the fields of pharmaceuticals, foods, cosmetics, paints, ceramics, resins, catalysts and other industrial products, and a process for producing the same. More specifically, since the present invention uses a 50% cumulative volume particle size at the time of extrusion granulation of crystalline cellulose having a particle size of 10 μm or less, the granule has a high hardness and good disintegration, so that even if extrusion granulation is performed, the particle size is 500 μm.
It is possible to provide a granule having a fine balance of 90% by weight or less of particles less than m and extremely fine particles.

【0002】[0002]

【従来の技術】従来、粒剤中に結晶セルロースを含有さ
せると粒剤が優れた特性を示すことが知られている。例
えば、特公昭56−2047号公報には、押出造粒法で
製造される粒剤である顆粒剤・細粒が結晶セルロースを
含有することにより、崩壊が速く、高強度で粉化率が少
ないという特性を示すことが記載されている。しかし、
押出造粒法では、押出造粒時の負荷の増大により生産性
が極めて悪く、実際上直径が0.5mm以下の、硬度が
高く崩壊性の良い細粒を得ることは困難であった。
2. Description of the Related Art Conventionally, it has been known that granules exhibit excellent properties when crystalline cellulose is contained in the granules. For example, in Japanese Examined Patent Publication No. 56-2047, granules and fine particles, which are granules produced by an extrusion granulation method, contain crystalline cellulose, so that they disintegrate rapidly, have high strength, and have a low pulverization rate. It is described that the characteristic is shown. But,
In the extrusion granulation method, the productivity is extremely poor due to an increase in load during extrusion granulation, and it is difficult to obtain fine granules having a diameter of 0.5 mm or less and having high hardness and good disintegration.

【0003】[0003]

【発明が解決しようとする課題】近年、医薬品の薬効の
確実な発現が要求されてきており、硬度が高く崩壊性の
良い細粒が求められている。しかし、従来の技術ではこ
の要求を満たす細粒が得られない。本発明は、医薬品、
食品、化粧品、工業用品等の広い分野において、特に医
薬品分野において十分利用可能な細粒を提供できると共
に実用的に効率よく製造できる粒剤の製法を提供するも
のである。
In recent years, there has been a demand for reliable manifestation of the medicinal effects of pharmaceuticals, and fine particles having high hardness and good disintegration are required. However, conventional techniques cannot provide fine particles that satisfy this requirement. The present invention is a pharmaceutical product,
The present invention provides a method for producing granules that can provide fine granules that can be sufficiently utilized in a wide range of fields such as foods, cosmetics, and industrial products, particularly in the field of pharmaceuticals, and that can be practically and efficiently manufactured.

【0004】[0004]

【課題を解決するための手段】本発明者らは、上記従来
技術の課題を種々検討した結果、積算体積50%の粒径
を10μm以下の結晶セルロース押出造粒時に用いてい
るので、粒剤の硬度が高く崩壊性の良いため押出造粒し
ても500μm未満の粒子が90重量%以下と極めて微
細な粒子をバランス良く有する粒剤を提供できる。
DISCLOSURE OF THE INVENTION As a result of various studies on the above-mentioned problems of the prior art, the present inventors have used a particle size of 50% in cumulative volume for extrusion granulation of crystalline cellulose of 10 μm or less. Since it has a high hardness and good disintegration property, it is possible to provide a granule having an extremely fine particle of 90% by weight or less of particles less than 500 μm even in extrusion granulation.

【0005】即ち、本発明は: 積算体積50%の粒径が10μm以下である結晶セ
ルロースを含有し、500μm未満の粒子が90重量%
以上である粒剤を提供する。また、 結晶セルロース、もしくは原料粉体と結晶セルロー
スの混合物を機械的に磨砕し、結晶セルロースの積算体
積50%の粒径を10μm以下として押出造粒する記
載の粒剤の製法を提供する。
That is, the present invention contains: crystalline cellulose having an integrated volume of 50% and a particle size of 10 μm or less, and 90% by weight of particles less than 500 μm.
The above-mentioned granules are provided. Further, there is provided a method for producing a granule, which comprises mechanically grinding crystalline cellulose or a mixture of a raw material powder and crystalline cellulose, and extruding and granulating the crystalline cellulose with an integrated volume of 50% to a particle size of 10 μm or less.

【0006】以下、本発明を詳細に説明する。本発明の
粒剤は、粒剤中に含まれる結晶セルロースの積算体積5
0%の粒径が10μm以下、好ましくは0.1〜10μ
m、より好ましくは0.3〜8μmであることが必要で
ある。すなわち、本発明の効果をより高めるためには積
算体積50%の粒径は8μm以下であることが好まし
い。本発明の粒剤の粒径の下限は特に限定されないが、
実用的な生産性を達成できるのは現在0.3μm程度ま
でである。
Hereinafter, the present invention will be described in detail. The granules of the present invention have a cumulative volume of crystalline cellulose contained in the granules of 5
0% particle size is 10 μm or less, preferably 0.1-10 μm
m, and more preferably 0.3 to 8 μm. That is, in order to further enhance the effects of the present invention, the particle size with an integrated volume of 50% is preferably 8 μm or less. The lower limit of the particle size of the granules of the present invention is not particularly limited,
At present, practical productivity can be achieved up to about 0.3 μm.

【0007】また、粒径が10μmを超えると押出造粒
時の負荷が増大して生産性が極めて悪く実用に耐えな
い。更に、粒径が10μmを越えると、結晶セルロース
粒子同士の結合性が弱くなり、細粒の強度が低下し、ま
た結合剤の過度の添加が必要となり細粒の崩壊性が悪く
なる。本発明の粒剤は、ロータップ式篩振盪機によりJ
IS標準篩を用い粒剤50gを20分間篩分した時の粒
剤の粒度分布において500μm未満の粒子が90重量
%以上であることが必要である。
If the particle size exceeds 10 μm, the load during extrusion granulation increases, resulting in extremely poor productivity and no practical use. Further, if the particle size exceeds 10 μm, the binding property between the crystalline cellulose particles becomes weak, the strength of the fine particles is lowered, and the excessive addition of the binder is required, and the disintegrating property of the fine particles is deteriorated. The granules of the present invention can be used in a J
In the particle size distribution of the granules obtained by sieving 50 g of the granules for 20 minutes using an IS standard sieve, it is necessary that 90% by weight or more of particles are less than 500 μm.

