JP2011102250A - Method for producing viable bacterial preparation - Google Patents
Method for producing viable bacterial preparation Download PDFInfo
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- JP2011102250A JP2011102250A JP2009256918A JP2009256918A JP2011102250A JP 2011102250 A JP2011102250 A JP 2011102250A JP 2009256918 A JP2009256918 A JP 2009256918A JP 2009256918 A JP2009256918 A JP 2009256918A JP 2011102250 A JP2011102250 A JP 2011102250A
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- 241000894006 Bacteria Species 0.000 claims abstract description 125
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- 238000000034 method Methods 0.000 claims abstract description 51
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
本発明は、生菌を含有する製剤の製造方法に関する。 The present invention relates to a method for producing a preparation containing viable bacteria.
乳酸菌、ビフィズス菌などの生菌は、整腸作用、免疫賦活作用など人体に有益な働きを持つことが知られており、広く医薬品、食品などに利用されている。例えば、生菌製剤としては、錠剤、カプセル、顆粒剤などが利用されている。 Live bacteria such as lactic acid bacteria and bifidobacteria are known to have beneficial effects on the human body such as intestinal regulation and immunostimulation, and are widely used in medicines, foods and the like. For example, tablets, capsules, granules and the like are used as viable bacterial preparations.
この中で、錠剤には、携帯性に優れる、一定量の生菌を容易に摂取できる等の利点がある。しかしながら、生菌を錠剤とする場合の製造上の問題の１つとして、有効成分である菌が、打錠工程で死滅することが挙げられる。また、一般に、製剤に含まれる生菌は、製剤中の水分量が少ないほど安定性が高いことが知られている。一方で、製剤を錠剤化する場合、製剤原料中の水分値が一定以下になると、打錠成型性が極端に低下するため、これが生菌製剤の錠剤化を困難にする一因となっている。従って、一定以上の生菌を含有する錠剤を定常的に製造するためには、打錠工程で死滅する菌数を考慮し、その分の生菌を増し仕込みする必要があり、含有生菌数の高い原薬が大量に必要になるなどコスト面で問題が生じている。また、打錠工程における菌の死滅を避けるために低打錠圧で打錠すると、錠剤強度が低下し、保管時又は搬送時に錠剤が割れやすくなるなど品質上の問題が生じる。従って、打錠工程における死滅率の高い菌又は高生菌数の原薬が得難い菌を生菌製剤とする場合には、散剤又はカプセル剤などで製品化されることが多かった。 Among these, tablets have advantages such as excellent portability and easy intake of a certain amount of viable bacteria. However, one of the manufacturing problems when using live bacteria as a tablet is that the active ingredient is killed in the tableting process. In general, it is known that viable bacteria contained in a preparation have higher stability as the amount of water in the preparation is smaller. On the other hand, when tableting the preparation, if the moisture value in the preparation raw material is below a certain level, the tableting moldability is extremely lowered, which is one factor that makes it difficult to tablet a viable bacterial preparation. . Therefore, in order to steadily produce tablets containing a certain number of viable bacteria, it is necessary to take into account the number of bacteria killed in the tableting process and increase the amount of viable bacteria. There is a problem in terms of cost, such as the need for a large amount of high drug substance. In addition, when tableting is performed at a low tableting pressure in order to avoid sterilization of bacteria in the tableting process, tablet strength is reduced, and quality problems such as tablet breakage during storage or transportation occur. Therefore, when a bacterium having a high killing rate in the tableting process or a bacterium having a high viable count is difficult to obtain, it is often commercialized as a powder or a capsule.
このため、生菌製剤を錠剤とする場合に、打錠工程における菌の生存率を高くすることができ、しかも適度な強度を有する錠剤を製造することができる方法が望まれていた。 For this reason, when making a living microbe formulation into a tablet, the method which can make the survival rate of the microbe in a tableting process high and can manufacture the tablet which has moderate intensity | strength was desired.
本発明は、上記現状に鑑み、生菌を有効成分とする生菌製剤において、製造時の菌生存率が高く、かつ製剤後の菌の死滅が少なく、さらに錠剤の硬度が高くて摩損度が小さく、しかも良好な崩壊性を有する生菌錠剤を製造することができる方法を提供することを目的とする。 In view of the present situation, the present invention provides a viable preparation containing viable bacteria as an active ingredient, has a high fungal survival rate at the time of manufacture, has a low killing of the fungus after the preparation, and has a high tablet hardness and friability. It is an object of the present invention to provide a method capable of producing a small viable tablet having good disintegration property.
