JP2006257049A - Lactobacillus preparation and digestive enzyme and method for producing tablet containing both of them and tablet produced thereby - Google Patents
Lactobacillus preparation and digestive enzyme and method for producing tablet containing both of them and tablet produced thereby Download PDFInfo
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本発明は、直接打錠法により製造した生菌剤や消化酵素剤およびその両方を含有する錠剤の製造方法およびそれによる錠剤に関する。 The present invention relates to a method for producing a tablet containing a viable bacterial agent, a digestive enzyme agent and both produced by a direct tableting method, and a tablet thereby.
一般に、錠剤の製造の方法は、使用する薬剤粉末に賦形剤、滑沢剤を加えて混合し、臼と杵を備えた打錠機を用いて圧縮成型する直接打錠法と、使用する薬剤粉末と賦形剤、結合剤さらに崩壊剤等の任意の成分を配合した原料粉末組成物に、水および／もしくは有機溶媒を加えて造粒し、得られた顆粒を臼と杵を備えた打錠機を用いて圧縮成形する湿式顆粒圧縮法のどちらかの方法で行われる。
直接打錠法と湿式顆粒圧縮法による錠剤の製造方法にはそれぞれ長所、短所はあるものの、経済性ではあきらかに直接打錠法が優れる。工程数が少ないために製造費が少なくてすむだけでなく、バリデーションにかかる費用も抑えることができるからである。
In general, a tablet is produced by using a direct tableting method in which excipients and lubricants are added to a drug powder to be used and mixed, and compression molding is performed using a tableting machine equipped with a mortar and a punch. Water and / or an organic solvent was added to the raw powder composition containing any ingredients such as drug powder, excipient, binder, and disintegrant, and granulated. It is carried out by either of the wet granule compression methods in which compression molding is performed using a tableting machine.
Although the direct tableting method and the tablet production method by the wet granule compression method have advantages and disadvantages, respectively, the direct tableting method is clearly superior in terms of economy. This is because the number of steps is small, so that not only the manufacturing cost is reduced, but also the cost for validation can be suppressed.
しかしながら、打錠に供する粉が単に粉体同士の混合であるために粉体そのものの性質が強く現れる。そのため、打錠時に粉体の流動性が悪く、含有する薬剤の含量の均一性を保つことが困難であることが多々ある。また、打錠時に圧縮するのに大きい圧力が必要であること、スティッキング等の打錠障害がおき易い等打錠が円滑にできないことがある。
そこで、そのような場合、湿式造粒による造粒を行い、表面改質して打錠が行われるが、薬剤の中には、湿式で造粒を行い、引き続き行う乾燥の工程で極めて不安定になり、薬効を失ったり、減じたりするものがある。例えば、生菌剤は、その代表的薬剤であり、その失活により直接打錠法でしか製造が困難である。
さらに、錠剤製造において、薬剤の中には大きい圧力により圧縮すると、その薬効を減ずるものがある。例えば、生菌剤１．０〜１．５ｔ／ｃｍ２の通常の打錠法では、生菌剤の多くが死菌となることが知られている。また、消化酵素剤のように、その薬効発現がたんぱく質の３次元構造に依存している場合、上記の通常の打錠圧では錠剤を製造するとその活性が減少することも知られている。
However, since the powder to be used for tableting is simply a mixture of powders, the properties of the powders are strong. Therefore, the fluidity of the powder is poor at the time of tableting, and it is often difficult to maintain the uniformity of the content of the contained drug. In addition, tableting may not be performed smoothly because a large pressure is required for compression during tableting and tableting troubles such as sticking are likely to occur.
Therefore, in such a case, granulation by wet granulation is performed, and the surface is modified and tableting is performed. However, some drugs are extremely unstable in the subsequent drying process after wet granulation. There are things that lose or reduce medicinal properties. For example, viable bacteria is a representative drug, and it is difficult to produce by a direct tableting method due to its inactivation.
Furthermore, in tablet manufacture, some drugs reduce their medicinal effects when compressed by a large pressure. For example, in a normal tableting method with a live bacterial agent of 1.0 to 1.5 t / cm 2 , it is known that many of the live bacterial agents are killed. Further, it is also known that when the drug expression is dependent on the three-dimensional structure of the protein, such as a digestive enzyme, the activity is reduced when a tablet is produced by the above-described normal tableting pressure.
以上のような理由から、生菌や消化酵素を含む錠剤の製造には、湿式により製造した顆粒圧縮法でなく直接打錠法により、さらに大きい圧力でなく、小さい圧力による打錠が薦められる。
ところが、生菌剤はその粉末の圧縮性が悪いため、直接打錠法により錠剤製造を行うと、大きい圧力が求められ、配合した生菌も錠剤中では半減するという問題がある。また、消化酵素も同様に直接打錠法での錠剤製造では大きい圧力による圧縮が求められるのでその活性が減るという問題がある。
For the above reasons, tableting with viable bacteria and digestive enzymes is recommended not by wet granulation compression but by direct tableting, and by tableting with a lower pressure rather than a higher pressure.
However, since the viable agent has poor powder compressibility, when a tablet is produced by the direct tableting method, a large pressure is required, and there is a problem that the compounded viable cell is also halved in the tablet. Similarly, the digestive enzyme also has a problem that its activity is reduced because the tablet production by the direct compression method requires compression under a large pressure.