【0008】このような粒度分布を有する粒剤を用いる
ことにより医薬品の薬局での調剤、患者の服用がし易く
なる等の利点がある。過去に市販結晶セルロース「アビ
セル」PH−101を含有し、500μm未満の粒子が
90重量%以下の細粒が得られているが、このものでは
比較例5で示すようにこの細粒中の結晶セルロースの積
算体積50%の粒径は10μmを越えており、細粒強度
が低下し細粒の崩壊が悪い。
The use of granules having such a particle size distribution has advantages such as preparation of a drug at a pharmacy and ease of taking by a patient. In the past, commercially available crystalline cellulose "Avicel" PH-101 was contained, and fine particles having a particle size of less than 500 [mu] m of 90% by weight or less were obtained. However, as shown in Comparative Example 5, crystals in the fine particles were obtained. The particle size of the cumulative volume of 50% of cellulose exceeds 10 μm, and the strength of fine particles is lowered, and the collapse of fine particles is poor.

【0009】また、これまで組成物中の結晶セルロース
の粒径を規定したものとして、特公昭55−16563
号公報に、β−1、4グルカン粉末(結晶セルロース)
と水溶性粘結剤を加えて練合した時、練合物中のβ−
1、4グルカン粉末の粒子径が5〜20μm以下(セイ
シン企業(株)製ミクロンフォトサイザー使用)である
錠剤組成物の記載がある。該公報における結晶セルロー
スの粒径に関する作用については、錠剤中での結晶セル
ロースの成形性を高めることについての記載があるのみ
である。また、該公報には、粒径が5〜20μm以下の
β−1、4グルカン粉末を含む練合物を造粒した例とし
て破砕型造粒機(不二パウダル(株)製「フラッシュミ
ル」FL−200型5mmφスクリーン)による造粒が
記載されているのみである。従って、これまでに粒径が
10μm以下の結晶セルロースを用いた押出造粒法によ
り、押出性を著しく向上し、得られた細粒の硬度を高
め、崩壊を速くすることが可能でことは知られていなか
った。
Further, the particle size of crystalline cellulose in the composition has been defined so far, as disclosed in Japanese Examined Patent Publication No. 55-16563.
Japanese Patent Publication, β-1,4 glucan powder (crystalline cellulose)
When a water-soluble binder is added and kneaded, β-
There is a description of a tablet composition in which the particle size of 1,4 glucan powder is 5 to 20 μm or less (using Micron Photosizer manufactured by Seishin Enterprise Co., Ltd.). Regarding the effect of the particle size of crystalline cellulose in this publication, there is only description about enhancing the moldability of crystalline cellulose in tablets. Further, in this publication, as an example of granulating a kneaded product containing β-1,4 glucan powder having a particle size of 5 to 20 μm or less, a crush type granulator (“Flash Mill” manufactured by Fuji Paudal Co., Ltd.). Only granulation with FL-200 type 5 mmφ screen) is described. Therefore, it is known that it is possible to remarkably improve the extrudability, increase the hardness of the obtained fine granules, and accelerate the disintegration by the extrusion granulation method using crystalline cellulose having a particle diameter of 10 μm or less. It wasn't done.

【0010】本発明の粒剤は具体的には以下の方法によ
り製造される。すなわち、結晶セルロース、もしくは原
料粉体と結晶セルロースの混合物を機械的に磨砕し、結
晶セルロースの積算体積50%の粒径を10μm以下と
して押出造粒することによって得られる。本発明でいう
結晶セルロースとは、木材パルプ、精製リンター、再生
繊維等のセルロース系素材を酸加水分解、アルカリ酸化
分解、酵素分解、スチームエクスプロージョン分解等に
よって解重合した後精製した重合度30〜375(銅安
法で測定)の水湿セルロース及びこれを乾燥したセルロ
ースである。また、パルプ等を鉱酸により軽度に加水分
解した後粉砕したセルロースであっても良い。
The granule of the present invention is specifically manufactured by the following method. That is, it can be obtained by mechanically grinding crystalline cellulose or a mixture of raw material powder and crystalline cellulose, and extruding and granulating the crystalline cellulose with a cumulative volume of 50% having a particle size of 10 μm or less. The crystalline cellulose as referred to in the present invention is a degree of polymerization of 30 to which is refined after depolymerization of cellulosic materials such as wood pulp, refined linter, and regenerated fiber by acid hydrolysis, alkaline oxidative decomposition, enzymatic decomposition, steam explosion decomposition and the like. 375 (measured by copper ammonium method) wet cellulose and dried cellulose. Alternatively, it may be cellulose that is obtained by lightly hydrolyzing pulp or the like with a mineral acid and then pulverizing the pulp.

【0011】本発明でいう原料粉体とは、主剤または補
助剤または主剤と補助剤とを含むものをいう。主剤とし
ては、医薬品薬効成分粉末の他、農薬成分粉末、肥料成
分粉末、飼料成分粉末、食品成分粉末、化粧品成分粉
末、色材粉末、金属粉末、セラミックス粉末、触媒粉
末、香料粉末、界面活性剤粉末等が挙げられる。
The raw material powder as referred to in the present invention means one containing a main agent or an auxiliary agent or a main agent and an auxiliary agent. As the main ingredient, in addition to powders of medicinal and pharmaceutical ingredients, agricultural chemical powders, fertilizer powders, feed powders, food powders, cosmetic powders, coloring powders, metal powders, ceramic powders, catalyst powders, fragrance powders, surfactants Powder etc. are mentioned.