本発明者らは、上記課題に鑑み鋭意研究を重ねた結果、デンプンを含有する賦形剤組成物を造粒し、得られた顆粒１質量部に対して０．１５〜１．０質量部の、二糖類、多糖類及び炭酸カルシウムを含有する粉体組成物を造粒せずに添加して混合し、さらに生菌を添加して混合することにより得られる生菌含有組成物は、造粒していない粉体の含量が高いにもかかわらず成型性が良好なものであることを見出した。また、該生菌含有組成物は、水分量（乾燥減量）が約１．５〜２．５％と少なくても成型性が良好なものであることを見出した。また、該生菌含有組成物を、打錠圧１０〜２０ｋＮ／ｃｍ２（５〜１０ｋＮ）で圧縮成形すると、打錠工程における菌の生存率を高くすることができること、１０〜２０ｋＮ／ｃｍ２の比較的低い打錠圧であっても成型性が良好であり、得られる錠剤は、硬度が高くて錠剤表面の摩損度が小さく、しかも良好な崩壊性を有するものであることを見出した。さらに、該生菌含有組成物を生菌製剤の原料として用いると、製剤中の水分量を少なくできることから、製剤中の菌の安定性を向上させることができるため、製剤後の菌の死滅を抑制できることを見出し、製造時及び製剤中の菌の生存率を高く保ったまま、硬度が高い生菌製剤を製造することができることに想到した。
本発明者らは、上記知見に基づきさらに研究を重ね、本発明を完成するに至った。
As a result of intensive studies in view of the above problems, the present inventors granulated an excipient composition containing starch, and 0.15 to 1.0 part by mass with respect to 1 part by mass of the obtained granule. A viable cell-containing composition obtained by adding and mixing a powder composition containing disaccharides, polysaccharides and calcium carbonate without granulation, and further adding and mixing viable cells, It has been found that the moldability is good despite the high content of non-granulated powder. Further, the present inventors have found that the viable cell-containing composition has good moldability even when the water content (loss on drying) is as low as about 1.5 to 2.5%. Moreover, when this live microbe containing composition is compression-molded by tableting pressure 10-20kN / cm < 2 > (5-10kN), the survival rate of the microbe in a tableting process can be made high, 10-20kN / cm < 2 >. It was found that the moldability was good even at a relatively low tableting pressure, and the resulting tablets had high hardness, low friability on the tablet surface, and good disintegration. Furthermore, when the composition containing viable bacteria is used as a raw material of a viable preparation, the amount of water in the preparation can be reduced, so that the stability of the fungus in the preparation can be improved. It was found that it can be suppressed, and it was conceived that a viable bacterial preparation having high hardness can be produced while maintaining a high survival rate of bacteria in the production and in the preparation.
The present inventors have further studied based on the above findings and have completed the present invention.
すなわち、本発明は、以下の項１．〜項１０．に関する。
項１． （１）デンプンを含有する賦形剤組成物（Ｉ）を造粒し、顆粒を得る工程、
（２）該顆粒と、二糖類、多糖類及び炭酸カルシウムを含有する粉体組成物（ＩＩ）と、生菌とを混合して生菌含有組成物を得る工程、及び、
（３）該生菌含有組成物を打錠圧１０〜２０ｋＮ／ｃｍ２で圧縮成形する工程、
を含み、工程（２）における粉体組成物（ＩＩ）の配合量が、顆粒１質量部に対して０．１５〜１．０質量部であることを特徴とする生菌製剤の製造方法。
項２． 生菌が、ビフィズス菌、乳酸菌、糖化菌、酪酸菌及び酵母からなる群より選ばれる少なくとも１種の菌である項１に記載の方法。
項３． デンプンの配合量が、賦形剤組成物（Ｉ）に対して２０〜５０質量％である項１又は２に記載の方法。
項４． デンプンが、トウモロコシデンプンである項１〜３の何れか１項に記載の方法。
項５． 粉体組成物（ＩＩ）に含有される二糖類が、麦芽糖である項１〜４のいずれか１項に記載の方法。
項６． 粉体組成物（ＩＩ）に含有される多糖類が、デキストリンである項１〜５のいずれか１項に記載の方法。
項７． 二糖類の配合量が、粉体組成物（ＩＩ）に対して３０〜７０質量％である項１〜６の何れか１項に記載の方法。
項８． 多糖類の配合量が、粉体組成物（ＩＩ）に対して２０〜６０質量％である項１〜７の何れか１項に記載の方法。
項９． 炭酸カルシウムの配合量が、粉体組成物（ＩＩ）に対して５〜２０質量％である項１〜８の何れか１項記載の方法。
項１０． 工程（２）において、さらに滑沢剤を添加して混合する項１〜９の何れか１項に記載の方法。
That is, the present invention provides the following items 1. To Item 10. About.
Item 1. (1) A step of granulating the excipient composition (I) containing starch to obtain granules,
(2) A step of mixing the granules, a powder composition (II) containing disaccharides, polysaccharides and calcium carbonate with viable bacteria to obtain a viable bacteria-containing composition; and
(3) a step of compression-molding the viable cell-containing composition at a tableting pressure of 10 to 20 kN / cm 2 ;
And the blending amount of the powder composition (II) in the step (2) is 0.15 to 1.0 part by mass with respect to 1 part by mass of the granule.
Item 2. Item 2. The method according to Item 1, wherein the living bacterium is at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, butyric acid bacterium, and yeast.
Item 3. Item 3. The method according to Item 1 or 2, wherein the compounding amount of starch is 20 to 50% by mass with respect to the excipient composition (I).
Item 4. Item 4. The method according to any one of Items 1 to 3, wherein the starch is corn starch.
Item 5. Item 5. The method according to any one of Items 1 to 4, wherein the disaccharide contained in the powder composition (II) is maltose.
Item 6. Item 6. The method according to any one of Items 1 to 5, wherein the polysaccharide contained in the powder composition (II) is dextrin.
Item 7. Item 7. The method according to any one of Items 1 to 6, wherein a blending amount of the disaccharide is 30 to 70% by mass with respect to the powder composition (II).
Item 8. Item 8. The method according to any one of Items 1 to 7, wherein the compounding amount of the polysaccharide is 20 to 60% by mass with respect to the powder composition (II).
Item 9. Item 9. The method according to any one of Items 1 to 8, wherein the amount of calcium carbonate is 5 to 20% by mass relative to the powder composition (II).
Item 10. Item 10. The method according to any one of Items 1 to 9, wherein a lubricant is further added and mixed in the step (2).
