JPH0549649B2 - - Google Patents
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- Publication number
- JPH0549649B2 JPH0549649B2 JP1225284A JP22528489A JPH0549649B2 JP H0549649 B2 JPH0549649 B2 JP H0549649B2 JP 1225284 A JP1225284 A JP 1225284A JP 22528489 A JP22528489 A JP 22528489A JP H0549649 B2 JPH0549649 B2 JP H0549649B2
- Authority
- JP
- Japan
- Prior art keywords
- weight
- sieve
- krestin
- minutes
- granulation
- 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.)
- Expired - Lifetime
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- 108010001062 polysaccharide-K Proteins 0.000 claims description 53
- 238000002360 preparation method Methods 0.000 claims description 48
- 238000005469 granulation Methods 0.000 claims description 39
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- 108090000623 proteins and genes Proteins 0.000 claims description 34
- 102000004169 proteins and genes Human genes 0.000 claims description 34
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- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
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- 239000000594 mannitol Substances 0.000 description 2
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- FYGDTMLNYKFZSV-WFYNLLPOSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,3s,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-WFYNLLPOSA-N 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
- Peptides Or Proteins (AREA)
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は抗腫瘍剤として使用されているかわら
たけ由来の蛋白多糖体の新しい経口投与製剤に関
し更に詳しくは、投薬時の飲みづらさ、例えば口
内付着及び容量が多いことによる等を原因とする
服用困難の問題点を解消したかわらたけ由来の蛋
白多糖体の粒状製剤に関する。Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a new oral preparation of a protein polysaccharide derived from Kawaratake that is used as an antitumor agent. The present invention relates to a granular preparation of a protein polysaccharide derived from Kawaratake that solves the problems of difficulty in taking it due to oral adhesion and large volume.
（従来の技術）
近年、各種のきのこや、菌体あるいは菌の生産
代謝物から得られた物質が、優れた抗腫瘍効果
や、細菌やウイルスに対する防御作用を有する事
が知られている。例えばシイタケの子実体より抽
出された多糖体に関する発明（特公昭47−37002
号、特公昭49−484号）、人型結核菌から抽出され
るリポ多糖体を有効成分とする抗腫瘍剤に関する
発明（特開昭57−18619号）が提案されている。
本発明者らも、先にかわらたけから抽出される蛋
白多糖体を有効成分とする抗腫瘍剤、血糖降下剤
等に関する発明（特公昭51−36322号、特公昭52
−44380号、特公昭55−23271号、特公昭56−
14275号、特公昭56−14276号、特公昭56−25312
号、特公昭57−40159号、特公昭59−32480号、特
開昭60−45532号、特開昭60−45533号）を提案し
た。(Prior Art) In recent years, it has been known that substances obtained from various mushrooms, bacterial bodies, or metabolites produced by bacteria have excellent antitumor effects and protective effects against bacteria and viruses. For example, an invention related to polysaccharides extracted from the fruiting bodies of shiitake mushrooms (Japanese Patent Publication No. 47-37002)
Japanese Patent Publication No. 49-484), and an invention relating to an antitumor agent containing lipopolysaccharide extracted from Mycobacterium tuberculosis as an active ingredient (Japanese Patent Application Laid-Open No. 18619/1982).
The present inventors also previously made inventions related to anti-tumor agents, hypoglycemic agents, etc. containing protein polysaccharides extracted from Kawaratake mushrooms as active ingredients (Japanese Patent Publication No. 36322-1983, Japanese Patent Publication No. 52-36322,
−44380, Special Publication No. 55-23271, Special Publication No. 1983-
No. 14275, Special Publication No. 14276, Special Publication No. 56-25312
No. 1, Special Publication No. 57-40159, Special Publication No. 59-32480, Japanese Patent Application Publication No. 60-45532, and Japanese Patent Application Publication No. 60-45533).
これらの内、抗腫瘍活性を有する物質の多く
は、皮内注射や静脈内投与により活性を示すこと
が知られており、臨床的にも皮内或いは静脈内投
与の注射剤として用いられている。 Among these substances, many of the substances with antitumor activity are known to show activity when administered intradermally or intravenously, and are also clinically used as injections for intradermal or intravenous administration. .
他方、かわらたけ由来の蛋白多糖体の一種のク
レスチンは皮内や静脈内投与により薬効を示すこ
とが報告されているが、経口投与によつても抗腫
瘍活性を示すことが特長であり、臨床的にも経口
投与製剤として用いられている。 On the other hand, Krestin, a type of protein polysaccharide derived from Kawaratake, has been reported to exhibit medicinal efficacy when administered intradermally or intravenously, but it also exhibits antitumor activity when administered orally. It is also used as an oral preparation.
クレスチンの薬効発現のメカニズムについては
種々の可能性が提示されているが、中でも、クレ
スチンの消化器管内に存在する免疫担当細胞への
賦活作用が重要であると指摘されてい。この様な
作用には、クレスチンの持つレクチン様活性が重
要であると考えられ、この様なクレスチン様活性
の発現には、クレスチンの溶解の状態、つまり消
化器管内でのクレスチンの分子の広がりや、レク
チン様活性を有するクレスチンの分子内の活性部
位を中心とする２次元、３次元的な分子の広がり
や、立体構造の状態が重要と考えられる。またク
レスチンが溶解した時に共存する物質によつて
は、レクチン様活性が阻害される事も知られてお
り、他の抗腫瘍剤や低分子の薬剤とは異なつた作
用機作、および活性発現能を有している。クレス
チンの様な特性を有する薬剤の投与剤形として
は、クレスチンを水に溶解した溶解液を服用する
事が最も望ましいと考えられるが、水溶液は保存
の問題、輸送錠の問題等実際の臨床上の適用には
数多くの問題を生ずる。そこで、現在、臨床で用
いられているクレスチンの剤形は、微粉末の散剤
である。 Various possibilities have been proposed regarding the mechanism by which Krestin exerts its medicinal effects, and among them, the activation effect of Krestin on immunocompetent cells present in the gastrointestinal tract has been pointed out to be important. The lectin-like activity of Krestin is thought to be important for this action, and the expression of Krestin-like activity depends on the dissolution state of Krestin, that is, the spread of Krestin molecules in the gastrointestinal tract. It is thought that the two-dimensional and three-dimensional spread of the molecule centering on the active site within the molecule of Krestin, which has lectin-like activity, and the state of the three-dimensional structure are important. It is also known that the lectin-like activity is inhibited by the substances that coexist when Krestin is dissolved. have. As a dosage form for drugs with properties similar to Krestin, it is considered most desirable to take a solution in which Krestin is dissolved in water. The application of this poses a number of problems. Therefore, the dosage form of Crestin currently used clinically is a fine powder.
クレスチンの臨床投与量は、癌患者に対して１
日３ｇ以上である。現行のクレスチン散剤が微粉
末であり、且つかさ密度が小さいため、服用時に
口内に付着する、容量が多く一度に飲めない等の
理由で大量の水を服用する必要があり、臨床適用
上数多くの問題点をかかえている。更に、その独
特の色調と、臭いのため、患者が薬をクレスチン
であると判断し、自らが癌だと知る等の問題が生
じており、クレスチンに適した剤形の開発が望ま
れていた。 The clinical dose of Krestin is 1 for cancer patients.
3g or more per day. The current Krestin powder is a fine powder and has a small bulk density, so it sticks to the mouth when taken, and the volume is too large to drink at once, requiring a large amount of water to be taken. I'm having problems. Furthermore, due to its unique color tone and odor, problems such as patients identifying the drug as Krestin and realizing that they have cancer have arisen, and it has been desired to develop a dosage form suitable for Krestin. .
一般に、投薬を簡便化するためには、微粉末を
適当な結合剤や崩壊剤を用いて顆粒化したり、錠
剤に成形したり、粉末をカプセルに封入する事
が、行なわれている。しかし、クレスチンの場合
には、前述した様に、経口投与後の消化器管内に
おける溶解状態、すなわち、クレスチンの分子構
造の広がり等が、その薬物活性を支配すると考え
られ、剤形による活性の変化について、特に注意
する事が必要である。 Generally, in order to simplify administration, fine powders are granulated using a suitable binder or disintegrant, formed into tablets, or encapsulated in capsules. However, in the case of Krestin, as mentioned above, the state of dissolution in the gastrointestinal tract after oral administration, that is, the spread of the molecular structure of Krestin, etc., is thought to control its drug activity, and the activity changes depending on the dosage form. It is necessary to be especially careful about this.
例えば、朝鮮にんじんの抽出エキスや他の漢方
薬の顆粒や錠剤、カプセル剤が多く市販されてい
るが、これらの薬物は、種々の多糖類と低分子物
質の混合物であり、比較的水に対する溶解性や分
散性が優れている他、顆粒剤や錠剤中に含まれる
活性成分の含有率が低いため、このような薬物の
製剤設計は比較的容易である。しかし、蛋白質を
主成分とする医薬品、例えば、酵素製剤や、血液
製剤の剤形については、特別な配慮が必要とされ
ている。つまり蛋白質あるいは蛋白質を含む多糖
類は、熱や圧力あるいは配合する物質により、そ
の活性が大きく変化することがしばしばあるから
である。 For example, many granules, tablets, and capsules of Korean carrot extract and other Chinese herbal medicines are commercially available, but these drugs are mixtures of various polysaccharides and low-molecular substances, and are relatively water-soluble. In addition to excellent dispersibility, formulation design of such drugs is relatively easy because the content of active ingredients in granules and tablets is low. However, special considerations are required regarding the dosage forms of pharmaceuticals containing protein as a main component, such as enzyme preparations and blood preparations. In other words, the activity of proteins or polysaccharides containing proteins often changes significantly depending on heat, pressure, or the substances they are mixed with.