【0012】医薬品薬効成分としては、例えばビタミン
製剤(例、ビタミンA、ビタミンB2、ビタミンB6、
ビタミンB12、ビタミンC、ビタミンD、ビタミン
E、ニコチン酸アミド、パントテン酸カルシウム等)、
胃腸薬(例、炭酸マグネシウム、炭酸水素ナトリウム、
メタケイ酸アルミン酸マグネシウム、合成ヒドロタルサ
イト、沈降炭酸カルシウム、酸化マグネシウム、ロート
エキス、ビオジアスターゼ、リパーゼAP、アルジオキ
サ等)、カゼ薬(例、アセトアミノフェン、アスピリ
ン、マレイン酸クロルフェニラミン、リン酸ジヒドロコ
デイン、ノスカピン、塩酸メチルエフェドリン、カフェ
イン、セラペプターゼ、塩化リゾチーム等)、
Examples of medicinal properties of pharmaceuticals include vitamin preparations (eg, vitamin A, vitamin B2, vitamin B6,
Vitamin B12, vitamin C, vitamin D, vitamin E, nicotinamide, calcium pantothenate, etc.),
Gastrointestinal drugs (eg magnesium carbonate, sodium bicarbonate,
Magnesium aluminometasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide, funnel extract, biodiastase, lipase AP, aldioxa, etc., case drug (eg, acetaminophen, aspirin, chlorpheniramine maleate, phosphate) Dihydrocodeine, noscapine, methylephedrine hydrochloride, caffeine, serrapeptase, lysozyme chloride, etc.),

【0013】鎮咳去痰薬(例、塩酸クロペラスチン、臭
化水素酸デキストロメトルファン、テオフィリン、グア
ヤコールスルホン酸カリウム等)、解熱鎮痛薬(例、エ
テンザミド、サリチルアミド、ブロムワレリル尿素、塩
酸チノリジン、無水カフェイン等)、抗生物質製剤
(例、セファレキシン、アモキシシリン、塩酸ピブメシ
リナム、塩酸セフォチアム等)、精神神経用剤(例、ジ
アゼパム、ロラゼパム、オキサゾラム、レオドパ等)、
鎮痙剤(例、臭化水素酸スコポラミン、塩酸ジフェンヒ
ドラミン、塩酸パパベリン、アミノフィリン等)、抗骨
粗鬆症剤(例、イプリフラボン等)、血圧降下剤(例、
塩酸デラプリル、カプトプリル、塩酸マニジピン等)、
血管拡張剤(例、モルシドミン、ニフェジピン、硝酸イ
ソソルビド、塩酸ジルチアゼム等)、アレルギー用薬
(例、アンレキサノクス、トラニラスト等)、催眠鎮静
剤(例、エスタゾラム、ニトラゼパム、フェノバルビタ
ールナトリウム等)、利尿薬(例、イソソルビド、フロ
セミド等)、利胆剤(例、トレピブトン、ウルソデスオ
キシコール酸等)等が用いられる。
Antitussive expectorants (eg, cloperastine hydrochloride, dextromethorphan hydrobromide, theophylline, potassium guaiacol sulfonate, etc.), antipyretic analgesics (eg, etenzamid, salicylamide, bromvalerylurea, tinoridine hydrochloride, anhydrous caffeine, etc.) ), Antibiotic preparations (eg, cephalexin, amoxicillin, pibmecillinum hydrochloride, cefotianum hydrochloride, etc.), neuropsychotic agents (eg, diazepam, lorazepam, oxazolam, leodopa, etc.),
Antispasmodics (eg, scopolamine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride, aminophylline, etc.), anti-osteoporosis agents (eg, ipriflavone, etc.), antihypertensive agents (eg,
Delapril hydrochloride, captopril, manidipine hydrochloride, etc.),
Vasodilators (eg, molsidomine, nifedipine, isosorbide dinitrate, diltiazem hydrochloride, etc.), drugs for allergies (eg, amlexanox, tranilast, etc.), hypnotics (eg, estazolam, nitrazepam, phenobarbital sodium, etc.), diuretics (eg,) , Isosorbide, furosemide, etc.), choleretic agents (eg, trepivtone, ursodesoxycholic acid, etc.) and the like are used.

【0014】補助剤としては希釈剤、結合剤、崩壊剤等
一般に主剤と共に用いられるものが挙げられる。該希釈
剤には、例えば、糖類(例、乳糖、グラニュー糖、コー
ンスターチ等)、糖アルコール類(例、マンニトール
等)及びその誘導体(例、ヒドロキシプロピルセルロー
ス等)、無機物類(例、タルク等)等が用いられる。該
結合剤にはヒドロキシプロピルセルロース、ヒドロキシ
プロピルメチルセルロース、メチルセルロース、デキス
トリン、アルファ化デンプン等が用いられる。
Examples of the auxiliary agent include diluents, binders, disintegrants and the like, which are generally used together with the main agent. Examples of the diluent include sugars (eg, lactose, granulated sugar, corn starch, etc.), sugar alcohols (eg, mannitol, etc.) and their derivatives (eg, hydroxypropyl cellulose, etc.), inorganic substances (eg, talc, etc.) Etc. are used. Hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextrin, pregelatinized starch and the like are used as the binder.