本発明の方法によれば、製剤製造中、特に打錠工程における菌の生存率を高くすることができ、しかも製剤中の菌の生存率が高い（死滅が少ない）生菌製剤を製造することができる。さらに、本発明の方法によれば、表面が強靭で摩損度が小さく、しかも良好な崩壊性を有する生菌錠剤等を製造することができる。このため本発明によれば、製剤製造時及び製剤後の生菌の生存率を高く維持しつつ、錠剤硬度を高くすることができる。また、本発明の方法によれば、錠剤の製造における造粒工程に要する時間を短縮化することもできる。 According to the method of the present invention, it is possible to increase the survival rate of bacteria in the tableting process, particularly during the preparation of the preparation, and to produce a viable cell preparation having a high survival rate (less killed) in the preparation. Can do. Furthermore, according to the method of the present invention, it is possible to produce viable bacteria tablets and the like having a tough surface, low friability, and good disintegration. For this reason, according to this invention, tablet hardness can be made high, maintaining the survival rate of the living microbe at the time of formulation manufacture and after a formulation high. Moreover, according to the method of the present invention, the time required for the granulation step in tablet production can be shortened.
本発明の生菌製剤の製造方法は、
（１）デンプンを含有する賦形剤組成物（Ｉ）を造粒し、顆粒を得る工程、
（２）該顆粒と、二糖類、多糖類及び炭酸カルシウムを含有する粉体組成物（ＩＩ）と、生菌とを混合して生菌含有組成物を得る工程、及び、
（３）該生菌含有組成物を打錠圧１０〜２０ｋＮ／ｃｍ２で圧縮成形する工程、
を含み、工程（２）における粉体組成物（ＩＩ）の配合量が、顆粒１質量部に対して０．１５〜１．０質量部である。
本発明の方法は、本発明の効果を奏する限り、上記（１）〜（３）以外の工程を含んでもよい。
The method for producing the viable cell preparation of the present invention comprises:
(1) A step of granulating the excipient composition (I) containing starch to obtain granules,
(2) A step of mixing the granules, a powder composition (II) containing disaccharides, polysaccharides and calcium carbonate with viable bacteria to obtain a viable bacteria-containing composition; and
(3) a step of compression-molding the viable cell-containing composition at a tableting pressure of 10 to 20 kN / cm 2 ;
The blending amount of the powder composition (II) in the step (2) is 0.15 to 1.0 part by mass with respect to 1 part by mass of the granule.
The method of the present invention may include steps other than the above (1) to (3) as long as the effects of the present invention are exhibited.
賦形剤組成物（Ｉ）とは、造粒の適用対象でデンプンを含有する粉体の処方物をいい、デンプンのみを含有するものであってもよいが、他の医薬品上許容される賦形剤を含んでもよい。また、必要に応じてその他の原料を含んでもよい。その他の原料としては、医薬品上許容される成分であればよく、例えば、香料、矯味剤（甘味料、酸味料など）等が挙げられる。 The excipient composition (I) refers to a powder formulation containing starch as a granulation application target, and may contain only starch, but other pharmaceutically acceptable additives. A form may also be included. Moreover, you may contain another raw material as needed. Other raw materials may be any components that are pharmaceutically acceptable and include, for example, fragrances, flavoring agents (sweeteners, acidulants, etc.) and the like.
賦形剤組成物（Ｉ）に含まれるデンプンとして、通常、トウモロコシデンプン、バレイショデンプン、コメデンプン、コムギデンプン等を１種または２種以上組合わせて用いることができる。好ましくは、トウモロコシデンプンである。デンプンの配合量は、賦形剤組成物（Ｉ）に対して約２０〜５０質量％とすることが好ましく、約３０〜４０質量％とすることがより好ましい。デンプンの配合量が上記範囲であると、成形性が良く、崩壊性が良く、乳酸菌の安定性が良いことから好ましい。 As the starch contained in the excipient composition (I), corn starch, potato starch, rice starch, wheat starch and the like can be usually used alone or in combination. Corn starch is preferable. The starch content is preferably about 20 to 50% by mass, more preferably about 30 to 40% by mass, based on the excipient composition (I). It is preferable for the amount of starch to be in the above range because moldability is good, disintegration is good, and stability of lactic acid bacteria is good.
他の医薬上許容される賦形剤は特に限定されず、通常使用されるものを適宜選択して用いることができる。例えば、乳糖水和物、麦芽糖、ショ糖（スクロース）、トレハロース等の二糖類；シクロデキストリン、デキストリン等の多糖類；沈降炭酸カルシウム等の炭酸カルシウム；結晶セルロース、ヒドロキシプロピルセルロース等のセルロース又はセルロース誘導体；軽質無水ケイ酸、リン酸ナトリウム等が挙げられる。賦形剤組成物（Ｉ）に含有される賦形剤としては、二糖類、多糖類、炭酸カルシウム等が好ましい。本発明の好ましい態様の１つは、賦形剤組成物（Ｉ）が、さらに、二糖類、多糖類及び炭酸カルシウムからなる群より選択される少なくとも１種を含有することである。 Other pharmaceutically acceptable excipients are not particularly limited, and those usually used can be appropriately selected and used. For example, disaccharides such as lactose hydrate, maltose, sucrose, trehalose; polysaccharides such as cyclodextrin and dextrin; calcium carbonate such as precipitated calcium carbonate; cellulose or cellulose derivatives such as crystalline cellulose and hydroxypropylcellulose Light anhydrous silicic acid, sodium phosphate and the like. As the excipient contained in the excipient composition (I), disaccharides, polysaccharides, calcium carbonate and the like are preferable. One of the preferable embodiments of the present invention is that the excipient composition (I) further contains at least one selected from the group consisting of disaccharides, polysaccharides, and calcium carbonate.