これらの物質の適正な剤形を提供するために
は、従来の低分子化合物や合成医薬品の場合には
見られなかつた種々の問題がある。たとえば顆粒
を作る時には、種々の熱処理による活性の低下や
不溶化による失活等が問題となる。これらの問題
点を解決する方法として、種々の糖類やアミノ
酸、無機化合物を多量混合し、活性成分である蛋
白質を含む多糖体の安定化をはかる事が行なわれ
る。それ故に、活性成分である蛋白質や、蛋白質
を含む多糖体の含量は、低下せざるをえない。 In order to provide appropriate dosage forms for these substances, there are various problems that have not been seen in the case of conventional low-molecular-weight compounds and synthetic drugs. For example, when making granules, there are problems such as reduction in activity due to various heat treatments and deactivation due to insolubilization. As a method to solve these problems, it is attempted to stabilize polysaccharides containing proteins, which are active ingredients, by mixing large amounts of various saccharides, amino acids, and inorganic compounds. Therefore, the content of active ingredients such as protein and protein-containing polysaccharide must be reduced.
蛋白質が結合した多糖体であるクレスチンのよ
うな物質の剤形とその活性との関係についての研
究、或いは技術報告はいままでほとんどみられな
かつた。 Until now, there have been almost no studies or technical reports on the relationship between the dosage form of a substance such as Krestin, which is a polysaccharide bound to proteins, and its activity.
クレスチンは、平均分子量が100000以上であ
り、その組成が、単純な多糖体ではなく、蛋白質
が結合している蛋白多糖体であり、又、活性発現
に必要な投与量が比較的大であるため、薬効を変
化させないでかつ投薬容量を増やさない、という
相反する課題を解決して製剤化する事が重要であ
る。 Krestin has an average molecular weight of 100,000 or more, its composition is not a simple polysaccharide, but a protein polysaccharide with proteins bound to it, and the dose required to express its activity is relatively large. It is important to formulate a drug by solving the contradictory issues of not changing the drug's efficacy and not increasing the dosage.
即ち、クレスチンは蛋白質が結合した高分子量
の多糖体であるので、経口投与した場合の薬効発
現メカニズムを考慮する時、その製剤化には従来
の製剤技術の単純な大様では、解決しえない難し
い技術的課題が残されている。 In other words, since Krestin is a high-molecular-weight polysaccharide bound to proteins, when considering the mechanism of drug efficacy when administered orally, it is difficult to formulate a drug using simple conventional formulation techniques. Difficult technical challenges remain.
つまり、投薬時の飲みづらさの原因である微粉
末であり、容量が大きいという問題点を解決し、
かつ生物活性を損わない製剤の形と、製剤化の方
法を確立する事が重要である。すなわち、微粉末
である事の飲みづらさを解決するためには、特定
の粒子径、或いは特定の粒度分布をもつ粒子であ
る事が必要であり、投薬の容量が大きく飲みづら
いという問題を解決するためには、できるだけ粒
子のかさ密度を上げることが必要である。更に、
前述したごとく、このような粒子は、投薬した
後、消化器管内ですみやかに溶解し、クレスチン
の特長とする作用を発揮出来るものでなければな
らない。 In other words, it solves the problem of being a fine powder and having a large volume, which makes it difficult to swallow when administering medication.
It is also important to establish a formulation form and formulation method that does not impair biological activity. In other words, in order to solve the difficulty of swallowing due to fine powder, it is necessary that the particles have a specific particle size or a specific particle size distribution, which solves the problem of the large volume of medication making it difficult to swallow. In order to achieve this, it is necessary to increase the bulk density of the particles as much as possible. Furthermore,
As mentioned above, such particles must be able to dissolve quickly in the gastrointestinal tract after administration and exhibit the characteristic effects of Krestin.
クレスチンの様な蛋白多糖体や蛋白質を粉末化
する方法としては、噴霧乾燥法、いわゆるスプレ
ードライヤーを用いた粉末の製造法を例示し得
る。この方法により得られた粉末は、乾燥時の熱
処理条件、風量、溶液の供給速度等、スプレード
ライヤーの操作条件により、クレスチンの薬理活
性が損なわれる事もあるが、熱風温度、風量、溶
液の供給速度を調整することにより、薬理活性を
損う事なくクレスチンを粉末化する事が出来る。 An example of a method for powdering a protein polysaccharide or protein such as Krestin is a spray drying method, a method for producing powder using a so-called spray dryer. The powder obtained by this method may lose the pharmacological activity of Krestin depending on the operating conditions of the spray dryer, such as the heat treatment conditions during drying, the air volume, and the solution supply rate. By adjusting the speed, Krestin can be powdered without compromising its pharmacological activity.
この様な、スプレードライ法により得られたク
レスチンの粉末は、１〜100μｍ径の大きさの中
空粒子であり、表面積が大であるが、粒子表面に
吸着した空気や、内包する空気が水との接触（ぬ
れ）を妨げ溶解か抑制される。また、このスプレ
ードライ法により得られた粉末のかさ密度は通常
0.30ｇ／cm3以下であり、この微粉末を投薬する
と、前述の様な問題点が生ずる。 Crestin powder obtained by the spray-drying method is a hollow particle with a diameter of 1 to 100 μm and has a large surface area, but the air adsorbed on the particle surface and the air contained therein may be mixed with water. prevents contact (wetting) and dissolves or is suppressed. In addition, the bulk density of the powder obtained by this spray drying method is usually
It is less than 0.30 g/cm 3 , and when this fine powder is administered, the above-mentioned problems occur.
そこで、クレスチンの粉末化の方法はもちろ
ん、造粒化の方法について鋭意検討し、得られた
粒子の特性と薬理活性を調べ、前述したクレスチ
ンの薬理活性を損う事なく、投薬時の困難さを解
決すべく検討を重ねた。 Therefore, we have carefully studied not only the method of powdering Krestin but also the method of granulating it, and investigated the characteristics and pharmacological activity of the obtained particles. We have repeatedly considered this issue in order to resolve the issue.
すなわち粉体の性状を変える事なく、かさ密度
を上げる方法について種々の検討を行なつた結
果、打錠機（スラツグマシン）或いはローラーコ
ンパクタを用いてスプレードライ粉末を圧縮し、
粉砕（以下重質化粉末と略称す）することが有用
である事を見出した。 In other words, as a result of various studies on how to increase the bulk density without changing the properties of the powder, we compressed the spray-dried powder using a tablet machine (slug machine) or roller compactor.
It has been found that pulverization (hereinafter abbreviated as heavy powder) is useful.
更に、この重質化粉末を用いて、薬物のバイ
オ・アベイラビリテイーを変化させる事なく、投
薬が容易な剤形について検討を行なつた。 Furthermore, using this heavy powder, we investigated a dosage form that would be easy to administer without changing the bioavailability of the drug.
投薬が容易な剤形としては、微粉末を適当な崩
壊剤、結合剤、賦形剤等の如き添加物と混合して
造粒する方法が知られているが、クレスチンの様
の独特な作用機作すなわち消化器管内での溶解・
分散状態が、そのものの薬理活性を左右する場合
には、薬効評価をも含めた巾広い検討が必要であ
り、後述の実施例で示すごとく造粒品の水に対す
る溶解特性、粒子の大きさ、かさ密度等の物理的
な性状の他、造粒時に添加する添加物の種類及び
含量が重要な因子であることが判つた。 As a dosage form that is easy to administer, it is known to mix fine powder with additives such as suitable disintegrants, binders, excipients, etc. and granulate it, but Mechanism: dissolution in the gastrointestinal tract
If the dispersion state affects the pharmacological activity of the product, a wide range of studies including evaluation of its medicinal efficacy are required. It has been found that in addition to physical properties such as bulk density, the type and content of additives added during granulation are important factors.
一方、造粒方法には、押出造粒法、流動造粒
法、転動造粒法等があるが、それぞれの製造法に
対応した添加物の選定、造粒条件の検討も必要で
ある。 On the other hand, granulation methods include extrusion granulation, fluidized granulation, rolling granulation, etc., and it is also necessary to select additives and consider granulation conditions corresponding to each manufacturing method.
本発明者らはスプレードライ粉末或いはそれを
ローラコンパクタ又は打錠機（スラツグマシン）
で重質化した重質化粉末、或いは凍結乾燥又は蒸
発乾固して得たクレスチン粉末を造粒原料として
用いて添加物、粒度、かさ密度、溶解性及び製造
法の検討、及び動物実験による薬理活性の発現状
況、更には、臨床における投薬の容易さについて
検討した結果、50重量％以上90重量％未満のクレ
スチンを含有し、且つ流動造粒法、押出造粒法又
は転動造粒法による造粒法によつて造粒した特定
の粒度分布の粒状製剤が水に対する溶出性が高
く、生体に投与した場合の薬理学的な活性が全く
損われなく、且つクレスチンスプレードライ粉末
及び現行のクレスチン市販品に見られる、飲みづ
らさ、例えば口内に付着し且つ容量が多くて一度
に飲めないといつた投薬の困難さを有していない
ことを見出し、これらの知見に基づいて本発明を
完成するに至つた。 The inventors have prepared spray-dried powder using a roller compactor or tablet machine (slug machine).
Using heavy powder obtained by weighting or freeze-drying or evaporation-drying powder as a granulation raw material, we investigated additives, particle size, bulk density, solubility, and manufacturing method, and conducted animal experiments. As a result of examining the expression of pharmacological activity and the ease of clinical administration, we found that products containing Krestin in an amount of 50% by weight or more and less than 90% by weight, and that were processed using fluidized granulation, extrusion granulation, or rolling granulation. Granular preparations with a specific particle size distribution granulated by the granulation method have high dissolution properties in water, do not impair pharmacological activity when administered to living organisms, and are similar to Krestin spray-dried powder and current It was discovered that Krestin does not have the difficulty of taking the drug, which is seen in commercially available products, such as the fact that it sticks to the mouth and is too large to drink at once. Based on these findings, the present invention was developed. It was completed.
（問題点を解決するための手段）
本発明の粒状製剤は、かわらたけ由来の蛋白多
糖体50重量％以上90重量％未満から成り、そのか
さ密度が0.30〜0.80ｇ／cm3で、パドル法に準ずる
溶出試験１における水に対するその溶解時間が４
分以上30分未満である。更に溶出試験２における
溶解時間が15分以内、その粒度分布は10号篩を通
過し、12号篩に残留する量が全重量の５重量％以
下で、200号篩を通過する量が全重量の10重量％
以下のものであることが好ましい。(Means for Solving the Problems) The granular preparation of the present invention is composed of 50% by weight or more and less than 90% by weight of protein polysaccharide derived from Kawaratake, has a bulk density of 0.30 to 0.80 g/cm 3 , and is prepared using the paddle method. The dissolution time in water in dissolution test 1 according to
Minutes or more but less than 30 minutes. Furthermore, the dissolution time in dissolution test 2 is within 15 minutes, the particle size distribution is such that it passes through No. 10 sieve, the amount remaining on No. 12 sieve is 5% by weight or less of the total weight, and the amount that passes through No. 200 sieve is 5% by weight or less of the total weight. 10% by weight of
The following are preferred.