【0015】該崩壊剤にはカルボキシメチルセルロース
カルシウム、カルボキシメチルセルロース、カルメロー
スナトリウムの架橋重合物(クロスカルメロースナトリ
ウム)、クロスポビドン、コーンスターチ等が用いられ
る。上述の補助剤は、主剤の種類や使用目的を考慮して
適宜選択すればよい。本発明でいう機械的な磨砕とは湿
式・乾式の別を問わず、ボールミル、ハンマーミル、ビ
ーズミル、チューブミル、振動ミル等の粉砕形式による
粉砕またはニーダー、プラネタリーミキサー、コロイド
ミル、リボンブレンダー等の汎用の練合機、磨砕機械ま
たはエクストルーダー等の押出造粒機等を用いての粉砕
により、結晶セルロースを微細化することをいう。
As the disintegrant, carboxymethyl cellulose calcium, carboxymethyl cellulose, a crosslinked polymer of carmellose sodium (croscarmellose sodium), crospovidone, corn starch and the like are used. The above-mentioned auxiliary agent may be appropriately selected in consideration of the type of main agent and the purpose of use. The mechanical grinding referred to in the present invention, whether wet or dry, may be crushed by a crushing method such as a ball mill, a hammer mill, a bead mill, a tube mill, a vibration mill or a kneader, a planetary mixer, a colloid mill, a ribbon blender. It means that the crystalline cellulose is micronized by pulverization using a general-purpose kneader such as, a grinding machine or an extrusion granulator such as an extruder.

【0016】好ましくはニーダー、プラネタリーミキサ
ー等の練合機中で水、または水溶性の結合液と共に練合
するのがよいが、この場合の水の量または水溶性結合液
の量としては、原料粉体と結晶セルロースの混合物が水
または水溶性結合液と練合された時、練合物がフニキュ
ラー、乃至キャピラリー領域(化学工学24、230
(1960)参照)を満足しているものでなければなら
ない。特にプラネタリーミキサー(例、品川工業所製5
−DM型)による磨砕では、本発明の実施例で示す結晶
セルロースを使用する場合、5分の短時間でも練合物中
の結晶セルロースの粒径を10μm以下に微細化できる
ので好ましい。
It is preferable to knead with water or a water-soluble binding solution in a kneader such as a kneader or a planetary mixer. In this case, the amount of water or the amount of water-soluble binding solution is When the mixture of the raw material powder and the crystalline cellulose is kneaded with water or the water-soluble binding liquid, the kneaded product is a funicular or a capillary region (chemical engineering 24, 230).
(See (1960)). Especially planetary mixers (eg Shinagawa Kogyo 5
In the case of using the crystalline cellulose shown in the examples of the present invention, the particle size of the crystalline cellulose in the kneaded product can be reduced to 10 μm or less by milling with (DM type), which is preferable.

【0017】プラネタリーミキサー等の練合機による練
合で結晶セルロースの積算体積50%の粒径が10μm
以下になるのは、理由は定かではないが結晶セルロース
の諸性質、例えば重合度、飽和吸水量、保水量が関係し
ていると思われ、適度な範囲の重合度、飽和吸水量、保
水量を有し、粒子間空隙が比較的狭い結晶セルロースを
用いると積算体積50%の粒径が10μm以下になり易
い。押出造粒に用いる装置やその運転操作等は公知の技
術を適用すれば良いが、装置については好ましくは一軸
または複数軸を有するスクリュー型押出造粒機であっ
て、前面に0.1〜1.0mmφ(好ましくは0.1〜
0.5mmφ更に好ましくは0.2〜0.4mmφ)の
範囲の孔径の孔を多数有する平板もしくは半球面上のダ
イを備えたスクリュー型押出造粒機が良く、市販されて
いる装置としては不二パウダル(株)製「ドームグラ
ン」「ツインドームグラン」等が挙げられる。
By kneading with a kneading machine such as a planetary mixer, the particle size of crystalline cellulose at an integrated volume of 50% is 10 μm.
Although the reason is not clear, the following properties are considered to be related to various properties of crystalline cellulose, such as the degree of polymerization, the saturated water absorption, and the water retention amount. If crystalline cellulose having a relatively narrow void between particles is used, the particle size with an integrated volume of 50% tends to be 10 μm or less. A known technique may be applied to an apparatus used for extrusion granulation and its operation, but the apparatus is preferably a screw type extrusion granulator having a single shaft or a plurality of shafts, and 0.1 to 1 is provided on the front surface. 0.0 mmφ (preferably 0.1 to
0.5 mmφ, more preferably 0.2 to 0.4 mmφ) A screw type extrusion granulator equipped with a flat plate or a hemispherical die having a large number of holes with a diameter in the range of 0.2 mm to 0.4 mmφ is good, and is not suitable as a commercially available device. Examples include “Dome Gran” and “Twin Dome Gran” manufactured by Nipaudal Co., Ltd.

【0018】本発明の粒剤は顆粒剤、散剤、細粒等であ
るが、好ましくは細粒であり、カプセル剤、錠剤、流動
食等の用途に用いることができる。本発明でいう積算体
積50%の粒径とは結晶セルロースを水に分散させ、堀
場製作所(株)製レーザー回折式粒度分布測定装置LA
−500型で測定する時(屈折率の設定;標準、分散
液;1%Tween20溶液、超音波分散時間2分)の
体積基準粒度分布における積算体積50%の粒径であ
る。ここでいう粒径とは粒剤10個についての粒径の平
均値を指す。
The granules of the present invention are granules, powders, fine granules and the like, but are preferably fine granules and can be used for capsules, tablets, liquid foods and the like. The particle size with an integrated volume of 50% referred to in the present invention means that a crystalline cellulose is dispersed in water, and a laser diffraction particle size distribution analyzer LA manufactured by Horiba, Ltd. is used.
The particle size is the cumulative volume of 50% in the volume-based particle size distribution when measured with a -500 type (setting of refractive index; standard, dispersion; 1% Tween20 solution, ultrasonic dispersion time 2 minutes). The particle size as used herein refers to an average value of particle sizes for 10 granules.