二糖類としては、麦芽糖、白糖、トレハロース、ラクトース等が好ましく、中でも麦芽糖が好ましい。麦芽糖としては、粉末のものが好ましく、例えば、アメ粉等が好ましい。多糖類としては、デキストリン、デキストラン、結晶セルロース、ヒドロキシプロピルセルロース（ＨＰＣ）、プルラン等が好ましく、中でもデキストリンが好ましい。炭酸カルシウムとしては、沈降炭酸カルシウムが好ましい。 As the disaccharide, maltose, sucrose, trehalose, lactose and the like are preferable, and maltose is particularly preferable. As maltose, a powder thing is preferable, for example, candy flour etc. are preferable. As the polysaccharide, dextrin, dextran, crystalline cellulose, hydroxypropylcellulose (HPC), pullulan and the like are preferable, and dextrin is particularly preferable. As calcium carbonate, precipitated calcium carbonate is preferred.
工程（１）では、デンプンを含有する賦形剤組成物（Ｉ）を造粒し、顆粒を製造する。造粒は、通常、乾式又は湿式により、公知の方法で行うことができる。本発明における造粒方法は、湿式造粒が好ましい。 In step (1), the excipient composition (I) containing starch is granulated to produce granules. Granulation can be performed by a known method, usually dry or wet. The granulation method in the present invention is preferably wet granulation.
乾式造粒を行なうための乾式造粒装置としては、例えばローラーコンパクター、ファーマパクタ、チルソネーターなどのタイプ（形式）のものが挙げられる。 Examples of the dry granulation apparatus for performing the dry granulation include types (forms) such as a roller compactor, a pharmapactor, and a chill sonator.
湿式造粒に使用される方法は、流動層造粒、攪拌造粒、押し出し造粒法等の通常医薬品等に利用される湿式造粒法であれば特に限定されない。好ましくは、流動層造粒である。湿式造粒は、例えば、一般的な流動層造粒機、転動撹拌造粒機、押し出し造粒機等を用いて行うことができる。湿式造粒を行なう場合の溶媒としては、水、エタノール等が好ましい。水としては、精製水が好ましい。エタノールとしては、通常約５０〜１００％のエタノールを使用する。中でも、本発明においては、水（好ましくは精製水）を用いて湿式造粒を行なうことが好ましいが、所望によりエタノールを加えてもよい。湿式造粒に用いる溶媒は、必要に応じて公知の結合剤、ヒドロキシプロピルセルロース（ＨＰＣ）、ポリビニルピロリドン（ＰＶＰ）等を含んでもよい。 The method used for wet granulation is not particularly limited as long as it is a wet granulation method commonly used for pharmaceutical products such as fluidized bed granulation, stirring granulation, and extrusion granulation. Preferably, fluidized bed granulation. The wet granulation can be performed using, for example, a general fluidized bed granulator, a rolling stirring granulator, an extrusion granulator, or the like. As the solvent for wet granulation, water, ethanol and the like are preferable. As water, purified water is preferred. As ethanol, about 50 to 100% ethanol is usually used. Among these, in the present invention, wet granulation is preferably performed using water (preferably purified water), but ethanol may be added as desired. The solvent used for wet granulation may contain a known binder, hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), and the like, if necessary.
湿式造粒における水の添加量としては、例えば、デンプンを含有する賦形剤組成物（Ｉ）１質量部に対して約０．１〜０．２質量部とすることが好ましい。より好ましくは、水の添加量は、該賦形剤組成物（Ｉ）１質量部に対して約０．１〜０．１５質量部である。エタノールを用いる場合には、通常、デンプンを含有する賦形剤組成物（Ｉ）１質量部に対して約０．１〜０．２質量部のエタノールを加えて湿式造粒する。 The amount of water added in wet granulation is preferably about 0.1 to 0.2 parts by mass with respect to 1 part by mass of the excipient composition (I) containing starch, for example. More preferably, the amount of water added is about 0.1 to 0.15 parts by mass with respect to 1 part by mass of the excipient composition (I). In the case of using ethanol, usually, about 0.1 to 0.2 parts by mass of ethanol is added to 1 part by mass of the excipient composition (I) containing starch, and wet granulation is performed.
本発明においては、工程（１）で得られた顆粒を乾燥させる工程を行なってもよい。乾燥温度は特に限定されず、通常約４０〜９０℃、好ましくは約５０〜７０℃で行う。 In the present invention, a step of drying the granules obtained in step (1) may be performed. The drying temperature is not particularly limited, and is usually about 40 to 90 ° C, preferably about 50 to 70 ° C.
本発明においては、工程（１）で得られた顆粒の粒度を揃える篩過工程を行なうことが好ましい。本発明の好ましい実施態様においては、顆粒の体積平均粒子径が、通常約４０〜１８０μｍ、好ましくは約６０〜１６０μｍ、より好ましくは約８０〜１４０μｍである。 In the present invention, it is preferable to carry out a sieving step to equalize the particle size of the granules obtained in step (1). In a preferred embodiment of the present invention, the volume average particle size of the granules is usually about 40 to 180 μm, preferably about 60 to 160 μm, more preferably about 80 to 140 μm.
工程（２）においては、上記顆粒と、二糖類、多糖類及び炭酸カルシウムを含有する粉体組成物（ＩＩ）と、生菌とを混合して生菌含有組成物を得る。
粉体組成物（ＩＩ）とは、通常、造粒工程を経ていない粉体の処方物をいい、二糖類、多糖類及び炭酸カルシウムのみを含有するものであってもよく、必要に応じて他の賦形剤、添加剤等を含有してもよい。工程（２）において、粉体組成物（ＩＩ）を、造粒せずに顆粒に加えて混合することにより、本発明の効果を十分に発揮することができる。
In the step (2), the above-mentioned granules, the powder composition (II) containing disaccharides, polysaccharides and calcium carbonate, and viable bacteria are mixed to obtain a viable bacteria-containing composition.