本発明のかわらたけ由来の蛋白多糖体は粒状製
剤中に50重量％以上90重量％未満、好ましくは75
重量％以上90重量％未満である。 The protein polysaccharide derived from Kawaratake of the present invention is contained in the granular preparation in an amount of 50% by weight or more and less than 90% by weight, preferably 75% by weight or more, but less than 90% by weight.
% by weight or more and less than 90% by weight.
本発明のかわらたけ由来の蛋白多糖体とは、か
わらたけ属に属する担子菌を培養して得られる菌
糸体、培養物（ブロス）又は子実体の、熱水又は
アルカル性水溶液による抽出物で、約18〜38％の
蛋白質を含み、分子量が5000以上（超遠心分離測
定法）のものである。 The protein polysaccharide derived from Kawaratake of the present invention is an extract of mycelium, culture (broth), or fruiting body obtained by culturing a basidiomycete belonging to the genus Kawaratake, using a hot water or alkaline aqueous solution. It contains about 18-38% protein and has a molecular weight of 5000 or more (according to ultracentrifugation measurement).
更に詳しくは、本発明に記載の蛋白多糖体は、
例えば特公昭51−36322号公報、特公昭56−14274
号公報（U.S.Patent No.4202969）、特公昭56−
14276号公報（U.S.Patent No.41410578）、特公
昭56−39288号公報（U.S.Patent No.4268505）
及びU.S.Patent No.4051314などに記載されてい
る方法で得られた物質であり、かわらたけ属に属
する担子菌を培養して得られる菌糸体、培養物
（ブロス）又は子実体の熱水又はアルカル性水溶
液による抽出物であつて、約18〜38％の蛋白質を
含み、5000以上（超遠心分離測定法）の分子量、
例えば5000〜300000（超遠心分離測定法）の分子
量を有するものである。 More specifically, the protein polysaccharide according to the present invention is
For example, Special Publication No. 51-36322, Special Publication No. 56-14274
US Patent No. 4202969, Special Publication No. 1987-
Publication No. 14276 (US Patent No. 41410578), Special Publication No. 56-39288 (US Patent No. 4268505)
It is a substance obtained by the method described in US Patent No. 4051314, etc., and is a substance obtained by culturing basidiomycetes belonging to the genus Kawaratake, using hot water or alkaline water of mycelium, culture (broth), or fruiting body. It is an aqueous extract containing about 18-38% protein, with a molecular weight of 5000 or more (ultracentrifugation measurement method),
For example, it has a molecular weight of 5,000 to 300,000 (ultracentrifugation measurement method).
本発明のかわらたけ由来の蛋白多糖体のうち、
かわらたけ菌糸体［FERM−P2412］に由来の、
ある蛋白多糖体は、クレスチンという商品名で市
販されているものであり［最近の新薬、第28集14
〜16ページ（1977年）、及び第29集96〜101ページ
（1978年）、医薬品要覧第６版、1346ページ（昭和
54年５月）薬業時報社発行、医療薬日本医薬品集
第７版240ページ（1983年）薬業時報社発行参
照］、その性状の一端を示せば次のとおりである。 Among the protein polysaccharides derived from Kawaratake of the present invention,
Derived from Kawaratake mycelium [FERM-P2412],
A certain protein polysaccharide is commercially available under the trade name Krestin [Recent New Drugs, Volume 28, 14
-16 pages (1977), and Volume 29, pages 96-101 (1978), Pharmaceutical Handbook, 6th edition, page 1346 (Showa
May 1954) Published by Yakugyo Jihosha, see Medical Drugs Japan Pharmaceutical Collection, 7th edition, p. 240 (1983) Published by Yakugyo Jihosha] Some of its properties are as follows.
主要画分の糖部分はβ−Ｄ−グルカンで、この
グルカン部分の構造は１→３、１→４、および１
→６結合を含む分枝構造で窒素含量が３〜６％の
蛋白質を含む多糖体であつて、蛋白質の構成アミ
ノ酸は、アスパラギン酸、グルタミン酸等の酸性
アミノ酸とバリン、ロイシン等の中性アミノ酸が
多く、リジン、アルギニン等の塩基性アミノ酸は
少ない、水に可溶で、メタノール、ピリジン、ク
ロロホルム、ベンゼン、ヘキサンには殆んど溶け
ない。約120℃から徐々に分解する。 The sugar moiety of the main fraction is β-D-glucan, and the structures of this glucan moiety are 1→3, 1→4, and 1.
→It is a polysaccharide containing protein with a branched structure containing 6 bonds and a nitrogen content of 3 to 6%.The amino acids that make up the protein are acidic amino acids such as aspartic acid and glutamic acid, and neutral amino acids such as valine and leucine. It is soluble in water, with a small amount of basic amino acids such as lysine and arginine, and almost insoluble in methanol, pyridine, chloroform, benzene, and hexane. Gradually decomposes from about 120℃.
上述の通り、該クレスチン（登録商標）は、抗
腫瘍剤として既に社会に提供されており、極めて
低毒性で、安全な物質である。 As mentioned above, Krestin (registered trademark) has already been provided to society as an antitumor agent, and is a safe substance with extremely low toxicity.
クレスチンの粉末化方法としては種々の方法が
挙げられるが、以下に述べるスプレードライ法は
個々の粒子の活性を損うことなく簡単に粉末化す
ることが可能であり、クレスチンの粉末化にはス
プレードライ法が好ましい。 There are various methods for powdering Krestin, but the spray drying method described below allows easy powdering without impairing the activity of individual particles. A dry method is preferred.
［スプレードライ法］
クレスチン水溶液（固形分濃度：10重量％）を
スプレードライヤー（二口社製、ASO 410型）
を用いて、熱風の入口温度140〜180℃、出口温度
70〜120℃、熱風量6M3／分、アトマイザー回転
数10000〜20000rpm、クレスチン水溶液の供給量
５〜10／分の条件下で噴霧乾燥してスプレード
ライ粉末を得る。得られたスプレードライ粉末の
かさ密度は0.15〜0.30ｇ／cm3である。[Spray drying method] Krestin aqueous solution (solid content concentration: 10% by weight) was dried using a spray dryer (manufactured by Futakuchi Co., Ltd., ASO 410 type).
Using hot air inlet temperature 140~180℃, outlet temperature
Spray drying is carried out under the conditions of 70 to 120°C, hot air flow rate of 6 M 3 /min, atomizer rotation speed of 10,000 to 20,000 rpm, and Krestin aqueous solution supply rate of 5 to 10 min. to obtain a spray-dried powder. The bulk density of the spray-dried powder obtained is 0.15-0.30 g/cm 3 .
本発明の出発原量のかわらたけ由来の蛋白多糖
体としては、上述のスプレードライ粉末の他、ロ
ーラーコンパクタ又はスラツグマシンを用いてス
プレードライ粉末を圧密化した重質化粉末を例示
し得る。 In addition to the above-mentioned spray-dried powder, examples of the starting material of the protein polysaccharide derived from Kawaratake in the present invention include a heavy powder obtained by compacting the spray-dried powder using a roller compactor or a slug machine.
［ローラーコンパクタを用いた造粒法］
ローラーコンパクタを用いてスプレードライ粉
末をロール圧0.3〜４トン／cm、好ましくは0.5〜
３トン／cmで圧縮して重質化し、製粒機を用いて
粒状化（重質化粉末）する方法である。この方法
は繰り返して、例えば２〜７回、好ましくは３〜
６回行なうことが好ましく、この場合のロール圧
は0.5〜1.4トン／cmが好ましい。[Pelletization method using a roller compactor] Spray-dried powder using a roller compactor at a roll pressure of 0.3 to 4 tons/cm, preferably 0.5 to
This is a method in which the material is compressed at a rate of 3 tons/cm to make it heavier, and then granulated (heavy-weighted powder) using a granulator. This method may be repeated, e.g. 2 to 7 times, preferably 3 to 7 times.
It is preferable to carry out 6 times, and in this case, the roll pressure is preferably 0.5 to 1.4 tons/cm.
［打錠機（スラツグマシン）を用いた造粒法］
打錠機（スラツグマシン）を用いてスプレード
ライ粉末を打錠圧２〜15トンで圧縮して重質化す
る方法である。得られた重質化物を製粒機を用い
て粒状化（重質化粉末）する。[Pelletization method using a tablet machine (slug machine)] This is a method in which spray-dried powder is compressed using a tablet machine (slug machine) at a compression pressure of 2 to 15 tons to make it heavier. The obtained heavy material is granulated (heavy powder) using a granulator.
必要に応じて、かわらたけ由来の蛋白多糖体に
添加物を加えて重質化粉末として用いても良い。
また添加物を加えた重質化粉末はそのまま粒状製
剤として用いても良い。 If necessary, additives may be added to the protein polysaccharide derived from Kawaratake and used as a heavy powder.
Further, the heavy powder to which additives have been added may be used as it is as a granular preparation.
本発明の添加物は崩解剤、結合剤として作用す
る。添加物の量は粒状製剤中に10重量％を超え50
重量％以下、好ましくは10重量％を超え25重量％
以下である。添加物の量が50重量％を超えると、
１回の投薬量が大きくなり、飲みづらくなるので
好ましくない。 The additive of the present invention acts as a disintegrant and a binder. The amount of additive exceeds 10% by weight in the granular formulation50
% by weight or less, preferably more than 10% by weight and 25% by weight
It is as follows. If the amount of additive exceeds 50% by weight,
This is undesirable because the dosage per dose becomes large and difficult to swallow.