また、直接打錠法の場合は、粉体そのものの混合であり、粉体の流動性がよくないための問題点もある。打錠に用いられる打錠機には、穴（臼）を設けた回転盤が備わっており、ここに顆粒をホッパから定量的に供給し、その穴に充填された顆粒を上下２組のスチール棒（上杵、下杵）で圧縮することにより錠剤が製造される。穴は、一定の直径で作られた円筒であり、その中に充填される重量は可能なかぎり一定になることが重要である。一定であればあるほど製造する重量が均一になり、同じ薬剤量を含有する錠剤が製造可能となる。 Further, in the case of the direct tableting method, there is a problem in that the powder itself is mixed and the fluidity of the powder is not good. The tableting machine used for tableting is equipped with a rotating disk with a hole (mortar), where the granules are supplied quantitatively from the hopper, and the granules filled in the holes are divided into two sets of steel. Tablets are produced by compression with bars (upper and lower punches). It is important that the hole is a cylinder made with a constant diameter and that the weight filled therein is as constant as possible. The more constant, the more uniform the weight to be produced, and the tablets containing the same amount of drug can be produced.
そのため、打錠に供される粉体の流動性は極めて重要である。流動性が悪いと粉体が穴に一定に入らず、重量のばらつきの多い錠剤となる。
直接打錠に用いられる賦形剤は、結晶セルロースや造粒乳糖が用いられるものの、結晶セルロース単独での流動性が悪く、そこで流動化剤として軽質無水ケイ酸が用いられることがある（例えば、特許文献１）。
また、造粒乳糖は、生菌剤と混合して用いる場合、大きい圧力で圧縮しないと実用に供する硬度を有する錠剤が得られない。
Therefore, the fluidity of the powder used for tableting is extremely important. When the fluidity is poor, the powder does not enter the hole uniformly, and the tablet has a large variation in weight.
Although excipients used for direct tableting are crystalline cellulose and granulated lactose, crystalline cellulose alone has poor fluidity, and light anhydrous silicic acid may be used as a fluidizing agent therefor (for example, Patent Document 1).
In addition, when granulated lactose is used in a mixture with a living bacterial agent, a tablet having a practically usable hardness cannot be obtained unless it is compressed with a large pressure.
さらに、錠剤が服用後速やかに崩壊することも医薬品として大切な要件であり、特に、消化酵素を配合した場合、胃または小腸上部で薬効を示すことが求められるため、崩壊性が良いことが極めて重要となる。錠剤の崩壊が悪いと、たとえ直接打錠法により低圧で作られても医薬品として条件を満たしていないものとなる。
しかしながら、従来の技術においては、生菌剤や生菌剤および消化酵素を含有した錠剤を直接打錠法によって製造すると、錠剤重量のばらつきがあり、しかもその薬効を減ずることになり、そこで小さい圧力で圧縮すると錠剤成形が行えないという問題がある。
また、流動性をよくするために混合する軽質無水ケイ酸は極めて軽い粉体物性をもつため、大量に取り扱う作業に長時間従事すると、塵肺症を起こすおそれがあることが指摘されており（第１４改、日本薬局方Ｄ−３２７）、この添加は好ましくないという問題がある。
However, in the prior art, if a tablet containing a viable agent or a viable agent and a digestive enzyme is produced by the direct compression method, there is a variation in the tablet weight, and its medicinal effect is reduced, and there is a small pressure. There is a problem that tableting cannot be performed when compressed with.
In addition, it has been pointed out that light anhydrous silicic acid mixed to improve fluidity has extremely light powder properties and may cause pneumoconiosis when engaged in a large amount of work for a long time. 14 revision, Japanese Pharmacopoeia D-327), there is a problem that this addition is not preferable.
そこで本発明は、賦形剤として結晶セルロース・軽質無水ケイ酸結合体を用い、かつ生菌剤や消化酵素剤あるいは生菌剤と消化酵素剤を同時に配合した粉末を混合した後に直接打錠することを特徴とする。
すなわち、生菌剤１００重量部に対して結晶セルロース・軽質無水ケイ酸結合体３００〜８０００重量部を含んでなる組成物により構成され、これによって小さい圧力で圧縮する直接打錠によって成型した錠剤の製造方法およびそれによる錠剤である。
Therefore, the present invention uses a crystalline cellulose / lightly anhydrous silicic acid conjugate as an excipient, and directly compresses tablets after mixing a viable agent, a digestive enzyme agent, or a powder containing a mixture of a viable agent and a digestive enzyme agent at the same time. It is characterized by that.
That is, it is composed of a composition comprising 300 to 8000 parts by weight of crystalline cellulose / light anhydrous silicic acid conjugate with respect to 100 parts by weight of the viable fungus, and thereby a tablet molded by direct compression compressed with a small pressure. Manufacturing method and tablet thereby.
さらに、消化酵素剤１００重量部に対して結晶セルロース・軽質無水ケイ酸結合体３００〜２０００重量部を含んでなる組成物により構成され、これによって小さい圧力で圧縮する直接打錠によって成型した錠剤の製造方法およびそれによる錠剤である。
さらに、生菌剤１００重量部および消化酵素剤１００重量部に対して結晶セルロース・軽質無水ケイ酸結合体３００〜８０００重量部を含んでなる組成物により構成され、これによって小さい圧力で圧縮する直接打錠によって成型した錠剤の製造方法およびそれによる錠剤である。
Furthermore, it is composed of a composition comprising 300 to 2000 parts by weight of crystalline cellulose / lightly anhydrous silicic acid conjugate with respect to 100 parts by weight of the digestive enzyme agent, thereby forming a tablet formed by direct compression which is compressed with a small pressure. Manufacturing method and tablet thereby.