The powder composition (II) usually refers to a powder formulation that has not been subjected to a granulation step, and may contain only disaccharides, polysaccharides, and calcium carbonate, and may be other as required. Excipients, additives and the like. In the step (2), the effect of the present invention can be sufficiently exerted by adding and mixing the powder composition (II) to the granule without granulating.
粉体組成物（ＩＩ）に含まれる二糖類としては、賦形剤組成物（Ｉ）と同様のものが挙げられる。中でも、麦芽糖、白糖、トレハロース等が好ましく、麦芽糖がより好ましい。麦芽糖としては、粉末のものが好ましく、例えば、アメ粉等が好ましい。多糖類としては、賦形剤組成物（Ｉ）と同様のものが挙げられる。中でも、デキストリン、トウモロコシデンプン、ヒドロキシプロピルセルロース（ＨＰＣ）、結晶セルロース等が好ましく、デキストリンがより好ましい。炭酸カルシウムとしては、沈降炭酸カルシウムが好ましい。 Examples of the disaccharide contained in the powder composition (II) include those similar to the excipient composition (I). Of these, maltose, sucrose, trehalose and the like are preferable, and maltose is more preferable. As maltose, a powder thing is preferable, for example, candy flour etc. are preferable. Examples of the polysaccharide include those similar to the excipient composition (I). Among these, dextrin, corn starch, hydroxypropyl cellulose (HPC), crystalline cellulose and the like are preferable, and dextrin is more preferable. As calcium carbonate, precipitated calcium carbonate is preferred.
粉体組成物（ＩＩ）における二糖類の配合量は、粉体組成物（ＩＩ）に対して約３０〜７０質量％であることが好ましく、約４０〜６０質量％であることがより好ましい。多糖類の配合量は、粉体組成物（ＩＩ）に対して約２０〜６０質量％であることが好ましく、約３０〜５０質量％であることがより好ましい。炭酸カルシウムの配合量は、粉体組成物（ＩＩ）に対して約５〜２０質量％であることが好ましく、約５〜１５質量％であることがより好ましい。このような範囲であると、錠剤成形性、崩壊性、成分菌の安定性等が良いことから好ましい。 The blending amount of the disaccharide in the powder composition (II) is preferably about 30 to 70% by mass and more preferably about 40 to 60% by mass with respect to the powder composition (II). The blending amount of the polysaccharide is preferably about 20 to 60% by mass, and more preferably about 30 to 50% by mass with respect to the powder composition (II). The blending amount of calcium carbonate is preferably about 5 to 20% by mass and more preferably about 5 to 15% by mass with respect to the powder composition (II). Such a range is preferable because tablet moldability, disintegration, stability of component bacteria, and the like are good.
粉体組成物（ＩＩ）には、必要に応じて、滑沢剤（ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカ等）、安定剤（亜硫酸水素ナトリウム、チオ硫酸ナトリウム、エデト酸ナトリウム、クエン酸ナトリウム、アスコルビン酸、ジブチルヒドロキシトルエン等）、着色剤、賦香剤、光沢剤等、当業界で使用される公知の添加剤等を適宜添加してもよい。これらの成分は、通常の製剤に使用される量を使用すればよい。
粉体組成物（ＩＩ）は、二糖類、多糖類及び炭酸カルシウムと、必要に応じて配合される賦形剤、添加剤等とを、通常の方法で、例えば、ボーレコンテナミキサー、Ｖ型混合機、ドラムミキサー、ロッキングミキサー、タンブラーミキサー等を使用して均一に混合することにより製造される。
In the powder composition (II), lubricants (magnesium stearate, calcium stearate, talc, colloidal silica, etc.), stabilizers (sodium bisulfite, sodium thiosulfate, sodium edetate, citric acid) are optionally added. Sodium, ascorbic acid, dibutylhydroxytoluene and the like), colorants, flavoring agents, brighteners, and other known additives used in the art may be added as appropriate. What is necessary is just to use the quantity used for a normal formulation for these components.
The powder composition (II) is prepared by mixing disaccharides, polysaccharides and calcium carbonate, and excipients, additives, and the like blended as necessary, for example, a Bole container mixer, V-type mixing. It is manufactured by mixing uniformly using a machine, a drum mixer, a rocking mixer, a tumbler mixer or the like.
工程（２）における粉体組成物（ＩＩ）の配合量は、顆粒１質量部に対して約０．１５〜１．０質量部である。この範囲であると、本発明の効果を十分に発揮することができる。好ましくは、粉体組成物（ＩＩ）の配合量は、顆粒１質量部に対して約０．２５〜０．７質量部である。また、粉体組成物（ＩＩ）の配合量は、最終製剤に対して約１０〜５０質量％となるようにすることが好ましく、約２０〜４０質量％となるようにすることがより好ましい。 The compounding quantity of the powder composition (II) in a process (2) is about 0.15-1.0 mass part with respect to 1 mass part of granule. Within this range, the effects of the present invention can be sufficiently exerted. Preferably, the compounding amount of the powder composition (II) is about 0.25 to 0.7 parts by mass with respect to 1 part by mass of the granules. Further, the blending amount of the powder composition (II) is preferably about 10 to 50% by mass, and more preferably about 20 to 40% by mass with respect to the final preparation.