添加物としては、グルコース、マンノース、白
糖等の糖類、マンニトール等の糖アルコール、ア
ビセル、ヒドロキシプロピルセルロース等のセル
ロース系化合物、デンプン類、寒天、ゼラチン、
アラビアゴム、ポリビニルピロリドン等が挙げら
れ、これらの中で、糖類、セルロース系化合物及
びデンプン類が好ましい。特に、白糖、ヒドロキ
シプロピルセルロース、及びデンプンがかわらた
け由来の蛋白多糖体の薬理活性を損なうことな
く、粒状製剤の崩壊性又は溶解性をスプレードラ
イ粉末より向上させ得るので好ましい。 Additives include sugars such as glucose, mannose, and white sugar, sugar alcohols such as mannitol, cellulose compounds such as Avicel and hydroxypropylcellulose, starches, agar, gelatin,
Examples include gum arabic and polyvinylpyrrolidone, and among these, saccharides, cellulose compounds and starches are preferred. In particular, white sugar, hydroxypropylcellulose, and starch are preferred because they can improve the disintegration or solubility of the granular preparation compared to spray-dried powder without impairing the pharmacological activity of the protein polysaccharide derived from Kawaratake.
本発明の粒状製剤のかさ密度は0.30〜0.80ｇ／
cm3、好ましくは0.35〜0.75ｇ／cm3である。かさ密
度が0.30ｇ／cm3未満である粒状製剤は飲みづらい
事の他、水に分散させた特粒子がくつつき合つて
大きなゲル状の塊となり溶解性が悪くなる。かさ
密度が0.80ｇ／cm3を超える粒状製剤の製造は困難
である。 The bulk density of the granular preparation of the present invention is 0.30 to 0.80 g/
cm 3 , preferably 0.35 to 0.75 g/cm 3 . Granular preparations with a bulk density of less than 0.30 g/cm 3 are not only difficult to swallow, but also have poor solubility as special particles dispersed in water stick together, forming large gel-like lumps. It is difficult to produce granular formulations with a bulk density greater than 0.80 g/cm 3 .
本発明の粒状製剤のパドル法に準ずる溶出試験
（溶出試験１）における水に対する可溶性画分の
完全溶解時間は、４分以上30分未満、好ましくは
４〜20分である。完全溶解時間が30分以上である
と、薬物のバイオ・アベイラビリテイ（生物学的
利用率）が低下し抗腫瘍活性が低下する傾向があ
る。 The complete dissolution time of the soluble fraction in water in the dissolution test (dissolution test 1) according to the paddle method of the granular preparation of the present invention is 4 minutes or more and less than 30 minutes, preferably 4 to 20 minutes. If the complete dissolution time is longer than 30 minutes, the bioavailability of the drug tends to decrease and the antitumor activity tends to decrease.
更に、本発明の粒状製剤１ｇをビーカーに入
れ、それに水100mlを一気に入れ、長さ３cmの攪
拌子を入れて200rpmで攪拌して可溶性画分の完
全に溶解する時間を測定する方法（溶出試験２）
における溶解時間が15分以内、好ましくは10分以
内であることが好ましい。この溶解時間が15分を
超えると、水に分散させた時、粒子がくつつき合
つて大きなゲル状の塊となり溶解性が悪くなり口
内付着性が増大し飲みづらくなる。 Furthermore, 1 g of the granular preparation of the present invention is placed in a beaker, 100 ml of water is added to it at once, a stirrer with a length of 3 cm is inserted, the mixture is stirred at 200 rpm, and the time for complete dissolution of the soluble fraction is measured (dissolution test). 2)
It is preferred that the dissolution time is within 15 minutes, preferably within 10 minutes. If the dissolution time exceeds 15 minutes, when dispersed in water, the particles will stick together and form a large gel-like mass, which will have poor solubility and become more sticky in the mouth, making it difficult to drink.
本発明の粒状製剤の粒度分布は、10号篩を通過
し12号篩に残留する量が全重量の５重量％以下で
200号篩を通過する量が全重量の10重量％以下で
あり、好ましくは12号篩を通過しないもの及び
200を通過するものが出来るだけ少ないような粒
度分布を有するものが好ましい。何故ならば、12
号篩に残存する粒子や、200号篩を通過する微粉
が飲みづらさの主原因であるからである。とりわ
け、200号篩を通過する量が、全重量の10重量％
を超えると、飲みづらくなることに加え、該微粉
が接着剤として作用し、粒状製剤の一部が大きな
ゲル状の塊となり溶解性が悪くなる。 The particle size distribution of the granular preparation of the present invention is such that the amount that passes through a No. 10 sieve and remains on a No. 12 sieve is 5% by weight or less of the total weight.
The amount that passes through a No. 200 sieve is 10% by weight or less of the total weight, and preferably does not pass through a No. 12 sieve.
It is preferable to have a particle size distribution in which as few particles as possible pass through 200 yen. Because 12
This is because particles remaining on the No. 200 sieve and fine powder passing through the No. 200 sieve are the main causes of difficulty in drinking. In particular, the amount passing through the No. 200 sieve is 10% by weight of the total weight.
If it exceeds this amount, not only will it be difficult to drink, but the fine powder will act as an adhesive, and part of the granular preparation will turn into a large gel-like mass, resulting in poor solubility.
本発明の粒状製剤は、かわらたけ由来の蛋白多
糖体と添加物とから成る出発原料を、
流動造粒法、
押出造粒法、
転動造粒法、
ローラーコンパクターを用いた造粒法、
打錠機を用いた造粒法
のいずれかの方法又は２つ以上の方法を組合せる
ことによつて造粒されたものである。 The granular preparation of the present invention is produced by using a starting material consisting of a protein polysaccharide derived from Kawaratake mushroom and an additive by a fluid granulation method, an extrusion granulation method, a rolling granulation method, a granulation method using a roller compactor, or a pulverization method. It is granulated by any of the granulation methods using a tablet machine or by a combination of two or more methods.
(1) 流動造粒法とは、重質化粉末と添加物を混合
し、グルコース、マンノース、白糖等の糖類、
ヒドロキシプロピルセルロース等のセルロース
系化合物、ゼラチン、アラビアゴム、ポリビニ
ルピロリドン等の結合剤を溶解した溶液を流動
層中で舞つている重質化粉末と添加物との混合
物に噴霧し、造粒する方法である。結合剤とし
ては、ヒドロキシプロピルセルロースが好まし
く、溶媒としては水及び／又はアルコール類が
使用し得る。溶液中の結合剤の濃度は10w／ｖ
％以下、好ましくは8w／ｖ％以下で、噴霧す
る溶液量は重質化粉末と添加物の混合物１Kgに
対し50〜200ml、好ましくは100〜1500mlであ
る。(1) Fluidized granulation method involves mixing heavy powder and additives to produce sugars such as glucose, mannose, white sugar, etc.
A method in which a solution containing a cellulose compound such as hydroxypropyl cellulose, gelatin, gum arabic, or a binder such as polyvinylpyrrolidone is sprayed onto a mixture of heavy powder and additives floating in a fluidized bed, and granulated. It is. As the binder, hydroxypropylcellulose is preferred, and as the solvent, water and/or alcohols can be used. The concentration of binder in the solution is 10w/v
%, preferably 8 w/v % or less, and the amount of solution to be sprayed is 50 to 200 ml, preferably 100 to 1500 ml, per 1 kg of the mixture of heavy powder and additive.
アルコール類としては、エタノール、イソプ
ロピルアルコール、ｎ−プロパノールを例示し
得る。 Examples of alcohols include ethanol, isopropyl alcohol, and n-propanol.
(2) 押出造粒法とは、重質化粉末あるいはスプレ
ードライ粉末と添加物とを混合し、結合剤を溶
解した溶液を添加し、練合後スクリーンから押
出して造粒する方法である。(2) The extrusion granulation method is a method in which heavy powder or spray-dried powder and additives are mixed, a solution containing a binder is added, and after kneading, the mixture is extruded through a screen and granulated.
結合剤としては前述のものが使用し得、その
中でヒドロキシプロピルセルロースが好まし
く、溶媒としては水及び／又はアルコール類が
使用し得る。 As the binder, those mentioned above can be used, among which hydroxypropylcellulose is preferred, and as the solvent, water and/or alcohols can be used.
溶液中の結合剤の濃度は10w／ｖ％以下、好
ましくは8w／ｖ％以下で、練合に用いる溶液
量は重質化粉末と添加物の混合物１Kgに対し、
100〜1000ml、好ましくは300〜800mlである。 The concentration of the binder in the solution is 10 w/v% or less, preferably 8 w/v% or less, and the amount of solution used for kneading is 1 kg of the mixture of heavy powder and additives.
The volume is 100-1000ml, preferably 300-800ml.
(3) 転動造粒法とは、結合剤等を溶解した溶液を
噴霧して湿らせた造粒核に、スプレードライ粉
末あるいは重質化粉末、又はこれらと添加物と
の混合物等を散布し、これらに振動又は回転運
動を与えて転動により緻密な球形粒子を造粒す
る方法である。(3) Rolling granulation method involves spraying spray-dried powder, heavy powder, or a mixture of these and additives onto granulation nuclei that have been moistened by spraying a solution containing a binder, etc. This is a method for granulating dense spherical particles by applying vibration or rotational motion to these particles and rolling them.
本法では造粒核を用い、通常造粒核としては
糖が用いられる。結合剤としてはヒドロキシプ
ロピルセルローズが、溶媒としては水及び／又
はアルコール類が用いられる。遠心造粒の際の
造粒条件は、ローター回転数50〜500rpm、好
ましくは100〜250rpmである。 In this method, granulation cores are used, and sugar is usually used as the granulation cores. Hydroxypropyl cellulose is used as the binder, and water and/or alcohols are used as the solvent. The granulation conditions during centrifugal granulation are a rotor rotation speed of 50 to 500 rpm, preferably 100 to 250 rpm.
(4) ローラコンパクトを用いた造粒法とは、ロー
ラーコンパクタを用いて出発原料粉末と添加物
との混合物をロール圧0.3〜４トン／cm、好ま
しくは0.5〜３トン／cmで圧縮して重質化し、
製粒機を用いて粒状化する方法である。この方
法は繰りかえして、例えば２〜７回、好ましく
は３〜６回行なうことが好ましく、この場合の
ロール圧は0.5〜1.4トン／cmが好ましい。(4) Granulation using a roller compactor means compressing a mixture of starting material powder and additives using a roller compactor at a roll pressure of 0.3 to 4 tons/cm, preferably 0.5 to 3 tons/cm. It becomes heavier,
This is a method of granulating using a granulator. This method is preferably repeated, for example, 2 to 7 times, preferably 3 to 6 times, and the roll pressure in this case is preferably 0.5 to 1.4 tons/cm.