【0019】[0019]

【実施例】以下に実施例を示し、本発明を更に詳しく説
明する。まず実施例、比較例で用いる結晶セルロース
(A)〜(D)のサンプルの調製について以下に示す。
製造例及び実施例における各種測定は以下の通りに行っ
た。 飽和吸水量;得られた結晶セルロース粉末の乾燥重
量5gに対して純水を滴下しながらヘラで練り、結晶セ
ルロース表面にわずかに水が滲み出る時を終点としてそ
の時の純水滴下量(ml)を結晶セルロース粉末乾燥重
量5gで除した値である。 保水量:結晶セルロース粉末の乾燥重量2gに純水
30mlを加え十分分散させ、遠心分離(7400G、
10分間)を行い、上澄みを除いた時の結晶セルロース
が保持できる純水の量(ml)を測定し、その量を結晶
セルロース粉末の乾燥重量2gで除した値である。
The present invention will be described in more detail with reference to the following examples. First, the preparation of samples of crystalline cellulose (A) to (D) used in Examples and Comparative Examples is shown below.
Various measurements in the production examples and the examples were performed as follows. Saturated water absorption; Kneading with a spatula while dripping pure water to 5 g of the dry weight of the obtained crystalline cellulose powder, when the water slightly exudes on the surface of crystalline cellulose, the end point is the pure water dropping amount (ml). Is a value obtained by dividing the crystalline cellulose powder dry weight by 5 g. Water retention amount: 30 ml of pure water was added to 2 g of dry weight of crystalline cellulose powder, sufficiently dispersed, and centrifuged (7400 G,
This is a value obtained by measuring the amount (ml) of pure water that the crystalline cellulose can hold when the supernatant was removed, and dividing the amount by 2 g of the dry weight of the crystalline cellulose powder.

【0020】 粒剤中の結晶セルロースの積算体積5
0%の粒径:粒剤500mgに純水0.8mlを加え、
さらに10N水酸化ナトリウム0.2ml、2M酢酸
1.6ml、純水25ml、10%グルコアミラーゼを
加えて37℃で2時間撹拌した。次いで、遠心分離(7
400G、10分間)し、上澄みを除いた後、残渣に純
水4ml、エタノール16mlを加え、遠心分離(74
00G、10分間)した。遠心分離後、上澄みを除き希
酸1ml、純水30mlを加え100℃30分間加温し
た。さらに遠心分離(7400G、10分間)し、上澄
みを除いた残渣に純水30mlを加え希アルカリで中和
後、再度遠心分離(7400G、10分間)し、上澄み
を除き、残渣を純水に分散し、レーザー回折式粒度分布
測定装置LA−500型(堀場製作所(株)製)にて積
算体積50%の粒径を測定した。
Integrated volume of crystalline cellulose in granules 5
0% particle size: 0.8 ml of pure water was added to 500 mg of granules,
Further, 0.2 ml of 10N sodium hydroxide, 1.6 ml of 2M acetic acid, 25 ml of pure water and 10% glucoamylase were added, and the mixture was stirred at 37 ° C. for 2 hours. Then, centrifuge (7
After 400 G for 10 minutes) and removing the supernatant, 4 ml of pure water and 16 ml of ethanol were added to the residue, followed by centrifugation (74
00G, 10 minutes). After centrifugation, the supernatant was removed, 1 ml of dilute acid and 30 ml of pure water were added, and the mixture was heated at 100 ° C. for 30 minutes. After further centrifugation (7400 G, 10 minutes), the supernatant was removed, 30 ml of pure water was added to the residue, neutralized with a dilute alkali, and then centrifuged again (7400 G, 10 minutes), the supernatant was removed, and the residue was dispersed in pure water. Then, the particle size of an integrated volume of 50% was measured with a laser diffraction type particle size distribution measuring device LA-500 type (manufactured by Horiba, Ltd.).

【0021】 離水の目視時期:押出の最中の離水を
目視で観察した。 粒度分布:表中の目開きを有するJIS標準篩を用
いて粒剤50gを20分間ロータップ式篩分機で篩分し
た時の粒度分布である。 摩損試験:粒剤10gを精秤し粒径は直径3mm、
100個と共に15分間摩損試験し、粉化した重量を測
定し粒剤重量10gで除して摩損度〔粉化率(%)〕を
算出する。
Visualization of water separation: Water separation was visually observed during extrusion. Particle size distribution: This is a particle size distribution when 50 g of granules are sieved with a low tap type sieving machine for 20 minutes using a JIS standard sieve having openings in the table. Abrasion test: 10 g of granules are precisely weighed and the particle size is 3 mm,
Abrasion test is performed with 100 pieces for 15 minutes, the weight of powder is measured, and the weight is divided by 10 g of the weight of granules to calculate the degree of abrasion [dusting rate (%)].

【0022】 崩壊時間:粒剤を355μmの篩で篩
い、篩上の残留物0.1gを網目の開き0.3μmの網
を有する補助筒6個に取る他は顆粒の崩壊試験に準じて
行い、試料の残留物を認めなくなる時間を測定した。
Disintegration time: Performed according to the disintegration test of granules except that the granules are sieved through a 355 μm sieve, and 0.1 g of the residue on the sieve is taken in 6 auxiliary cylinders having a mesh of 0.3 μm mesh. The time when no residue of the sample was observed was measured.

【0023】<結晶セルロースの製造> (製造例1)市販DPパルプ(a)1kgを細断し、1
%塩酸溶液中で加圧下120℃、30分間加水分解し、
得られた酸不要残渣を濾過洗浄し、風乾後、ハンマーミ
ルで解砕し60号(目開き250μm)の篩で粗大物を
除き、篩下積算分布の粒子径D50が32μm、重合度1
30(銅安法で測定)、飽和吸水量1.66、保水量1
75%の結晶セルロース(A)を650g得た。
<Production of Crystalline Cellulose> (Production Example 1) 1 kg of commercially available DP pulp (a) was chopped into 1 pieces.
Hydrolyzed in a 30% hydrochloric acid solution under pressure at 120 ° C. for 30 minutes,
The acid-free residue thus obtained was washed by filtration, air-dried, then crushed with a hammer mill and coarse particles were removed using a No. 60 (mesh opening 250 μm) sieve, and the particle size D 50 of the cumulative distribution under the sieve was 32 μm, and the degree of polymerization was 1
30 (measured by copper ammonium method), saturated water absorption 1.66, water retention 1
650 g of 75% crystalline cellulose (A) was obtained.