Further, it is composed of a composition comprising 300 to 8000 parts by weight of a crystalline cellulose / lightly anhydrous silicic acid conjugate with respect to 100 parts by weight of a living bacterial agent and 100 parts by weight of a digestive enzyme agent, thereby directly compressing at a low pressure. The manufacturing method of the tablet shape | molded by tableting, and the tablet by it.
また、これらの錠剤の製造方法およびそれによる錠剤において、錠剤硬度の調整を可能にするため上記割合の組成物に対して３００〜８０００重量部の乾燥酵母を添加して成型した錠剤の製造方法およびそれによる錠剤である。 Further, in the method for producing these tablets and the tablets thereby, a method for producing tablets formed by adding 300 to 8000 parts by weight of dry yeast to the above-mentioned composition in order to enable adjustment of tablet hardness, and It is a tablet by it.
これにより、本発明は、賦形剤として結晶セルロース・軽質無水ケイ酸結合体を使用することによって、生菌剤や消化酵素剤あるいはその両者を含有する錠剤を小さい圧力による圧縮でしかも直接打錠で製造することができる効果を有する。
これにより、大きい圧力の圧縮成型による生菌剤における生菌数の減少、消化酵素剤における酵素活性の減少がほとんどない生菌剤、消化酵素剤を含有した錠剤を得ることができる。
As a result, the present invention uses a crystalline cellulose / lightly anhydrous silicic acid conjugate as an excipient, so that tablets containing viable bacterial agents, digestive enzyme agents, or both can be directly compressed with low pressure. It has the effect which can be manufactured with.
As a result, it is possible to obtain a tablet containing a viable bacterial agent and a digestive enzyme agent with little decrease in the number of viable bacteria in the viable agent due to compression molding under a large pressure and almost no decrease in the enzyme activity in the digestive enzyme agent.
また、製造された錠剤は、日本薬局方の崩壊試験法に従い、崩壊試験を行うとき、その崩壊時間は２分以内であり、薬効発現にも優れた錠剤となる。 Moreover, when the disintegration test is performed according to the disintegration test method of the Japanese Pharmacopoeia, the manufactured tablet has a disintegration time of 2 minutes or less, and has excellent drug efficacy.
本発明において、生菌剤とは、いわゆる乳酸菌製剤と呼ばれるもので、腸内で乳酸を産生させて腸内のｐＨを低下させることによって、悪玉菌（大腸菌、病原菌）の発育を抑制し、腸の蠕動運動を促進することで、腸内細菌叢の異常により起こる便秘、下痢の症状を改善するものである。
このような生菌剤を具体的に例示すると、ビフィズス菌、アシドフィルス菌、フェカリス菌、宮入菌、乳酸菌、ラクトバチルス菌、酪酸菌、有胞子性乳酸菌（ラクボン原末）、ビスバン原末、ビオナットミン等があげられる。
In the present invention, the viable agent is a so-called lactic acid bacterium preparation, which suppresses the growth of bad bacteria (E. coli, pathogen) by producing lactic acid in the intestine and lowering the pH in the intestine. By promoting peristaltic movements of the body, it improves constipation and diarrhea caused by abnormalities in the intestinal flora.
Specific examples of such viable agents include bifidobacteria, acidophilus, fecalis, Miyairi, lactic acid, lactobacilli, butyric acid, spore-forming lactic acid bacteria (lacbon bulk powder), bisvan bulk powder, bionutmin, etc. Can be given.
また、消化酵素剤とは、食事により取り入れたそれぞれの栄養素に対応できるように消化酵素を製剤化したものである。消化酵素には、ジアスターゼ、リパーゼ、ペプシン、パンクレアチン、セルラーゼとあるが、そのうち、でんぷん消化酵素としてのビオジアスターゼやタカジアスターゼ、脂肪消化酵素としてのリパーゼが使用できる具体的な消化酵素剤としてあげられる。 Moreover, a digestive enzyme agent formulates a digestive enzyme so that it can respond to each nutrient taken in by the meal. Digestases include diastase, lipase, pepsin, pancreatin, and cellulase. Among them, biodiastase and takadiastase as starch digestive enzymes and lipases as fat digestive enzymes can be used as specific digestive enzyme agents. .
本発明の錠剤では、賦形剤として、結晶セルロース・軽質無水ケイ酸結合体（例えば、株式会社ＪＲＳ製、商品名プロソルブ）を使用するものである。これは、結晶セルロースのスラリー中に軽質無水ケイ酸をコロイド状にして分散した後、噴霧乾燥等により粉末化した結合体であり、結晶セルロースに比べて高い表面積（約５倍）をもち、さらに、高い流動性、圧縮性をもち、結晶セルロースと軽質無水ケイ酸の混合物とはまったく違う特性をもっているものである。無論、本品を用いて錠剤製造工程中に軽質無水ケイ酸の飛散はない。なお、本実施例では、結晶セルロースと軽質無水ケイ酸が重量比で９８：２のものを用いた。 In the tablet of the present invention, a crystalline cellulose / lightly anhydrous silicic acid conjugate (for example, product name Prosolv, manufactured by JRS Co., Ltd.) is used as an excipient. This is a bonded body in which light anhydrous silicic acid is colloidally dispersed in a slurry of crystalline cellulose and then pulverized by spray drying or the like, and has a high surface area (about 5 times) compared to crystalline cellulose. It has high fluidity and compressibility, and has completely different characteristics from a mixture of crystalline cellulose and light anhydrous silicic acid. Of course, there is no light silicic acid dispersion during the tablet manufacturing process using this product. In this example, crystalline cellulose and light anhydrous silicic acid having a weight ratio of 98: 2 were used.