本発明の方法により製剤化される菌は特に限定されず、例えば、ビフィズス菌、乳酸菌、糖化菌、酪酸菌、納豆菌、酵母などの生菌が挙げられる。中でも、本発明においては、生菌が、ビフィズス菌、乳酸菌、糖化菌、酪酸菌及び酵母からなる群より選ばれる少なくとも１種であることが好ましい。より好ましくは、生菌が、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも１種であることである。 The bacteria formulated by the method of the present invention are not particularly limited, and examples thereof include live bacteria such as bifidobacteria, lactic acid bacteria, saccharifying bacteria, butyric acid bacteria, natto bacteria, and yeast. Especially, in this invention, it is preferable that a living microbe is at least 1 sort (s) chosen from the group which consists of bifidobacteria, lactic acid bacteria, saccharifying bacteria, butyric acid bacteria, and yeast. More preferably, the live bacteria is at least one selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
本発明における好ましい菌として、具体的には例えば、Bifidobacterium bifidum、B. longum、 B. breve、B. adolescentis、B. infantis、B.pseudolongum、B.thermophilum等のビフィズス菌；例えば、Lactobacillus acidophilus、L. casei、L. gasseri、L. plantarum、L. delbrueckii subsp bulgaricus、L. delbrueckii subsp lactis、L. fermentum、L. helveticus、L. johnsonii、L. paracasei subsp. paracasei、L. reuteri、L. rhamnosus、L. salivarius、L. brevis等の乳酸桿菌；例えば、Leuconostoc mesenteroides、Streptococcus(Enterococcus) faecalis、Streptococcus(Enterococcus) faecium、 Streptococcus(Enterococcus) hirae、Streptococcus thermophilus、 Lactococcus lactis、L. cremoris、Tetragenococcus halophilus、Pediococcus acidilactici、P. pentosaceus、Oenococcus oeni等の乳酸球菌；例えば、Bacillus subtilis、Bacillus mesentericus、Bacillus polyfermenticus等の糖化菌；例えば、Bacillus coagulans等の有胞子性乳酸菌； Bacillus toyoi、B．licheniformis、Clostridium butyricum等の酪酸菌；その他の有用菌が挙げられる。本発明においては、このようなビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌の生菌を使用することが好ましい。
これらの菌体は、例えばＡＴＣＣ又はＩＦＯなどの機関や財団法人 日本ビフィズス菌センターなどから容易に入手することができる。また、市販されているものを適宜使用することもできる。
Specific examples of preferred bacteria in the present invention include bifidobacteria such as Bifidobacterium bifidum, B. longum, B. breve, B. adolescentis, B. infantis, B. pseudolongum, B. thermophilum; casei, L. gasseri, L. plantarum, L. delbrueckii subsp bulgaricus, L. delbrueckii subsp lactis, L. fermentum, L. helveticus, L. johnsonii, L. paracasei subsp. paracasei, L. reuteri, L. rhamnosus, Lactobacilli such as L. salivarius, L. brevis; for example, Leuconostoc mesenteroides, Streptococcus (Enterococcus) faecalis, Streptococcus (Enterococcus) faecium, Streptococcus (Enterococcus) hirae, Streptococcus thermophilus, Lactococcus mori lactic occo Lactococcus such as Bacillus subtilis, Bacillus mesentericus, Bacillus polyfermenticus; For example, spore-forming lactic acid bacteria such as Bacillus coagulans; Bac illus toyoi, B.B. Examples include butyric acid bacteria such as licheniformis and Clostridium butyricum; and other useful bacteria. In the present invention, it is preferable to use a living bacterium of at least one kind selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
These cells can be easily obtained from, for example, an organization such as ATCC or IFO or the Japan Bifidobacteria Center. Moreover, what is marketed can also be used suitably.
本発明で使用する生菌としては、乳酸菌及び／又はビフィズス菌がより好ましい。中でも、ビフィズス菌がより好ましく、Bifidobacterium bifidum、Bifidobacterium longum、Bifidobacterium infantis、Bifidobacterium breveがさらに好ましく、Bifidobacterium bifidum、Bifidobacterium longumが特に好ましい。複数の菌を組み合わせて使用する場合には、ビフィズス菌と乳酸菌と糖化菌、ビフィズス菌と乳酸菌、ビフィズス菌と糖化菌、又は乳酸菌と糖化菌の組み合わせが好ましく、中でも、（ｉ）Bifidobacterium bifidum、（ｉｉ）Lactobacillus acidophilus、（ｉｉｉ）Lactobacillus gasseri、（ｉｖ）Streptococcus(Enterococcus) faecalis、（ｖ）Streptococcus(Enterococcus) faecium、（ｖｉ）Bacillus subtilis、（ｖｉｉ）Bacillus mesentericusの（ｉ）〜（ｖｉｉ）のうちの２種以上の組み合わせがより好ましい。ビフィズス菌、乳酸菌及び糖化菌及び酪酸菌のうちの２種以上を組み合わせて用いる場合の配合比率は特に限定されない。 As viable bacteria used in the present invention, lactic acid bacteria and / or bifidobacteria are more preferable. Among them, bifidobacteria are more preferable, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium infantis, and Bifidobacterium breve are more preferable, and Bifidobacterium bifidum and Bifidobacterium longum are particularly preferable. When a plurality of bacteria are used in combination, bifidobacteria and lactic acid bacteria and saccharifying bacteria, bifidobacteria and lactic acid bacteria, bifidobacteria and saccharifying bacteria, or a combination of lactic acid bacteria and saccharifying bacteria are preferable. ii) Lactobacillus acidophilus, (iii) Lactobacillus gasseri, (iv) Streptococcus (Enterococcus) faecalis, (v) Streptococcus (Enterococcus) faecium, (vi) Bacillus subtilis, (vi) Bacillus mesentericus (i) to (vi) A combination of two or more of these is more preferred. There are no particular limitations on the blending ratio when two or more of Bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria are used in combination.