【0024】(製造例2)市販DPパルプ(b)1kg
を細断し、10%塩酸溶液中で加圧下105℃20分間
加水分解し、得られた酸不要残渣を濾過洗浄し、風乾
後、ハンマーミルで解砕し60号(目開き250μm)
の篩で粗大物を除き、篩下積算分布の粒子径D50が35
μm、重合度180(銅安法で測定)、飽和吸水量2.
18、保水量221%の結晶セルロース(B)を600
g得た。
(Production Example 2) 1 kg of commercially available DP pulp (b)
Shredded and hydrolyzed in a 10% hydrochloric acid solution under pressure at 105 ° C. for 20 minutes, the resulting acid-free residue is filtered, washed, air-dried, and then crushed with a hammer mill to produce No. 60 (opening 250 μm)
The sieve to remove coarse material, the particle diameter D 50 of the cumulative under sieve distribution 35
μm, degree of polymerization 180 (measured by copper ammonium method), saturated water absorption 2.
18, 600% crystalline cellulose (B) with a water retention capacity of 221%
g was obtained.

【0025】(製造例3)市販DPパルプ(c)1kg
を細断し、9%塩酸溶液中で加圧下105℃20分間加
水分解し、得られた酸不要残渣を濾過洗浄し、風乾後、
ハンマーミルで解砕しミクロンセパレーターで30μm
以上の粗大粒子を除き、篩下積算分布の粒子径D50が2
9μm、重合度140(銅安法で測定)、飽和吸水量
1.16、保水量135%の結晶セルロース(C)を5
40g得た。
(Production Example 3) Commercially available DP pulp (c) 1 kg
Was shredded, hydrolyzed in a 9% hydrochloric acid solution under pressure at 105 ° C. for 20 minutes, the obtained acid-free residue was filtered, washed, air-dried,
30 μm with a micron separator after crushing with a hammer mill
Excluding the above coarse particles, the particle size D 50 of the cumulative distribution under the sieve is 2
5 μm of crystalline cellulose (C) having 9 μm, a degree of polymerization of 140 (measured by copper ammonium method), a saturated water absorption of 1.16 and a water retention of 135%.
40 g was obtained.

【0026】(製造例4)市販DPパルプ(d)1kg
を細断し、9%塩酸溶液中で加圧下105℃20分間加
水分解し、得られた酸不要残渣を濾過洗浄し、風乾後、
ハンマーミルで解砕しミクロンセパレーターで30μm
以上の粗大粒子を除き、篩下積算分布の粒子径D50が1
3μm、重合度140(銅安法で測定)、飽和吸水量
1.12、保水量140%の結晶セルロース(D)を6
00g得た。
(Production Example 4) 1 kg of commercially available DP pulp (d)
Was shredded, hydrolyzed in a 9% hydrochloric acid solution under pressure at 105 ° C. for 20 minutes, the obtained acid-free residue was filtered, washed, air-dried,
30 μm with a micron separator after crushing with a hammer mill
Excluding the above coarse particles, the particle size D 50 of the cumulative distribution under the sieve is 1
3 μm, degree of polymerization 140 (measured by copper ammonium method), saturated water absorption 1.12, water retention 140% crystalline cellulose (D) 6
00g was obtained.

【0027】<粒剤の製造> (実施例1)製造例1の結晶セルロース(A)300g
をプラネタリーミキサー(品川工業所製5−DM型、パ
ドルはビーター型使用)内に仕込み、加水量(仕込み重
量に対する純水の体積;ml/g−仕込み)を下表のよ
うにし、63rpmで5分間練合し、練合物の一部を水
に分散させ、レーザー回折式粒度分布測定装置で練合物
中の結晶セルロース(A)の積算体積50%の粒径を測
定し、粒径を算出した。
<Production of Granules> (Example 1) 300 g of crystalline cellulose (A) of Production Example 1
Was charged in a planetary mixer (5-DM type manufactured by Shinagawa Kogyo Seisakusho, using a beater type paddle), the amount of water added (volume of pure water relative to the charged weight; ml / g-charged) was set to 63 rpm at 63 rpm. Kneading for 5 minutes, a part of the kneaded product is dispersed in water, and the particle size of crystalline cellulose (A) in the kneaded product at an integrated volume of 50% is measured by a laser diffraction type particle size distribution measuring device. Was calculated.

【0028】また、これらの練合物を0.3mmφの押
出ダイを備える押出造粒機(不二パウダル(株)製「ド
ームグラン」DG−L1型)で造粒した。この方法によ
り得られた造粒物の重量を測定し1分間当たりの排出量
を測定した(この場合、練合物はホッパーに一度に投入
した)。押出状態、押出された造粒物同士の付着性、ダ
イ表面からの水の排出(離水)は目視により観察を行っ
た。その結果を表1に示す。また得られた粒剤の粒度分
布を表2に示す。
These kneaded materials were granulated by an extrusion granulator ("Dome Grand" DG-L1 type manufactured by Fuji Paudal Co., Ltd.) equipped with an extrusion die of 0.3 mmφ. The weight of the granulated product obtained by this method was measured and the discharge amount per minute was measured (in this case, the kneaded product was put into the hopper at one time). The extrusion state, the adhesion between the extruded granules, and the discharge (water separation) of water from the die surface were visually observed. Table 1 shows the results. Table 2 shows the particle size distribution of the obtained granules.