ローラーコンパクタを用いた造粒法におい
て、添加物としては結合剤、崩解剤、滑沢剤が
挙げられる。結合剤、崩解剤としては前述のも
のが用いられ、滑沢剤としてはタルク、ステア
リン酸マグネシウム、ステアリン酸カルシウ
ム、トウモロコシデンプン等が例示される。滑
沢剤の含量は全量の５重量％以下で、好ましく
は３重量％以下である。又滑沢剤は、２種類以
上を混合して用いることもできる。 In the granulation method using a roller compactor, additives include binders, disintegrants, and lubricants. As the binder and disintegrant, those mentioned above are used, and as the lubricant, talc, magnesium stearate, calcium stearate, corn starch, etc. are exemplified. The content of the lubricant is not more than 5% by weight, preferably not more than 3% by weight of the total amount. Moreover, two or more types of lubricants can also be used in combination.
(5) 打錠機を用いた造粒法とは、スラツグマシン
を用いて出発原料物質と添加物との混合物を打
錠圧２〜15トンで圧縮して重質化し、得られた
重質化物を製粒機を用いて粒状化する方法であ
る。(5) The granulation method using a tablet machine is a slug machine that compresses a mixture of starting raw materials and additives at a tableting pressure of 2 to 15 tons to make it heavy. This is a method of granulating the powder using a granulator.
本法における添加物としては、結合剤、崩解
剤、滑沢剤が挙げられる。これらの添加物は前
述にのものが使用し得る。 Additives in this method include binders, disintegrants, and lubricants. These additives may be those mentioned above.
本願の粒状製剤には必要に応じて、着色剤、芳
香剤、矯味剤、賦形剤、安定剤等を加えることも
出来る。 Coloring agents, fragrances, flavoring agents, excipients, stabilizers, etc. can also be added to the granular preparation of the present application, if necessary.
（発明の効果）
本発明の粒状製剤は、その薬理活性が従来の溶
液製剤や、微粉末製剤を投与した場合と全く変わ
る事なく、且つ、溶液製剤の安定性、特に保存の
問題や、微粉末製剤を用いた場合の投薬時の飲み
づらさ、例えば口内に付着すること、容量が多く
て一度に飲めない等の数多くの問題点を解決する
ものであり、実際の臨床適用に優れたものであ
る。(Effects of the Invention) The granular preparation of the present invention has no difference in pharmacological activity from administration of conventional solution preparations or fine powder preparations, and has no problems with the stability of solution preparations, especially storage problems and fine powder preparations. This solution solves a number of problems that arise when using a powder formulation, such as difficulty in swallowing when administering medication, such as sticking in the mouth and the large volume making it difficult to swallow at once, making it excellent for actual clinical applications. It is.
（実施例）
以下、実施例により本発明を具体的に説明する
が、本発明はこれら実施例に限定されるものでは
ない。(Examples) Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.
各パラメーターの測定方法は以下の通りであ
る。 The method for measuring each parameter is as follows.
かさ密度
JIS K5101で規格されたかさ測定器（蔵持科学
機器社製）を水平な振動のない台上に固定し、漏
斗部の下部に重量を正確に測定した水洗乾燥した
受器を装着し、試料を漏斗部の上端から自然落下
による受器に投入し、受器の上側の山状部を受器
に振動を与えないようにして摺切で取除き、試料
が入つた受器の重量を正確に測定し、次の式を用
いてかさ密度を測定した。Bulk Density A bulk measuring device (manufactured by Kuramochi Scientific Instruments Co., Ltd.) compliant with JIS K5101 is fixed on a horizontal, vibration-free table, and a washed and dried receiver that accurately measures the weight is attached to the bottom of the funnel. Inject the sample into the receiver by gravity falling from the top of the funnel, remove the mountain-like part on the upper side of the receiver with a sliding cutter without causing any vibration to the receiver, and weigh the receiver containing the sample. The bulk density was measured accurately and using the following formula.
ρ（ｇ／cm3）＝WF−WE／WC
（ρ：かさ密度、WF：試料の入つた受器の重量、
WE：空の受器の重量、WC：受器の内容積）
尚、かさ密度の測定は18〜28℃で55〜65％RH
の条件下でおこなつた。 ρ (g/cm 3 )=W F −W E /W C (ρ: Bulk density, W F : Weight of the receiver containing the sample,
W E : Weight of empty receiver, W C : Inner volume of receiver) Bulk density is measured at 18-28℃ and 55-65% RH.
It was conducted under the following conditions.
溶出試験１
６連式自動溶出試験システム（富山産業社製）
を用いて、第11改正日本薬局方一般試験法に規定
する溶出試験法のうちパドル法を準用した方法で
おこなつた。Dissolution test 1 6-unit automatic dissolution test system (manufactured by Toyama Sangyo Co., Ltd.)
The dissolution test method stipulated in the 11th revised Japanese Pharmacopoeia General Test Methods was carried out using a mutatis mutandis method of the paddle method.
即ち、脱気した精製水900mlを試験器に入れ37
℃に加温し、試験液の温度を37±℃で維持し、試
料200mgを試験器の内壁とパドルの心棒のほぼ中
間点に試験液に２〜３秒間で添加し、添加後直ち
に攪拌速度100rpmでパドルの攪拌をおこなつた。
攪拌開始後、10分迄は１分間隔で、10〜30分迄は
２分間隔でサンプリングを行ない、280nｍにお
ける吸光度を測定した。尚、吸光度を測定したサ
ンプルは次のサンプリングを行なう前に試験器に
戻した。測定は６サンプル同時に行なつた。 That is, put 900ml of degassed purified water into the tester37
℃, maintain the temperature of the test liquid at 37 ± ℃, add 200 mg of sample to the test liquid at approximately the midpoint between the inner wall of the tester and the paddle stem for 2 to 3 seconds, and immediately after addition, increase the stirring speed. Paddle stirring was performed at 100 rpm.
After the start of stirring, sampling was performed at 1 minute intervals for 10 minutes and at 2 minute intervals from 10 to 30 minutes, and the absorbance at 280 nm was measured. The sample whose absorbance was measured was returned to the tester before the next sampling. Measurements were performed on 6 samples simultaneously.
連続したサンプリングにおける吸光度の増加が
光透過部として１cmのセルを用いた時に平均0.01
以下である時に可溶性画分が全量溶解したものと
した。 The average increase in absorbance during consecutive sampling is 0.01 when using a 1 cm cell as the light transmitting part.
It was assumed that the entire amount of the soluble fraction was dissolved when:
溶出試験２
前述の通り、直径60〜70mm、容量200mlのビー
カーに試料１ｇを入れ、脱気した精製水10ml（25
±１℃）を一気に加え、これに長さ３cmの攪拌子
を入れて攪拌速度200rpmで攪拌した。Elution test 2 As mentioned above, put 1 g of sample into a beaker with a diameter of 60 to 70 mm and a capacity of 200 ml, and add 10 ml of degassed purified water (25
±1°C) was added all at once, and a stirring bar with a length of 3 cm was placed therein and the mixture was stirred at a stirring speed of 200 rpm.
この試験は３個のビーカーで同時におこない、
各々、５分、10分、15分間攪拌した。攪拌終了時
直ちにこの溶液を白色の樹脂性バツト（サイズ：
200×180mm以上）にあけ、溶液を均一に広げて観
察した。 This test was carried out in three beakers at the same time.
The mixture was stirred for 5 minutes, 10 minutes, and 15 minutes, respectively. Immediately after stirring, pour this solution into a white resin vat (size:
(200 x 180 mm or more), spread the solution uniformly, and observe.
不溶分或いはゲル状物が認められず、全体が均
一であると認められる時、全量溶解したものとし
た。 When no insoluble matter or gel-like substance was observed and the whole solution was found to be homogeneous, it was determined that the entire amount was dissolved.
抗腫瘍活性
１群10匹のICRマウスの腋下部皮下にザルコー
マ180腫瘍を１×106個移植し、移植翌日より試料
（かわらたけ由来の蛋白多糖体として）を体重１
Kg当り1000mgずつ１日１回、20日間連続経口投与
し、投与終了２日後に屠殺し、腫瘍部分を摘出
し、その腫瘍の重量をＴとし、試料のかわりに生
理食塩水を投与したコントロール群の腫瘍の重量
をＣとして、（１−Ｔ／Ｃ）×100の式により抗腫瘍活
性（％）を求めた。Antitumor activity: 1 × 10 6 Sarcoma 180 tumors were implanted subcutaneously in the axillary region of 10 ICR mice per group, and from the day after implantation, samples (as protein polysaccharides derived from Kawaratake mushrooms) were implanted at a rate of 1 body weight.
A control group in which 1000mg per kg was orally administered once a day for 20 consecutive days, sacrificed 2 days after the end of administration, the tumor part was removed, the weight of the tumor was T, and physiological saline was administered instead of the sample. The antitumor activity (%) was determined using the formula (1-T/C)×100, where C is the weight of the tumor.
実施例 １
クレスチン水溶液（固形分濃度10重量％）を、
二口社製（ASO 410型機）スプレードライヤー
にて、噴霧乾燥し、微粉末を得る。即ち、スプレ
ードライヤーに、熱風（入口温度150℃、出口温
度90℃、熱風量6M3／分）を送風しながら、アト
マイザー（回転数15000rpm）にクレスチン水溶
液を6.6／分で供給して、クレスチンスプレー
ドライ粉末を得た。得られた粉末の収率は、95％
で、かさ密度は、0.19ｇ／cm3で、平均粒径は15μ
ｍであつた。Example 1 Krestin aqueous solution (solid content concentration 10% by weight),
Spray dry with a Futakuchi (ASO 410 model) spray dryer to obtain a fine powder. That is, while blowing hot air (inlet temperature 150°C, outlet temperature 90°C, hot air volume 6M 3 /min) to the spray dryer, the Krestin aqueous solution was supplied to the atomizer (rotation speed 15000 rpm) at a rate of 6.6/min, and the Krestin spray was produced. A dry powder was obtained. The yield of the obtained powder is 95%
The bulk density is 0.19g/ cm3 , and the average particle size is 15μ.