上記結晶セルロース・軽質無水ケイ酸結合体の配合量は、生菌剤１００重量部に対して３００〜８０００重量部であり、好ましくは５００〜７０００重量部である。
ここで、結晶セルロース・軽質無水ケイ酸結合体の配合量が、生菌剤１００重量部に対して３００重量部より少ないと、生菌剤の粉末の性質が強く現れ、粉末の圧縮性が悪くなり、結果として製造される錠剤の硬度が小さいものとなり、実用に供することができない。他方、８０００重量部を超えると、一定重量の錠剤を製造しようとすると錠剤の直径が大きくなり過ぎて服用性が悪くなり実用に供するには問題となる。
The compounding amount of the crystalline cellulose / lightly anhydrous silicic acid conjugate is 300 to 8000 parts by weight, preferably 500 to 7000 parts by weight, with respect to 100 parts by weight of the living bacterial agent.
Here, when the blending amount of the crystalline cellulose / lightly anhydrous silicic acid conjugate is less than 300 parts by weight with respect to 100 parts by weight of the living bacterial agent, the properties of the powder of the living bacterial agent appear strongly, and the compressibility of the powder is poor. As a result, the hardness of the manufactured tablet is small and cannot be put to practical use. On the other hand, when the amount exceeds 8000 parts by weight, when trying to produce a tablet having a constant weight, the diameter of the tablet becomes too large, and the ingestibility becomes worse, which is problematic for practical use.
また、消化酵素剤は、消化酵素剤１００重量部に対して結晶セルロース・軽質無水ケイ酸結合体の配合量は、３００〜２０００重量部、好ましくは５００〜１５００重量部である。
ここで、結晶セルロース・軽質無水ケイ酸結合体の配合量が、生菌剤１００重量部に対して３００重量部より少ない場合、消化酵素剤の粉末の性質が強く現れ、粉末の圧縮性が悪くなり、結果として製造される錠剤の硬度が小さいものになり、実用に供することができない。他方、この結晶セルロース・軽質無水ケイ酸結合体の配合量が２０００重量部を超えると、一定量の錠剤を製造しようとすると錠剤の直径が大きくなり過ぎて服用性が悪く、実用に供するには問題となる。
In the digestive enzyme agent, the blending amount of the crystalline cellulose / lightly anhydrous silicic acid conjugate is 300 to 2000 parts by weight, preferably 500 to 1500 parts by weight with respect to 100 parts by weight of the digestive enzyme agent.
Here, when the blending amount of the crystalline cellulose / lightly anhydrous silicic acid conjugate is less than 300 parts by weight with respect to 100 parts by weight of the viable bacterial agent, the properties of the powder of the digestive enzyme agent strongly appear and the compressibility of the powder is poor. As a result, the hardness of the manufactured tablet is small and cannot be put to practical use. On the other hand, if the blended amount of the crystalline cellulose / lightly anhydrous silicic acid conjugate exceeds 2000 parts by weight, when trying to produce a certain amount of tablets, the diameter of the tablets becomes too large and the dosage is poor, so that it can be put to practical use. It becomes a problem.
生菌剤と消化酵素剤を共に配合する場合においては、生菌剤１００重量部と消化酵素剤１００重量部に対して、結晶セルロース・軽質無水ケイ酸結合体の配合量は、３００から８０００重量部、好ましくは５００〜７０００重量部である。ここで、結晶セルロース・軽質無水ケイ酸結合体の配合量が、生菌剤及び消化酵素剤の各１００重量部に対して３００重量部より少ないと、生菌剤および消化酵素の粉末の性質が強く現れ、粉末の圧縮性が悪くなり、結果として製造される錠剤の硬度が小さいものとなり、実用に供することができない。他方、この結晶セルロース・軽質無水ケイ酸結合体の配合量が８０００重量部を超えると、一定重量の錠剤を製造しようとすると錠剤の直径が大きくなり過ぎて服用性が悪く、実用に供するには問題となる。 In the case where both the viable agent and the digestive enzyme agent are blended, the blending amount of the crystalline cellulose / light anhydrous silicic acid conjugate is 300 to 8000 weights with respect to 100 parts by weight of the viable agent and 100 parts by weight of the digestive enzyme agent. Parts, preferably 500 to 7000 parts by weight. Here, when the blending amount of the crystalline cellulose / lightly anhydrous silicic acid conjugate is less than 300 parts by weight with respect to 100 parts by weight of each of the viable fungus and the digestive enzyme, the properties of the powder of the live fungus and the digestive enzyme are reduced. It appears strongly, the compressibility of the powder is deteriorated, and as a result, the hardness of the produced tablet becomes small and cannot be put to practical use. On the other hand, when the blending amount of the crystalline cellulose / lightly anhydrous silicic acid conjugate exceeds 8000 parts by weight, when trying to produce a tablet having a constant weight, the diameter of the tablet becomes too large to be taken, so that it can be put into practical use. It becomes a problem.