上記生菌の菌体は、公知の条件又はそれに準じる条件で培養することにより得ることができる。例えば、ビフィズス菌又は乳酸菌の場合は、通常、グルコ−ス、酵母エキス、及びペプトン等を含む液体培地で前記ビフィズス菌や乳酸菌の１種又は２種以上を通常約２５〜４５℃程度で約４〜７２時間程度、好気又は嫌気培養し、培養液から菌体を集菌し、湿菌体を得る。また、糖化菌の場合は、通常、肉エキス、カゼイン製ペプトン、塩化ナトリウム等を含む寒天培地で１種又は２種以上を通常約２５〜４５℃程度で約４〜７２時間程度、好気培養し、培地から菌体を集菌し、湿菌体を得る。 The microbial cells of the above living bacteria can be obtained by culturing under known conditions or similar conditions. For example, in the case of bifidobacteria or lactic acid bacteria, usually one or more of the bifidobacteria and lactic acid bacteria is about 4 at about 25-45 ° C. in a liquid medium containing glucose, yeast extract, peptone and the like. The aerobic or anaerobic culture is performed for about 72 hours, and the cells are collected from the culture solution to obtain wet cells. In the case of saccharifying bacteria, aerobic culture is usually carried out at about 25 to 45 ° C. for about 4 to 72 hours in an agar medium containing meat extract, casein peptone, sodium chloride and the like. Then, the cells are collected from the medium to obtain wet cells.
本発明においては、通常、上記の菌類の生菌を乾燥処理した乾燥物（菌体乾燥物）が配合される。菌体乾燥物とは、通常は乾燥された個々の菌体又は乾燥された菌体の集合物をいう。生菌の乾燥処理は、常法、例えば、熱乾燥、凍結乾燥、噴霧乾燥などにより行うことができる。菌体乾燥物を得るには、適当な安定剤、例えばグルタミン酸モノナトリウム塩、アドニトールなどを加えた中性の緩衝液に菌を懸濁させておき、自体公知の方法で乾燥することもできる。 In the present invention, a dry product (dry cell product) obtained by drying the above-mentioned fungi is usually blended. The dried microbial cell usually refers to a dried individual microbial cell or a collection of dried microbial cells. The dry treatment of viable bacteria can be performed by conventional methods, for example, heat drying, freeze drying, spray drying and the like. In order to obtain a dried microbial cell product, the bacterium can be suspended in a neutral buffer containing an appropriate stabilizer such as monosodium glutamate or adonitol, and dried by a method known per se.
本発明においては、菌体乾燥物を粉末化したもの又はシングルミクロンの菌体乾燥物を用いることが好ましい。シングルミクロンとは、小数第１位を四捨五入して１〜１０μｍとなる範囲をいう。本発明に使用されるビフィズス菌、乳酸菌、糖化菌、酪酸菌及び酵母からなる群より選ばれる少なくとも１種の菌として、シングルミクロンの菌体乾燥物を使用すると、得られる製剤中の生菌率がより向上するため好ましい。 In the present invention, it is preferable to use a powdered dried microbial cell product or a single micron dried microbial cell product. Single micron means a range of 1 to 10 μm by rounding off the first decimal place. When at least one type of bacteria selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, butyric acid bacteria, and yeast used in the present invention is used, a single micron dried cell product yields a viable cell rate in the resulting preparation. Is preferable because it improves more.
本発明において用いられる菌体乾燥物は、例えば、ビフィズス菌、乳酸菌、糖化菌、酪酸菌及び酵母からなる群より選ばれる少なくとも１種の菌を含有する場合には、生菌数が約１０６〜１０１２ＣＦＵ／ｇであることが好ましい。より好ましくは、生菌数が約１０８〜１０１２ＣＦＵ／ｇである。 When the dried microbial cell product used in the present invention contains, for example, at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, butyric acid bacterium, and yeast, the number of viable bacteria is about 10 6. It is preferable that it is -10 < 12 > CFU / g. More preferably, the viable count is about 10 8 to 10 12 CFU / g.
生菌の配合量は特に限定されず、菌の種類等に応じて適宜設定すればよい。例えば、通常、菌体乾燥物が、最終製剤中に約０．０００００１〜９９質量％の範囲となるように適宜選択して決定することができる。好ましくは、菌体乾燥物が、最終製剤中に約０．１〜１０質量％となるようにする。 The blending amount of viable bacteria is not particularly limited, and may be set as appropriate according to the type of bacteria. For example, it can usually be determined by appropriately selecting so that the dried bacterial cell product is in the range of about 0.000001 to 99% by mass in the final preparation. Preferably, the dry cell product is about 0.1 to 10% by mass in the final preparation.
工程（２）において、粉体組成物（ＩＩ）及び生菌を、顆粒と混合する順番等は特に限定されず、例えば、（Ａ）粉体組成物（ＩＩ）と、生菌とを同時に顆粒に添加して混合してもよく、（Ｂ）まず顆粒に粉体組成物（ＩＩ）の一部又は全部を添加して混合し、次いで残りの粉体組成物（ＩＩ）及び生菌を添加して混合してもよく、（Ｃ）まず顆粒に生菌を添加して混合し、次いで粉体組成物（ＩＩ）を添加して混合してもよい。また、あらかじめ粉体組成物（ＩＩ）と生菌とを混合しておき、この組成物を顆粒に添加して混合してもよい。中でも、粉体組成物（ＩＩ）と生菌とを同時に顆粒に添加して混合することが好ましい。また、上記混合の際に、必要に応じて、上述した滑沢剤、安定剤、着色剤、賦香剤、光沢剤等、当業界で使用される公知の添加剤等を適宜添加してもよい。これらの成分は、通常の製剤に使用される量を使用すればよい。さらに、必要に応じて、他の薬効成分を添加してもよい。 In the step (2), the order of mixing the powder composition (II) and viable bacteria with the granules is not particularly limited. For example, (A) the powder composition (II) and viable bacteria are granulated simultaneously. (B) First, a part or all of the powder composition (II) is added to the granules and mixed, and then the remaining powder composition (II) and viable bacteria are added. (C) First, viable bacteria may be added to the granules and mixed, and then the powder composition (II) may be added and mixed. Alternatively, the powder composition (II) and viable bacteria may be mixed in advance, and this composition may be added to the granules and mixed. Among these, it is preferable to add and mix the powder composition (II) and viable bacteria into the granules at the same time. In addition, when mixing, the above-described lubricants, stabilizers, coloring agents, flavoring agents, brightening agents, and the like, which are known in the art, may be added as necessary. Good. What is necessary is just to use the quantity used for a normal formulation for these components. Furthermore, you may add another medicinal component as needed.