It was m.
得られたスプレードライ粉末500ｇに、白糖150
ｇおよびトウモロコシデンプン150ｇを混合し、
エタノールに溶解した3w／ｖ％のヒドロキシプ
ロピルセルロース溶液500mlを加え、均一のペー
スト状になるまで、ニーダーを用いて練合した。
次に、16号篩（東京スクリーン社製）を用いて押
出造粒し終了後60℃にて通風乾燥した。この造粒
物のうち12号篩を通過するが、200号篩を通過し
ない画分を集めて512ｇの粒状製剤を得た。 Add 150 g of white sugar to 500 g of the spray-dried powder obtained.
g and 150 g of corn starch,
500 ml of a 3 w/v % hydroxypropyl cellulose solution dissolved in ethanol was added and kneaded using a kneader until it became a uniform paste.
Next, extrusion granulation was performed using a No. 16 sieve (manufactured by Tokyo Screen Co., Ltd.), and after completion, the mixture was dried with ventilation at 60°C. Of the granules, a fraction that passed through a No. 12 sieve but did not pass through a No. 200 sieve was collected to obtain 512 g of a granular preparation.
得られた粒状製剤中の添加物の量は38.6重量％
で、その粒度分布は、10号篩に残存するものはな
く、12号篩に残留する量が全重量の0.5重量％で、
200号篩を通過する量が全重量の1.3重量％であ
り、かさ密度は0.35ｇ／cm3であり、溶出試験１に
よる溶解時間は４分で、溶出試験２による溶解時
間は５分以内であつた。 The amount of additives in the resulting granular formulation was 38.6% by weight
As for the particle size distribution, there is nothing left on the No. 10 sieve, and the amount remaining on the No. 12 sieve is 0.5% by weight of the total weight.
The amount passing through the No. 200 sieve is 1.3% by weight of the total weight, the bulk density is 0.35g/ cm3 , the dissolution time according to dissolution test 1 is 4 minutes, and the dissolution time according to dissolution test 2 is within 5 minutes. It was hot.
得られた粒状製剤の抗腫瘍活性は、90.1％であ
つた。 The antitumor activity of the obtained granular preparation was 90.1%.
尚、クレスチン現市販品及びクレスチンスプレ
ードライ粉末の抗腫瘍活性はそれぞれ83.8％及び
80.0％であつた。 The antitumor activity of Krestin's current commercially available product and Krestin spray-dried powder is 83.8% and 83.8%, respectively.
It was 80.0%.
実際の臨床適用における投薬の良否を検討すべ
く、10名のパネラーにクレスチンスプレードライ
粉末、クレスチン現市販品、本発明のクレスチン
粒状製剤、ノンパレル101
（フロイント産業社
製）を各１ｇずつ分配し、これらを水で服用した
時の飲み易さに関する評価を行つた。ここで本粒
状製剤の原料であるクレスチンスプレードライ粉
末に１点を与え、飲み易さに定評のあるノンパレ
ル101
に10点を与えた場合の相対的な飲み易さ
を点数で示し合計した。その結果、クレスチンの
現製品は20点で、本粒状製剤は73点であつた。 In order to examine the suitability of dosing in actual clinical applications, 1 g each of Krestin spray-dried powder, Krestin commercially available product, Krestin granular preparation of the present invention, and Nonparell 101 (manufactured by Freund Sangyo Co., Ltd.) was distributed to 10 panelists. We evaluated the ease of drinking these when taken with water. Here, 1 point was given to Krestin spray-dried powder, which is the raw material for this granular preparation, and 10 points were given to Nonpareil 101, which has a reputation for being easy to drink.The relative ease of drinking was given as a score and totaled. As a result, the current Krestin product scored 20 points, and this granular formulation scored 73 points.
更に200号篩を通過する微粉末が飲みやすさに
どのように影響するかについて検討した。本発明
の粒状製剤に200号篩を通過する微粉を加えて、
該画分が２重量％、５重量％、10重量％、15重量
％及び20重量％含まれるものについての飲みやす
さを上述の方法で測定した結果、それぞれ73点、
70点、62点、45点及び38点であつた。 Furthermore, we investigated how the fine powder that passes through a No. 200 sieve affects drinkability. Adding fine powder that passes through a No. 200 sieve to the granular preparation of the present invention,
The drinkability of products containing 2% by weight, 5% by weight, 10% by weight, 15% by weight, and 20% by weight of the fraction was measured using the above method, and the result was 73 points, respectively.
They were 70 points, 62 points, 45 points and 38 points.
比較例 １
クレスチン（Lot No.95A）は10号篩及び12号
篩を通過し、200号篩を通過する量は19.9重量％
である。かさ密度は0.49ｇ／cm3で、溶出試験１に
おける溶解時間は２分で、溶出試験２における溶
解時間は15分以上であつた。Comparative Example 1 Krestin (Lot No. 95A) passes through No. 10 sieve and No. 12 sieve, and the amount passing through No. 200 sieve is 19.9% by weight.
It is. The bulk density was 0.49 g/cm 3 , the dissolution time in dissolution test 1 was 2 minutes, and the dissolution time in dissolution test 2 was 15 minutes or more.
比較例 ２
クレスチンスプレードライ粉末は200号篩を通
過し、このかさ密度は0.19ｇ／cm3で、溶出試験１
及び２の溶解時間は30分以上及び15分以上であつ
た。Comparative Example 2 Krestin spray-dried powder passed through a No. 200 sieve, and its bulk density was 0.19 g/ cm3 .
The dissolution time of samples 2 and 2 was 30 minutes or more and 15 minutes or more.
実施例 ２
実施例１と同じ方法で得たクレスチンのスプレ
ードライ粉末をローラーコンパクタにて重質化
後、破砕した。これらの工程を５回繰返して得た
重質化粉末（かさ密度0.64ｇ／cm3）500ｇに白糖
25ｇ、トウモロコシデンプン25ｇを混合し、エタ
ノールに溶解した3w／ｖ％ヒドロキシプロピル
セルロース溶液250mlを加えて練合し、16号篩
（東京スクリーン社製）で押出造粒し、次いで80
℃にて流動層乾燥し、粒状物を作製した。この粒
状物の内、12号篩は通過するが200号篩は通過し
な画分を集めて390ｇを得た。Example 2 A spray-dried Krestin powder obtained in the same manner as in Example 1 was made into a heavy mass using a roller compactor and then crushed. Add white sugar to 500 g of heavy powder (bulk density 0.64 g/cm 3 ) obtained by repeating these steps 5 times.
25g of corn starch, 250ml of 3w/v% hydroxypropylcellulose solution dissolved in ethanol were added, kneaded, extruded through a No. 16 sieve (manufactured by Tokyo Screen Co., Ltd.), and then granulated using a No. 80 sieve.
Fluidized bed drying was performed at °C to produce granules. Of this granular material, a fraction that passed through a No. 12 sieve but did not pass through a No. 200 sieve was collected to obtain 390 g.
得られた粒状製剤を10号篩でふるうと篩上に残
存するものは存在せず、12号篩上に残存するもの
は全重量の0.5重量％で、200号篩を通過するもの
は全重量の1.0重量％であつた。 When the obtained granular preparation is sieved through a No. 10 sieve, there is no substance remaining on the sieve, 0.5% of the total weight remains on the No. 12 sieve, and 0.5% of the total weight passes through the No. 200 sieve. It was 1.0% by weight.
更に、得られた粒状製剤中の添加物の量は10.3
重量％で、そのかさ密度、溶出試験１の溶解時
間、溶出試験２の溶解時間及び抗腫瘍活性はそれ
ぞれ0.56ｇ／cm3、10分、10分以内及び93.1％であ
つた。 Additionally, the amount of additive in the resulting granular formulation was 10.3
In weight percent, its bulk density, dissolution time in dissolution test 1, dissolution time in dissolution test 2 and antitumor activity were 0.56 g/cm 3 , 10 minutes, within 10 minutes and 93.1%, respectively.
飲みやすさを実施例１と同様に測定した結果、
80点であつた。 As a result of measuring ease of drinking in the same manner as in Example 1,
I scored 80 points.
実施例 ３
実施例１と同じ方法で得たクレスチンスプレー
ドライ粉末800ｇ及びマンニトール200ｇを均一に
なるまで混和した。Example 3 800 g of Krestin spray-dried powder obtained in the same manner as in Example 1 and 200 g of mannitol were mixed until uniform.
遠心造粒機CF−360S型（フロイント産業社製）
を用い、スプレー空気圧1.5Kg／cm2、ローター回
転数170rpm、スリツト空気量200N／分、空気
温度27〜35℃で、この遠心造粒機に、造粒核とし
てノンパレル101
（32〜42メツシユ）（フロイン
ト産業社製）500ｇを投入し、この造粒核に結合
剤腋として3w／ｖ％ヒドロキシプロピルセルロ
ース水溶液700mlを噴霧しながら、先に調製した
クレスチンとマントニールとの混和粉末を散布
し、流星運動によつて転動造粒法による粒状製剤
を作製した。この作製した粒状製剤は60℃で乾燥
し、このうち12号篩は通過し42号篩は通過しない
粒状製剤1015ｇを得た。得られた粒状製剤の粒度
分布は、10号篩上に存在するものはなく、12号篩
上に存在するものが全重量の0.1重量％で、200号
篩を通過するものが全重量の0.1重量％であつた。
この粒状製剤中の添加物の量は47.0重量％で、そ
のかさ密度は0.46ｇ／cm3で、溶出試験１の溶解時
間は４分で、溶出試験２の溶解時間は５分以内で
且つ抗腫瘍活性は88.5％であつた。飲みやすさを
実施例１と同様に測定した結果、90点であつた。 Centrifugal granulator CF-360S type (manufactured by Freund Sangyo Co., Ltd.)