生菌剤、消化酵素剤そして生菌剤と消化酵素剤を共に配合し、結晶セルロース・軽質無水ケイ酸結合体を加え、直接打錠により錠剤を製造する場合、さらに、錠剤硬度の調整として乾燥酵母を配合してもよい。
乾燥酵母は、日本温薬局方に収載されており、主としてビール醸造の際に得られるビール酵母より製したものである。
In the case of producing tablets by direct tableting by adding live bacteria agent, digestive enzyme agent and live bacteria agent and digestive enzyme agent together, adding crystalline cellulose / lightly silicic acid conjugate, and further adjusting the tablet hardness You may mix | blend yeast.
Dried yeast is listed in the Japanese Wen Pharmacopoeia, and is mainly made from brewer's yeast obtained during brewing.
前記したとおり、賦形剤として結晶セルロース・軽質無水ケイ酸結合体を用いると、生菌剤や消化酵素剤を配合しても流動性がよく、錠剤を製造することが可能であるが、製造した錠剤の硬度が非常に大きいことがわかった。硬度が大きいと、製造した錠剤の搬送等の際の外部からの力に対しては有効にはたらき、錠剤の割れや欠けが少なくなりよいものの、必要以上に硬度が大きいと錠剤の崩壊が悪くなり、投与後体内でその有効性を発揮することができないことになる。その意味で錠剤硬度の調整は重要である。 As described above, when crystalline cellulose / lightly anhydrous silicic acid conjugate is used as an excipient, it is possible to produce a tablet with good fluidity even if a live fungus agent or digestive enzyme agent is added. The hardness of the prepared tablets was found to be very large. If the hardness is high, it will work effectively against external forces when transporting the manufactured tablets, etc., and the tablet may be less cracked or chipped, but if the hardness is higher than necessary, the tablets will not collapse. It will not be able to exert its effectiveness in the body after administration. In that sense, adjustment of tablet hardness is important.
乾燥酵母は、錠剤の硬度調整剤としての配合量は、生菌剤１００重量部、結晶セルロース・軽質無水ケイ酸結合体に対して３００〜８０００重量部の組成物に対して乾燥酵母は３００〜８０００重量部である。好ましくは、同組成物に対して、５００〜７０００重量部である。
また、消化酵素剤１００重量部、結晶セルロース・軽質無水ケイ酸結合体に対して３００〜８０００重量部の組成物に対して乾燥酵母は２００〜１０００重量部である。好ましくは、同組成物に対して５００〜７０００重量部である。
The dry yeast is blended as a tablet hardness adjusting agent in an amount of 100 to 100 parts by weight of the living bacterial agent, and 300 to 8000 parts by weight of the dry yeast to 300 to 8000 parts by weight of the crystalline cellulose / lightly anhydrous silicic acid conjugate. 8000 parts by weight. Preferably, it is 500 to 7000 parts by weight with respect to the same composition.
Moreover, dry yeast is 200-1000 weight part with respect to a composition of 300-8000 weight part with respect to a digestive enzyme agent 100 weight part and a crystalline cellulose and light anhydrous silicic acid conjugate. Preferably, it is 500-7000 weight part with respect to the same composition.
さらに、生菌剤１００重量部、消化酵素剤１００重量部、結晶セルロース・軽質無水ケイ酸結合体に対して３００〜８０００重量部の組成物に対して乾燥酵母は３００〜８０００重量部である。好ましくは、同組成物に対して５００〜７０００重量部である。
ここで、乾燥酵母の配合量が、消化酵素剤１００重量部に対して２００重量部より少ない場合、できあがった錠剤の硬度が１５ｋｇｆ以上と大きく、崩壊時間が大きくなり、期待する薬効がうまく発揮できない。
Furthermore, dry yeast is 300-8000 weight part with respect to a composition of 300-8000 weight part with respect to 100 weight part of live bacteria agents, 100 weight part of digestive enzyme agent, and crystalline cellulose and light anhydrous silicic acid conjugate. Preferably, it is 500-7000 weight part with respect to the same composition.
Here, when the amount of dry yeast is less than 200 parts by weight with respect to 100 parts by weight of the digestive enzyme agent, the hardness of the finished tablet is as large as 15 kgf or more, the disintegration time is increased, and the expected medicinal effect cannot be exhibited well. .
他方、乾燥酵母の配合量が８０００重量部より多い場合、一定重量の錠剤を製造しようとすると、できあがった錠剤の硬度が５ｋｇｆ以下となり、錠剤の割れ、欠けが多くなり、実用に供するには問題がでてくるのみならず、錠剤の直径が大きくなり過ぎて服用性が悪くなる。
以上の組成からなる本発明の顆粒の製造方法は、特に制限されるものではなく、生菌剤１００重量部、結晶セルロース・軽質無水ケイ酸結合体３００〜８０００重量部、乾燥酵母３００〜８０００重量部および滑沢剤１〜５０重量部とを含む原料粉末組成物を得、これを直接打錠するものである。
On the other hand, when the amount of dry yeast is more than 8000 parts by weight, when trying to produce a tablet with a constant weight, the hardness of the finished tablet becomes 5 kgf or less, and the tablet is cracked and chipped, which is problematic for practical use. Not only does this occur, but the diameter of the tablet becomes too large, resulting in poor dosage.