【0029】[0029]

【表1】 [Table 1]

【0030】[0030]

【表2】 [Table 2]

【0031】(比較例1)製造例1の結晶セルロース
(A)の代わりに製造例2の結晶セルロース(B)を用
い、それ以外は実施例1と同様に操作した。その結果を
表3に示す。また得られた粒剤の粒度分布を表4に示
す。
Comparative Example 1 The crystalline cellulose (B) of Production Example 2 was used in place of the crystalline cellulose (A) of Production Example 1, and the same operation as in Example 1 was carried out. Table 3 shows the results. Table 4 shows the particle size distribution of the obtained granules.

【0032】[0032]

【表3】 [Table 3]

【0033】[0033]

【表4】 [Table 4]

【0034】(比較例2)製造例1の結晶セルロース
(A)の代わりに製造例3の結晶セルロース(C)を用
い、それ以外は実施例1と同様に操作した。その結果を
表5に示す。
Comparative Example 2 The crystalline cellulose (C) of Production Example 3 was used in place of the crystalline cellulose (A) of Production Example 1, and the same operation as in Example 1 was carried out. The results are shown in Table 5.

【表5】 [Table 5]

【0035】(比較例3)製造例1の結晶セルロース
(A)の代わりに製造例4の結晶セルロース(D)を用
い、それ以外は実施例1と同様に操作した。結果を表6
に示す。
Comparative Example 3 The crystalline cellulose (D) of Production Example 4 was used in place of the crystalline cellulose (A) of Production Example 1, and the same operation as in Example 1 was carried out. Table 6 shows the results
Shown in

【表6】 [Table 6]

【0036】(実施例2)製造例1の結晶セルロース
(A)150gと200メッシュ乳糖(DMV製)10
5g、コーンスターチ(日澱化学製)45gとをビニー
ル袋内で混合した後、その混合物をプラネタリーミキサ
ー(品川工業所製5−DM型、パドルはビーター型使
用)内に仕込み、加水量(仕込み重量に対する純水の体
積;ml/g−仕込み)は表7記載のようにし、63r
pmで5分間練合し、0.3mmφの押出ダイを備える
押出造粒機(不二パウダル(株)製「ドームグラン」D
G−L1型)で造粒した。
(Example 2) 150 g of crystalline cellulose (A) of Production Example 1 and 200 mesh lactose (manufactured by DMV) 10
After mixing 5 g and 45 g of corn starch (manufactured by Nippon Starch Chemical Co., Ltd.) in a plastic bag, the mixture was charged in a planetary mixer (5-DM type manufactured by Shinagawa Kogyosho, using a beater type paddle), and the amount of water added (prepared) The volume of pure water relative to the weight; ml / g-preparation) was as shown in Table 7, and was 63r.
Extrusion granulator equipped with 0.3 mmφ extrusion die (“Dome Gran” D manufactured by Fuji Paudal Co., Ltd.)
Granulation (G-L1 type).

【0037】また、押出造粒により得られた造粒物の重
量を測定し1分間当たりの排出量を測定した(この場
合、練合物はホッパーに一度に投入した)。押出状態、
押出された造粒物同士の付着性、ダイ表面からの水の排
出(離水)は目視により観察を行った。その結果を表7
に示す。また得られた粒剤の粒度分布を表8に示す。ま
た、摩損度試験の結果を表9に示す。
Further, the weight of the granulated product obtained by extrusion granulation was measured to measure the discharge amount per minute (in this case, the kneaded product was put into the hopper at once). Extruded state,
The adhesion between the extruded granules and the discharge (water separation) of water from the die surface were visually observed. Table 7 shows the results.
Shown in Table 8 shows the particle size distribution of the obtained granules. The results of the friability test are shown in Table 9.

【0038】[0038]

【表7】 [Table 7]

【0039】[0039]

【表8】 [Table 8]

【0040】[0040]

【表9】 [Table 9]

【0041】(比較例4)製造例1記載の結晶セルロー
ス(A)の代わりに製造例2記載の結晶セルロース
(B)を用いる以外は実施例2と同様に操作した。その
結果を表10に示す。また得られた粒剤の粒度分布を表
11に示す。また摩損度試験の結果を表12に示す。
Comparative Example 4 The procedure of Example 2 was repeated except that the crystalline cellulose (B) described in Production Example 2 was used instead of the crystalline cellulose (A) described in Production Example 1. The results are shown in Table 10. Table 11 shows the particle size distribution of the obtained granules. Table 12 shows the results of the friability test.

【表10】 [Table 10]

【0042】[0042]

【表11】 [Table 11]

【0043】[0043]

【表12】 [Table 12]

【0044】(実施例3)アセトアミノフェン(山本化
学製)500g、結晶セルロース(A)240g、20
0メッシュ乳糖(DMV製)700g、コーンスターチ
(日澱化学製)300gとをビニール袋内で混合した
後、その混合物をプラネタリーミキサー(品川工業所製
5−DM型、パドルはビーター型使用)内に仕込み、加
水量(仕込み重量に対する純水の体積;ml/g−仕込
み)は表13記載のようにし、63rpmで5分間練合
し、0.3mmφの押出ダイを備える押出造粒機(不二
パウダル(株)製「ドームグラン」DG−L1型)で造
粒した。乾燥後の粒剤中の500μm未満の粒子は90
重量%以上であった。
Example 3 Acetaminophen (Yamamoto Chemical Co., Ltd.) 500 g, crystalline cellulose (A) 240 g, 20
After mixing 700 g of 0 mesh lactose (DMV) and 300 g of corn starch (Nippon Kagaku) in a plastic bag, the mixture is placed in a planetary mixer (Shinagawa Kogyo 5-DM type, paddle using beater type). The amount of water added (volume of pure water relative to the charged weight; ml / g-charged) was as shown in Table 13, kneaded at 63 rpm for 5 minutes, and an extrusion granulator equipped with an extrusion die of 0.3 mmφ ( It was granulated by "Dome Gran" DG-L1 type manufactured by Ni-Powdal Co., Ltd. 90 particles less than 500 μm in the dried granules
% By weight or more.