Using a spray air pressure of 1.5 Kg/cm 2 , rotor rotation speed of 170 rpm, slit air flow of 200 N/min, and air temperature of 27 to 35°C, Nonpareil 101 (32 to 42 meshes) was added as a granulation core to this centrifugal granulator. (manufactured by Freund Sangyo Co., Ltd.), and while spraying 700 ml of a 3w/v% hydroxypropyl cellulose aqueous solution as a binder axillary to the granulation cores, the mixed powder of Krestin and Mantonil prepared earlier was sprinkled. Granular formulations were prepared by rolling granulation method using meteor motion. The prepared granular preparation was dried at 60° C. to obtain 1015 g of a granular preparation that passed through a No. 12 sieve but did not pass through a No. 42 sieve. The particle size distribution of the obtained granular preparation was such that none of the particles were present on the No. 10 sieve, 0.1% by weight of the total weight was present on the No. 12 sieve, and 0.1% of the total weight was present on the No. 200 sieve. It was in weight%.
The amount of additive in this granular preparation was 47.0% by weight, its bulk density was 0.46 g/ cm3 , the dissolution time for dissolution test 1 was 4 minutes, the dissolution time for dissolution test 2 was within 5 minutes, and Tumor activity was 88.5%. The ease of drinking was measured in the same manner as in Example 1, and the result was 90 points.
実施例 ４
クレスチンのスプレードライ粉末1600ｇ、白糖
320ｇ、ステアリン酸マグネシウム30ｇを混合均
一化の後、ローラーコンパクタTF−Mini（フロ
イント産業社製）を用い、板状固型物（フレー
ク）とし、24メツシユの金網付の製粒機で粉砕造
粒した。この工程をロール負荷電流が0.8〜2.2A
の範囲で５回繰り返して、1905ｇの造粒物を得
た。Example 4 Krestin spray-dried powder 1600g, white sugar
After mixing and homogenizing 320 g of magnesium stearate and 30 g of magnesium stearate, it was made into plate-shaped solids (flakes) using a roller compactor TF-Mini (manufactured by Freund Sangyo Co., Ltd.), and then crushed and granulated using a granulator with a 24-mesh wire mesh. did. This process rolls load current 0.8~2.2A
The procedure was repeated five times within the range of 1,905 g to obtain 1,905 g of granules.
日局ヒドロキシプロピルセルロース50ｇをイソ
プロピルアルコールに溶解し、1000mlとした。一
方、先に得られた造粒物1800ｇを万能製剤機ニー
ダー（畑鉄工所社製）に投入後、調製したヒドロ
キシプロピルセルロースのイソプロピルアルコー
ル溶液935mlを添加し、練合後押出造粒機EXKS
型（不二パウダル社製）（スクリーン穴１mm）押
出造粒した。この造粒物を球形整粒機マルメライ
ザーＱ−230型（不二パウダル社製）を用い整粒
した。 50 g of hydroxypropyl cellulose (Japanese Pharmacopoeia) was dissolved in isopropyl alcohol to make 1000 ml. On the other hand, 1800 g of the granulated material obtained earlier was put into a multipurpose formulation machine kneader (manufactured by Hata Tekkosho Co., Ltd.), 935 ml of the prepared isopropyl alcohol solution of hydroxypropyl cellulose was added, and after kneading, the extrusion granulator EXKS
Extrusion granulation was carried out using a mold (manufactured by Fuji Paudal Co., Ltd.) (screen hole 1 mm). This granulated material was sized using a spherical sizing machine Marmerizer Model Q-230 (manufactured by Fuji Paudal Co., Ltd.).
得られた粒子を篩別し、12号篩は通過するが、
42号篩を通過しない粒状製剤を集め棚段熱風乾燥
機で60℃、５時間乾燥して、1410ｇの粒状製剤を
得た。得られた粒状製剤の粒度分布は、10号篩上
に存在するものはなく、12号篩上に存在するもの
が全重量の0.1重量％で、200号篩を通過するもの
が全重量の0.1重量％であつた。 The obtained particles are sieved and passed through a No. 12 sieve, but
The granular preparations that did not pass through the No. 42 sieve were collected and dried in a tray hot air dryer at 60°C for 5 hours to obtain 1410 g of granular preparations. The particle size distribution of the obtained granular preparation was such that none of the particles were present on the No. 10 sieve, 0.1% by weight of the total weight was present on the No. 12 sieve, and 0.1% of the total weight was present on the No. 200 sieve. It was in weight%.
得られた粒状製剤中の添加物の量は20.0重量％
でかさ密度は0.58ｇ／cm3で、溶出試験１の溶解時
間は６分で、溶出試験２の溶解時間は10分以内
で、抗腫瘍活性は90.0％であつた。飲みやすさを
実施例１と同様に測定した結果、92点であつた。 The amount of additive in the obtained granular formulation is 20.0% by weight
The bulk density was 0.58 g/cm 3 , the dissolution time in dissolution test 1 was 6 minutes, the dissolution time in dissolution test 2 was within 10 minutes, and the antitumor activity was 90.0%. The ease of drinking was measured in the same manner as in Example 1, and the result was 92 points.
実施例 ５
クレスチンのスプレードライ粉末1600ｇ、トウ
モロコシデンプン320ｇ、ステアリン酸マグネシ
ウム30ｇを混合均一化の後、ローラーコンパクタ
TF−Mini（フロイント産業社製）を用い、板状
固型物（フレーク）とし、24メツシユの金網付の
製粒機で粉砕造粒した。この工程をロール負荷電
流が0.8〜2.2Aの範囲で５回繰り返して1875ｇの
造粒物を得た。Example 5 1600 g of Krestin spray-dried powder, 320 g of corn starch, and 30 g of magnesium stearate were mixed and homogenized using a roller compactor.
Using TF-Mini (manufactured by Freund Sangyo Co., Ltd.), it was made into plate-shaped solids (flakes), and pulverized and granulated using a granulator equipped with a 24-mesh wire mesh. This process was repeated five times at a roll load current in the range of 0.8 to 2.2 A to obtain 1875 g of granules.
日局ヒドロキシプロピルセルロース50ｇをエタ
ノールに溶解し1000mlとした。一方、先に得られ
た造粒物1800ｇを万能製剤機ニーダー（畑鉄工所
社製）に投入後、調製したヒドロキシプロピルセ
ルロースのエタノール溶液975mlを添加し、練合
後押出造粒機EXKS型（不二パウダル社製）（ス
クリーン穴１mm）押し出し造粒した。この造粒物
を球形整粒機マルメライザーＱ−230型（不二パ
ウダル社製）を用い整粒した。 50 g of hydroxypropyl cellulose (Japanese Pharmacopoeia) was dissolved in ethanol to make 1000 ml. On the other hand, 1800 g of the granulated material obtained earlier was put into a multi-purpose formulation machine kneader (manufactured by Hata Tekkosho Co., Ltd.), 975 ml of the prepared hydroxypropylcellulose ethanol solution was added, and after kneading, an extrusion granulator model EXKS ( (manufactured by Fuji Paudal Co., Ltd.) (screen hole 1 mm) was extruded and granulated. This granulated material was sized using a spherical sizing machine Marmerizer Model Q-230 (manufactured by Fuji Paudal Co., Ltd.).
得られた粒子を篩別し、12号篩は通過するが、
42号篩を通過しない粒状製剤を集め、棚段熱風乾
燥機で60℃、５時間乾燥して1450ｇの粒状製剤を
得た。得られた粒状製剤の粒度分布は、10号篩上
に存在するものはなく、12号篩に存在するものが
全重量の0.1重量％で、200号篩を通過するものが
全重量の0.1重量％であつた。得られた粒状製剤
中の添加物の量は20.0重量％で、かさ密度は0.55
ｇ／cm3で溶出試験１の溶解時間は10分で、溶出試
験２の溶解時間は10分以内で、抗腫瘍活性は85.5
％であつた。飲みやすさを実施例１と同様に測定
した結果、88点であつた。 The obtained particles are sieved and passed through a No. 12 sieve, but
The granular preparations that did not pass through the No. 42 sieve were collected and dried in a tray hot air dryer at 60°C for 5 hours to obtain 1450 g of granular preparations. The particle size distribution of the obtained granular preparation was such that none of the particles passed through the No. 10 sieve, 0.1% of the total weight passed through the No. 12 sieve, and 0.1% of the total weight passed through the No. 200 sieve. It was %. The amount of additive in the obtained granular formulation was 20.0% by weight, and the bulk density was 0.55
g/ cm3 , the dissolution time of dissolution test 1 is 10 minutes, the dissolution time of dissolution test 2 is within 10 minutes, and the antitumor activity is 85.5
It was %. The ease of drinking was measured in the same manner as in Example 1, and the result was 88 points.
実施例 ６
実施例２と同じ方法で得たクレスチン重質化粉
末480ｇと白糖120ｇとを流動造粒機FLO−１型
（フロイント産業社製）に入れ、２分間攪拌し、
3w／ｖ％ヒドロキシプロピルセルロースのエタ
ノール溶液250mlを30分間で噴霧し、20分間乾燥
した。Example 6 480 g of Krestin heavy powder obtained in the same manner as in Example 2 and 120 g of white sugar were placed in a fluidized granulator model FLO-1 (manufactured by Freund Sangyo Co., Ltd.), stirred for 2 minutes,
250 ml of 3 w/v% hydroxypropylcellulose in ethanol was sprayed over 30 minutes and dried for 20 minutes.
得られた粒状製剤のうち、30号篩（500μｍ）
を通過し200号篩を通過しない粒状製剤のみを集
め480ｇを得た。得られた粒状製剤は10号及び20
号篩上に残存するものはなく、200号篩を通過す
るものは全重量の0.3重量％であつた。更に、得
られた粒状製剤中の添加物の量は21.0重量％であ
り、この粒状製剤のかさ密度は0.47ｇ／cm3であ
り、その溶出試験１の溶解時間は７分で、溶出試
験２の溶解時間は10分以内で、且つ抗腫瘍活性は
80.7％であつた。飲みやすさを実施例１と同様に
測定した結果、77点であつた。 Of the obtained granular preparations, No. 30 sieve (500μm)
Only the granular preparations that passed through and did not pass through a No. 200 sieve were collected to obtain 480 g. The obtained granular preparations were No. 10 and No. 20.
Nothing remained on the No. 200 sieve, and the amount that passed through the No. 200 sieve was 0.3% by weight of the total weight. Furthermore, the amount of additive in the obtained granular preparation was 21.0% by weight, the bulk density of this granular preparation was 0.47 g/cm 3 , the dissolution time of the dissolution test 1 was 7 minutes, and the dissolution time of the dissolution test 2 was 7 minutes. The dissolution time is within 10 minutes, and the antitumor activity is
It was 80.7%. The ease of drinking was measured in the same manner as in Example 1, and the result was 77 points.