The method for producing the granule of the present invention having the above composition is not particularly limited, and 100 parts by weight of the viable bacterial agent, 300 to 8000 parts by weight of crystalline cellulose / light anhydrous silicic acid conjugate, 300 to 8000 parts by weight of dry yeast. A raw material powder composition containing 1 part by weight and 1 to 50 parts by weight of a lubricant is obtained and directly compressed.
結晶セルロース・軽質無水ケイ酸結合体と乾燥酵母を配合したときの製造した錠剤の硬度調整に関する検討結果を図１に示す。
図１に示す如く、打錠圧６５０〜７００ｋｇｆで錠剤を製造し、結晶セルロース・軽質無水ケイ酸結合体を単独で用いたときの錠剤硬度は２５ｋｇｆ以上であり、あまりにも大き過ぎる硬度となるが、乾燥酵母を加えるにしたがって徐々に硬度が小さくなることが明らかとなった。
The examination result regarding the hardness adjustment of the manufactured tablet when the crystalline cellulose / light anhydrous silicic acid conjugate and dry yeast are blended is shown in FIG.
As shown in FIG. 1, when a tablet is produced at a tableting pressure of 650 to 700 kgf and the crystalline cellulose / lightly anhydrous silicic acid conjugate is used alone, the tablet hardness is 25 kgf or more, which is too high. It was revealed that the hardness gradually decreased as dry yeast was added.
結晶セルロース・軽質無水ケイ酸結合体と乾燥酵母を１：１にしたときには、硬度は薬５ｋｇｆになる。また、１：１の配合の場合に、錠剤の製造時の打錠圧を大きくするにしたがって、錠剤硬度も大きくなることがわかり（図２）、結晶セルロース・改質無水ケイ酸結合体と乾燥酵母の比率と打錠圧を換えることにより、希望する錠剤が得られることがわかった。 When the crystalline cellulose / lightly anhydrous silicic acid conjugate and dry yeast are in a ratio of 1: 1, the hardness is 5 kgf. In addition, in the case of the 1: 1 formulation, it can be seen that as the tableting pressure at the time of tablet production is increased, the tablet hardness increases (FIG. 2), and the crystalline cellulose / modified silicic acid conjugate and dried It was found that the desired tablet can be obtained by changing the yeast ratio and tableting pressure.
乾燥酵母は、このように錠剤硬度調整用の粉末として機能する他、乳酸菌の生育を助ける栄養補強源としての役割もはたすことができる。
打錠に供する粉体の混合は、特別な混合機を使用する必要はなく、通常製薬で使用されるものでよいが、好ましくはＶ型混合機と呼ばれるものがよい。
混合後の粉体を用いて錠剤を製造する場合、通常は滑沢剤を加えて圧縮成型すればよく、使用する打錠機は、公知のものでよい。
In addition to functioning as a powder for adjusting tablet hardness, dry yeast can also serve as a nutrient reinforcement source that helps the growth of lactic acid bacteria.
The mixing of the powder to be used for tableting does not need to use a special mixer, and may be usually used in pharmaceuticals, but is preferably a so-called V-type mixer.
When a tablet is produced using the powder after mixing, usually a lubricant may be added and compression molded, and the tableting machine used may be a known one.
このようにして製造した錠剤には、フィルムコーティングまたは糖衣コーティングを施すコーティング工程を適宜に設けてもよい。
なお、本発明の顆粒は、上記のように錠剤に成型するだけでなく、カプセルに充填してカプセル剤として使用しても有用である。この場合も、カプセルへの充填装置は公知のものが使用可能である。
The tablets thus produced may be appropriately provided with a coating process for applying film coating or sugar coating.
The granules of the present invention are useful not only for forming into tablets as described above, but also for filling capsules and using them as capsules. Also in this case, a known device for filling capsules can be used.
実施例
以下に本発明の実施例を説明する。
なお、錠剤の硬度、崩壊時間の値は、以下の方法により測定した。
錠剤の硬度の測定
錠剤の硬度は、第１３日本薬局方の錠剤の項に記載された方法、すなわち、側面方向の破壊強度を測定するものである。測定した機器は、富山産業株式会社製の錠剤硬度計、ＴＨ−２０３ＭＰである。
Examples of the present invention will be described below.
The tablet hardness and disintegration time were measured by the following methods.
Measurement of tablet hardness Tablet hardness is the method described in the 13th Japanese Pharmacopoeia tablet section, that is, the fracture strength in the lateral direction is measured. The measured instrument is a tablet hardness meter, TH-203MP, manufactured by Toyama Sangyo Co., Ltd.
錠剤の崩壊時間の測定
錠剤の崩壊時間は、第１３日本薬局方の錠剤の項に記載された方法、すなわち、水の中で錠剤を入れたバスケットを一定時間、上下運動させて残留物がなくなるかあるいは軟質物がわずかになる時間を測定するものである。測定した機器は、富山産業株式会社製の錠剤崩壊試験器、ＮＴ−２０ＨＳである。
Measurement of tablet disintegration time The tablet disintegration time is determined by the method described in the 13th Japanese Pharmacopoeia tablet section, that is, the basket containing the tablets in water is moved up and down for a certain period of time to eliminate residues. Alternatively, the time when the soft material becomes small is measured. The measured instrument is a tablet disintegration tester, NT-20HS, manufactured by Toyama Sangyo Co., Ltd.