【0045】粒剤中の結晶セルロースの積算体積50%
の粒径の測定は実施例2と同様にして行った。粒剤の摩
損度試験及び、崩壊試験を行った結果を表13に示す。
Integrated volume of crystalline cellulose in granules 50%
The particle size of was measured in the same manner as in Example 2. Table 13 shows the results of the friability test and the disintegration test of the granules.

【表13】 [Table 13]

【0046】(比較例5)アセトアミノフェン(山本化
学製)500g、結晶セルロース「アビセル」PH−1
01、240g、200メッシュ乳糖(DMV製)70
0g、コーンスターチ(日澱化学製)300g結合剤H
PC−EFP(信越化学工業製)75gとをビニール袋
内で混合した後、その混合物をプラネタリーミキサー
(品川工業所製5−DM型、パドルはビーター型使用)
内に仕込み、加水量(仕込み重量に対する純水の体積;
ml/g−仕込み)は表中記載のようにし、63rpm
で5分間練合し、0.3mmφの押出ダイを備える押出
造粒機(不二パウダル(株)製「ドームグラン」DG−
L1型)で造粒した。乾燥後の粒剤中の500μm未満
の粒子は90重量%以上であった。
Comparative Example 5 Acetaminophen (Yamamoto Chemical Co., Ltd.) 500 g, crystalline cellulose "Avicel" PH-1
01, 240 g, 200 mesh lactose (DMV) 70
0 g, cornstarch (manufactured by Nippon Starch Chemical Co., Ltd.) 300 g Binder H
After mixing 75 g of PC-EFP (manufactured by Shin-Etsu Chemical Co., Ltd.) in a plastic bag, the mixture is used as a planetary mixer (5-DM type manufactured by Shinagawa Kogyosho, beater type paddle is used).
The amount of water added to the inside (volume of pure water with respect to the charged weight;
ml / g-preparation) as described in the table, 63 rpm
Extrusion granulator equipped with 0.3 mmφ extrusion die (“Dome Gran” DG- manufactured by Fuji Paudal Co., Ltd.)
Granulation (L1 type). The particles of less than 500 μm in the dried granules were 90% by weight or more.

【0047】粒剤中の結晶セルロースの積算体積50%
の粒径の測定は実施例2と同様にして行った。粒剤の摩
損度試験し、崩壊試験を行った結果を表14に示す。
Integrated volume of crystalline cellulose in granules 50%
The particle size of was measured in the same manner as in Example 2. Table 14 shows the results of the friability test and the disintegration test of the granules.

【表14】 [Table 14]

【0048】[0048]

【発明の効果】以上の通り、本発明では、積算体積50
%の粒径を10μm以下の結晶セルロース押出造粒時に
用いているので、粒剤の硬度が高く崩壊性の良いため押
出造粒しても500μm未満の粒子が90重量%以下と
極めて微細な粒子をバランス良く有する粒剤を提供でき
る。
As described above, in the present invention, the cumulative volume is 50
% Is used at the time of extrusion granulation of crystalline cellulose having a particle size of 10 μm or less, and the hardness of the granule is high and the disintegration property is good. A granule having a good balance can be provided.

Claims (2)

【特許請求の範囲】[Claims] 【請求項1】 積算体積50%の粒径が10μm以下で
ある結晶セルロースを含有し、500μm未満の粒子が
90重量%以上であることを特徴とする粒剤。
1. A granule containing crystalline cellulose having an integrated volume of 50% and a particle size of 10 μm or less, and 90% by weight or more of particles having a particle size of less than 500 μm.
【請求項2】 結晶セルロース、もしくは原料粉体と結
晶セルロースの混合物を機械的に磨砕し、結晶セルロー
スの積算体積50%の粒径を10μm以下として押出造
粒することを特徴とする請求項1記載の粒剤の製法。
2. A crystalline cellulose or a mixture of a raw material powder and a crystalline cellulose is mechanically ground, and extrusion granulation is performed with a cumulative volume of crystalline cellulose of 50% having a particle size of 10 μm or less. 1. The method for producing the granule according to 1.
JP19574595A 1995-07-10 1995-07-10 Granule and its production method Expired - Lifetime JP4100723B2 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002040011A1 (en) * 2000-11-16 2002-05-23 Ajinomoto Co., Inc. Process for producing drug granules containing branched amino acids
WO2009066644A1 (en) 2007-11-19 2009-05-28 Freund Corporation Spherical particle and method for producing the same
JP2013028594A (en) * 2011-06-20 2013-02-07 Astellas Pharma Inc Medicinal composition for oral administration
JP2017184669A (en) * 2016-04-06 2017-10-12 オーストリッチファーマ株式会社 Ostrich yellow egg antibody-containing candy production method and ostrich yellow egg antibody-containing candy

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002040011A1 (en) * 2000-11-16 2002-05-23 Ajinomoto Co., Inc. Process for producing drug granules containing branched amino acids
JP2002154958A (en) * 2000-11-16 2002-05-28 Ajinomoto Co Inc Method for producing pharmaceutical granule containing branched-chain amino acid
WO2009066644A1 (en) 2007-11-19 2009-05-28 Freund Corporation Spherical particle and method for producing the same
JP2013028594A (en) * 2011-06-20 2013-02-07 Astellas Pharma Inc Medicinal composition for oral administration
JP2017184669A (en) * 2016-04-06 2017-10-12 オーストリッチファーマ株式会社 Ostrich yellow egg antibody-containing candy production method and ostrich yellow egg antibody-containing candy

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