一方、200号篩を通過する画分を集め91ｇを得
た。 On the other hand, the fractions passing through a No. 200 sieve were collected to obtain 91 g.
この画分のかさ密度は0.32ｇ／cm3、溶出試験１
及び２の溶解時間はそれぞれ30分以上、及び15分
以上で、抗腫瘍活性は74.5％であつた。飲みやす
さを実施例１と同様に測定した結果、16点であつ
た。 The bulk density of this fraction is 0.32 g/cm 3 , dissolution test 1
The dissolution times of and 2 were 30 minutes or more and 15 minutes or more, respectively, and the antitumor activity was 74.5%. The ease of drinking was measured in the same manner as in Example 1, and the result was 16 points.
実施例 ７
実施例１と同様な方法で得たクレスチンのスプ
レードライ粉末4515ｇ、トウモロコシデンプン
500ｇ及びステアリン酸マグネシウム60ｇをスラ
ツグ打錠機HT−E5S型（畑鉄工所社製）で錠剤
化した。このときの打錠機の杵先直径は20mmを用
い打錠圧は５〜８トンで圧縮した。下杵のすいこ
み長さは12mmで、作成した錠剤の厚みは2.6〜2.8
mmであつた。Example 7 4515 g of Krestin spray-dried powder obtained in the same manner as in Example 1, corn starch
500 g and 60 g of magnesium stearate were tableted using a slug tableting machine HT-E5S model (manufactured by Hata Tekkosho Co., Ltd.). At this time, the diameter of the punch tip of the tableting machine was 20 mm, and the tableting pressure was 5 to 8 tons. The plunging length of the lower punch is 12 mm, and the thickness of the tablets made is 2.6 to 2.8.
It was warm in mm.
このスラツグ錠剤を32メツシユの金網を付した
製粒機で粉砕し重質化粉末を得た。この重質化粉
末を30号及び200号の篩でふるい、30号の篩を通
過し、200号の篩を通過しない分画を集め、3045
ｇの粒状製剤を得た。得られた粒状製剤の粒度分
布は10号篩及び12号篩上に残存するものはなく
200号篩を通過するものは全重量の0.8重量％であ
つた。粒状製剤中の添加の量は11.1重量％であつ
た。この粒状製剤のかさ密度は0.45ｇ／cm3で、溶
出試験１の溶解時間は５分で、溶出試験２の溶解
時間は５分以内で、且つ抗腫瘍活性は87.8％であ
つた。飲みやすさを実施例１と同様に測定した結
果、63点であつた。 This slug tablet was crushed using a granulator equipped with a 32-mesh wire mesh to obtain a heavy powder. This heavy powder was sieved through No. 30 and No. 200 sieves, and the fractions that passed through the No. 30 sieve and did not pass through the No. 200 sieve were collected.
A granular formulation of g was obtained. The particle size distribution of the obtained granular preparation shows that no particles remain on the No. 10 and No. 12 sieves.
What passed through the No. 200 sieve was 0.8% by weight of the total weight. The amount of addition in the granular formulation was 11.1% by weight. The bulk density of this granular preparation was 0.45 g/cm 3 , the dissolution time in dissolution test 1 was 5 minutes, the dissolution time in dissolution test 2 was within 5 minutes, and the antitumor activity was 87.8%. The ease of drinking was measured in the same manner as in Example 1, and the result was 63 points.
実施例 ８
実施例１と同じ方法で得たクレスチンのスプレ
ードライ粉末1600ｇ、白糖320ｇ、ステアリン酸
マグネシウム30ｇをローラーコンパクタTF−
Mini（フロイント産業社製）にかけて重質化を行
つた。この時のフイードのスクリユー形式はＢ
型、ロールはDPS型を用い、線圧0.9トン／cmで
圧縮した。圧縮成形物は24メツシユの金網付の製
粒機で粉砕した。この工程をロール負荷が同一と
なるような条件で５回繰り返した。ただし、５回
重質化後の粉砕は32メツシユの金網付の製粒機で
粉砕した。５回処理後の収量は1860ｇであつた。
この重質化粉末を30号（500μｍ）の篩及び200号
の篩でふるい、30号の篩を通過し200号の篩を通
過しない分画を集めた。1209ｇの粒状製剤を得
た。添加物の量は17.5重量％であつた。Example 8 1600 g of Krestin spray-dried powder obtained in the same manner as in Example 1, 320 g of white sugar, and 30 g of magnesium stearate were packed in a roller compactor TF-
The weight was increased by applying the Mini (manufactured by Freund Sangyo Co., Ltd.). At this time, the feed screw format is B
A DPS mold was used as the mold and roll, and compression was performed at a linear pressure of 0.9 ton/cm. The compression molded product was pulverized using a granulator equipped with a 24-mesh wire mesh. This process was repeated five times under conditions such that the roll load was the same. However, the material was crushed after 5 times of pulverization using a granulator equipped with a 32-mesh wire mesh. The yield after 5 treatments was 1860 g.
This weighted powder was sieved through a No. 30 (500 μm) sieve and a No. 200 sieve, and the fractions that passed through the No. 30 sieve but did not pass through the No. 200 sieve were collected. 1209g of granular formulation was obtained. The amount of additive was 17.5% by weight.
得られた粒状製剤の粒度分布は、10号篩及び12
号篩に残存するものはなく、200号篩を通過する
量が全重量の1.3重量％であり、かさ密度は0.56
ｇ／cm3で、溶出試験１による溶解時間は８分で、
溶出試験２により溶解時間は10分以内で、抗腫瘍
性活性は82.3％であつた。飲みやすさを実施例１
と同様に測定した結果、70点であつた。 The particle size distribution of the obtained granular preparation was determined using a No. 10 sieve and a No. 12 sieve.
There was nothing remaining on the No. 200 sieve, and the amount passing through the No. 200 sieve was 1.3% by weight of the total weight, and the bulk density was 0.56.
g/ cm3 , the dissolution time according to dissolution test 1 is 8 minutes,
According to dissolution test 2, the dissolution time was within 10 minutes, and the antitumor activity was 82.3%. Example 1 for ease of drinking
The result was 70 points.
Claims (1)
重量％未満と添加物10重量％を超え50重量％以下
から成り、かさ密度が0.30〜0.80ｇ／cm3で、パド
ル法に準ずる溶出試験における水に対する溶解時
間が４分以上30分未満であることを特徴とする粒
状製剤。 ２ 10号篩を通過し、12号篩に残留する量が全重
量の５重量％以下で200号篩を通過する量が全重
量の10重量％以下の粒度分布を有することを特徴
とする請求項１の粒状製剤。 ３ かわらたけ由来の蛋白多糖体が75重量％以上
90重量％未満である請求項１の粒状製剤。 ４ かわらたけ由来の蛋白多糖体がクレスチンで
ある請求項１の粒状製剤。 ５ 流動造粒法、押出造粒法、ローラーコンパク
タを用いた造粒法、打錠機を用いた造粒法或いは
転動造粒法によつて造粒することを特徴とする請
求項１の粒状製剤。[Claims] 1. Protein polysaccharide derived from Kawaratake mushroom 50% by weight or more90
It consists of less than 10% by weight and less than 50% by weight of additives, has a bulk density of 0.30 to 0.80g/ cm3 , and has a dissolution time in water of 4 minutes or more and less than 30 minutes in a dissolution test according to the paddle method. A granular preparation characterized by: 2. A claim characterized by having a particle size distribution in which the amount that passes through a No. 10 sieve and remains on a No. 12 sieve is 5% by weight or less of the total weight, and the amount that passes through a No. 200 sieve is 10% by weight or less of the total weight. Granular formulation of item 1. 3 Protein polysaccharide derived from Kawaratake mushroom is 75% or more by weight
The granular formulation of claim 1, which is less than 90% by weight. 4. The granular preparation according to claim 1, wherein the protein polysaccharide derived from Kawaratake mushroom is Krestin. 5. The granulation according to claim 1, characterized in that the granulation is carried out by a fluidized granulation method, an extrusion granulation method, a granulation method using a roller compactor, a granulation method using a tablet machine, or a rolling granulation method. Granular formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1225284A JPH02167229A (en) | 1988-09-01 | 1989-08-31 | Granular pharmaceutical of protein polysaccharide substance derived from coriolus versicolor quel. |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-219177 | 1988-09-01 | ||
| JP21917788 | 1988-09-01 | ||
| JP1225284A JPH02167229A (en) | 1988-09-01 | 1989-08-31 | Granular pharmaceutical of protein polysaccharide substance derived from coriolus versicolor quel. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02167229A JPH02167229A (en) | 1990-06-27 |
| JPH0549649B2 true JPH0549649B2 (en) | 1993-07-26 |
Family
ID=16731409
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1225284A Granted JPH02167229A (en) | 1988-09-01 | 1989-08-31 | Granular pharmaceutical of protein polysaccharide substance derived from coriolus versicolor quel. |
| JP1225285A Granted JPH02174722A (en) | 1988-09-01 | 1989-08-31 | Granular lipid of protein polysaccharide derived from coriolus versicolor |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1225285A Granted JPH02174722A (en) | 1988-09-01 | 1989-08-31 | Granular lipid of protein polysaccharide derived from coriolus versicolor |
Country Status (1)
| Country | Link |
|---|---|
| JP (2) | JPH02167229A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4752233B2 (en) * | 2001-04-27 | 2011-08-17 | 味の素株式会社 | Immunostimulator |
| CN101091725A (en) | 2006-06-23 | 2007-12-26 | 天津天士力制药股份有限公司 | Chinese traditional medicine grains and preparation method |
| JP6086798B2 (en) * | 2013-04-25 | 2017-03-01 | 小林製薬株式会社 | Tablet manufacturing method |
-
1989
- 1989-08-31 JP JP1225284A patent/JPH02167229A/en active Granted
- 1989-08-31 JP JP1225285A patent/JPH02174722A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0549650B2 (en) | 1993-07-26 |
| JPH02167229A (en) | 1990-06-27 |
| JPH02174722A (en) | 1990-07-06 |
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