第１実施例
ビフィズス菌３３．３重量部、フェカリス菌３３．３重量部、アシドフィルス菌３３．３重量部、結晶セルロース・軽質無水ケイ酸結合体５７０重量部、乾燥酵母５７０重量部をＶ型混合機で２０分間、２５ｒｐｍで混合し、その後、ステアリン酸マグネシウム６．７重量部を同じＶ型混合機に投入し、２分間、２５ｒｐｍで混合し、打錠用の粉体とした。
Example 1 V-shaped mixture of 33.3 parts by weight of Bifidobacterium, 33.3 parts by weight of Peculiaris, 33.3 parts by weight of Acidophilus, 570 parts by weight of crystalline cellulose / lightly anhydrous silicic acid conjugate, and 570 parts by weight of dry yeast Then, 6.7 parts by weight of magnesium stearate was charged into the same V-type mixer and mixed at 25 rpm for 2 minutes to obtain a powder for tableting.
この粉体を、打錠機（株式会社菊水社製 Ｖｉｒｇｏ）を用い、打錠圧６００ｋｇ／ｃｍ２、回転数２５ｒｐｍの条件で、直径８ｍｍ、重量２２５ｍｇの錠剤を製造した。
製造した錠剤の硬度は６ｋｇｆであり、崩壊時間は２分であった。
製造した錠剤中の生菌数は、ビフィズス菌、フェカリス菌、アシドフィルス菌を合わせた総生菌数は、１錠中３．７×１０８個であった。
Using this powder, a tablet having a diameter of 8 mm and a weight of 225 mg was produced using a tableting machine (Virgo, manufactured by Kikusui Co., Ltd.) under the conditions of a tableting pressure of 600 kg / cm 2 and a rotation speed of 25 rpm.
The manufactured tablet had a hardness of 6 kgf and a disintegration time of 2 minutes.
The total number of viable bacteria in the tablets produced was 3.7 × 10 8 in one tablet, including bifidobacteria, fecalis, and acidophilus.
第２実施例
ビオヂオスターゼ１００重量部、結晶セルロース・軽質無水ケイ酸結合体３８９重量部、乾燥酵母３４０重量部をＶ型混合機を用いて２０分間、２５ｒｐｍで混合し、その後、ステアリン酸マグネシウム４重量部を同じＶ型混合機に投入し、２分間、２５ｒｐｍで混合し、打錠用の粉体とした。
Second Example 100 parts by weight of biodiostase, 389 parts by weight of crystalline cellulose / light anhydrous silicic acid conjugate, and 340 parts by weight of dry yeast were mixed at 25 rpm for 20 minutes using a V-type mixer, and then 4 parts by weight of magnesium stearate. The parts were put into the same V-type mixer and mixed at 25 rpm for 2 minutes to obtain a powder for tableting.
この粉体を、打錠機（株式会社菊水社製 Ｖｉｒｇｏ）を用い、打錠圧５００ｋｇ／ｃｍ２、回転数２５ｒｐｍの条件で、直径８ｍｍ、重量２５０ｍｇの錠剤を製造した。
製造した錠剤の硬度は９ｋｇｆであり、崩壊時間は２分であった。
製造した錠剤中のアミラーゼ力価は、１．７×１０５単位／ｇであり、中性プロテアーゼ力価は３．５×１０３単位／ｇであった。
Using this tablet, tablets with a diameter of 8 mm and a weight of 250 mg were produced using a tableting machine (Virgo, manufactured by Kikusui Co., Ltd.) under the conditions of a tableting pressure of 500 kg / cm 2 and a rotation speed of 25 rpm.
The manufactured tablet had a hardness of 9 kgf and a disintegration time of 2 minutes.
The amylase titer in the manufactured tablet was 1.7 × 10 5 units / g, and the neutral protease titer was 3.5 × 10 3 units / g.
第３実施例
リパーゼ１００重量部、結晶セルロース・軽質無水ケイ酸結合体６０９重量部、乾燥酵母５３５重量部をＶ型混合機を用いて２０分間、２５ｒｐｍで混合し、その後、ステアリン酸マグネシウム６重量部を同じＶ型混合機に投入し、２分間、２５ｒｐｍで混合し、打錠用の粉体とした。
Third Example 100 parts by weight of lipase, 609 parts by weight of crystalline cellulose / lightly anhydrous silicic acid conjugate, and 535 parts by weight of dry yeast were mixed for 20 minutes at 25 rpm using a V-type mixer, and then 6 parts by weight of magnesium stearate. The parts were put into the same V-type mixer and mixed at 25 rpm for 2 minutes to obtain a powder for tableting.
この粉体を、打錠機（株式会社菊水社製 Ｖｉｒｇｏ）を用い、打錠圧５００ｋｇ／ｃｍ２、回転数２５ｒｐｍの条件で、直径８ｍｍ、重量２５０ｍｇの錠剤を製造した。
製造した錠剤の硬度は７．５ｋｇｆであり、崩壊時間は２分であった。
製造した錠剤中のリパーゼ力価は、７１単位／ｇであった。
上記各実施例の比較例を１〜６として表１に示す。
Using this tablet, tablets with a diameter of 8 mm and a weight of 250 mg were produced using a tableting machine (Virgo, manufactured by Kikusui Co., Ltd.) under the conditions of a tableting pressure of 500 kg / cm 2 and a rotation speed of 25 rpm.
The manufactured tablet had a hardness of 7.5 kgf and a disintegration time of 2 minutes.
The lipase titer in the manufactured tablets was 71 units / g.
Table 1 shows Comparative Examples 1 to 6 of the above examples.
それぞれを打錠圧を変更した以外は、実施例１〜３と同様にして錠剤を製造した。
それぞれの打錠圧で得られた錠剤中のビフィズス菌、フェカリス菌、アシドフィルス菌、を合わせた総生菌数、アミラーゼ力価、中性プロテアーゼ力価、リパーゼ力価をそれぞれ測定して比較し、表１に示した。
Tablets were produced in the same manner as in Examples 1 to 3, except that the tableting pressure was changed.
The total number of viable bacteria, amylase titer, neutral protease titer, and lipase titer combined with bifidobacteria, fecalis, and acidophilus in the tablets obtained at each tableting pressure were measured and compared, It is shown in Table 1.
ビフィズス菌３３．３重量部、フェカリス菌３３．３重量部、アシドフィルス菌３３．３重量部、ビオジオスターゼ１６７重量部、リパーゼ１１１重量部、結晶セルロース・軽質無水ケイ酸結合体１９５０重量部、乾燥酵母１９５０重量部をＶ型混合機で２０分間、２５ｒｐｍで混合し、その後、ステアリン酸マグネシウム６．７重量部を同じＶ型混合機に投入し、２分間、２５ｒｐｍで混合し、打錠用の粉体とした。
Bifidobacteria 33.3 parts, Fecalis 33.3 parts, Acidophilus 33.3 parts, Biodiostase 167 parts, Lipase 111 parts, Crystalline cellulose / light anhydrous silicic acid conjugate 1950 parts, dried 1950 parts by weight of yeast was mixed with a V-type mixer for 20 minutes at 25 rpm, and then 6.7 parts by weight of magnesium stearate was added to the same V-type mixer and mixed for 2 minutes at 25 rpm for tableting. Powdered.
この粉体を、打錠機（株式会社菊水社製 Ｖｉｒｇｏ）を用い、打錠圧６５０ｋｇ／ｃｍ２、回転数２５ｒｐｍの条件で、直径８ｍｍ、重量２７０ｍｇの錠剤を製造した。
製造した錠剤の硬度は６ｋｇｆであり、崩壊時間は２分であった。
製造した錠剤中の生菌数は、ビフィズス菌、フェカリス菌、アシドフィルス菌を合わせた総生菌数は、１錠中３．７×１０８個であった。
Using this powder, a tablet having a diameter of 8 mm and a weight of 270 mg was produced using a tableting machine (Virgo manufactured by Kikusui Co., Ltd.) under the conditions of a tableting pressure of 650 kg / cm 2 and a rotation speed of 25 rpm.
The manufactured tablet had a hardness of 6 kgf and a disintegration time of 2 minutes.
The total number of viable bacteria in the tablets produced was 3.7 × 10 8 in one tablet, including bifidobacteria, fecalis, and acidophilus.
製造した錠剤中のアミラーゼ力価は、１．７×１０５単位／ｇ、中性プロテアーゼ力価は３．５×１０３単位／ｇ、リパーゼ力価は、７１単位／ｇであった。 The produced tablet had an amylase titer of 1.7 × 10 5 units / g, a neutral protease titer of 3.5 × 10 3 units / g, and a lipase titer of 71 units / g.
Claims (9)
6. A tablet according to claim 5, comprising 300 to 8000 parts by weight of dry yeast for each composition.
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|---|---|---|---|---|
| JP2013537531A (en) * | 2010-08-04 | 2013-10-03 | トーマス・ジュリアス・ボロディ | Composition for faecal flora transplantation and methods for making and using it and device for delivering the same |
| JP2016193894A (en) * | 2015-04-01 | 2016-11-17 | 京都薬品工業株式会社 | Viable cell-containing preparation |
| CN112220916A (en) * | 2020-10-26 | 2021-01-15 | 西南药业股份有限公司 | Preparation process of biological enzyme tablet and product thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH054926A (en) * | 1991-06-27 | 1993-01-14 | Dainippon Pharmaceut Co Ltd | Enteral useful bacterium-containing sugar-coated tablet |
| JPH11139978A (en) * | 1997-11-06 | 1999-05-25 | Asahi Beer Yakuhin Kk | Enteric live bacterium preparation |
| WO2000078292A1 (en) * | 1999-06-18 | 2000-12-28 | Takeda Chemical Industries, Ltd. | Quickly disintegrating solid preparations |
-
2005
- 2005-03-18 JP JP2005079476A patent/JP5073174B2/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH054926A (en) * | 1991-06-27 | 1993-01-14 | Dainippon Pharmaceut Co Ltd | Enteral useful bacterium-containing sugar-coated tablet |
| JPH11139978A (en) * | 1997-11-06 | 1999-05-25 | Asahi Beer Yakuhin Kk | Enteric live bacterium preparation |
| WO2000078292A1 (en) * | 1999-06-18 | 2000-12-28 | Takeda Chemical Industries, Ltd. | Quickly disintegrating solid preparations |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013537531A (en) * | 2010-08-04 | 2013-10-03 | トーマス・ジュリアス・ボロディ | Composition for faecal flora transplantation and methods for making and using it and device for delivering the same |
| JP2016193894A (en) * | 2015-04-01 | 2016-11-17 | 京都薬品工業株式会社 | Viable cell-containing preparation |
| CN112220916A (en) * | 2020-10-26 | 2021-01-15 | 西南药业股份有限公司 | Preparation process of biological enzyme tablet and product thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5073174B2 (en) | 2012-11-14 |
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