微量の有効成分（生菌）を大量の他の粉末及び顆粒と混合し均一な組成物を得るためには、いわゆる段階的混合法を採るのが好ましい。例えば、有効成分をその１００〜２００容量倍の粉末及び顆粒と混合して均一な粉末を得、これを残りの粉末と混合すると均一な粉末を得ることができる。 In order to obtain a uniform composition by mixing a small amount of active ingredient (live bacteria) with a large amount of other powders and granules, it is preferable to employ a so-called stepwise mixing method. For example, the active ingredient is mixed with 100 to 200 times its volume of powder and granule to obtain a uniform powder, and when this is mixed with the remaining powder, a uniform powder can be obtained.
工程（２）における混合は、通常、ボーレコンテナミキサー、Ｖ型混合機、ドラムミキサー、ロッキングミキサー、タンブラーミキサー等を用いて行うことができる。混合の際の温度は、特に限定されず、通常約０〜５０℃、好ましくは約１５〜３０℃で行う。混合時間は、通常約３分〜３０分である。 The mixing in the step (2) can be usually performed using a Boule container mixer, a V-type mixer, a drum mixer, a rocking mixer, a tumbler mixer, and the like. The temperature at the time of mixing is not specifically limited, Usually, about 0-50 degreeC, Preferably it carries out at about 15-30 degreeC. The mixing time is usually about 3 to 30 minutes.
本発明における生菌含有組成物は、成型性が良好であり、約１０〜２０ｋＮ／ｃｍ２（約５〜１０ｋＮ）の打錠圧で良好に圧縮成形することができるものである。本発明における生菌含有組成物はまた、例えば、乾燥減量（水分含量）が約１．５〜２．５質量％であっても、上記打錠圧で良好に圧縮成形することができるものである。乾燥減量は、（第十五改正日本薬局方 乾燥減量試験法）に記載の方法で測定することができる。 The viable cell-containing composition of the present invention has good moldability and can be favorably compressed with a tableting pressure of about 10 to 20 kN / cm 2 (about 5 to 10 kN). The viable cell-containing composition in the present invention can also be compression-molded satisfactorily with the above tableting pressure even when the loss on drying (water content) is about 1.5 to 2.5% by mass. is there. Loss on drying can be measured by the method described in (Fifteenth Amendment Japanese Pharmacopoeia Drying Loss Test Method).
工程（３）においては、生菌含有組成物を打錠圧約１０〜２０ｋＮ／ｃｍ２で圧縮成形する。打錠圧は、約１２〜１６ｋＮ／ｃｍ２（約６〜８ｋＮ）であることが好ましい。圧縮成形においては、公知の打錠機を用いることができる。打錠機としては、例えば、単発式打錠機又はロータリー型打錠機等が挙げられる。なお、得られる錠剤の硬度は、通常４０〜２００Ｎ程度であり、錠剤の硬度は錠剤破壊強度測定器等を用いて測定することができる。 In the step (3), the viable cell-containing composition is compression-molded at a tableting pressure of about 10 to 20 kN / cm 2 . The tableting pressure is preferably about 12 to 16 kN / cm 2 (about 6 to 8 kN). In compression molding, a known tableting machine can be used. Examples of the tableting machine include a single-shot tableting machine and a rotary tableting machine. In addition, the hardness of the tablet obtained is about 40-200N normally, and the hardness of a tablet can be measured using a tablet breaking strength measuring instrument etc.
本発明の方法によれば、錠剤の製造に用いた生菌の打錠間生残率（錠剤中の生菌数／生菌含有組成物中の生菌数×１００）（％）を、通常約３０％以上、好ましくは約５０％以上にすることができる。 According to the method of the present invention, the survival rate between live-compressed bacteria used for tablet production (viable bacteria count in tablets / viable bacteria count in viable bacteria-containing composition × 100) (%) It can be about 30% or more, preferably about 50% or more.
本発明においては、例えば、工程（３）の後に、圧縮成形により得られた製剤を乾燥させる工程等を含んでもよい。乾燥方法は特に限定されず、公知の方法で行うことができる。乾燥温度は、菌の種類等によって適宜設定することができるが、通常約４０〜７０℃、好ましくは約４０〜６０℃である。さらに、圧縮成形により得られた錠剤、丸剤等を、糖類や高分子等で公知の方法によりコーティングすることもできる。 In the present invention, for example, a step of drying a preparation obtained by compression molding may be included after step (3). The drying method is not particularly limited and can be performed by a known method. The drying temperature can be appropriately set depending on the type of bacteria and the like, but is usually about 40 to 70 ° C, preferably about 40 to 60 ° C. Furthermore, tablets, pills, and the like obtained by compression molding can be coated with saccharides, polymers, and the like by a known method.
本発明の方法により製造される生菌製剤の剤形は、生菌と賦形剤とを含有する製剤原料を圧縮成形して製造される製剤であればよく、例えば、錠剤、丸剤、トローチ剤、チュアブル剤等の固形製剤が挙げられる。中でも本発明の方法は、生菌を有効成分とする錠剤の製造に好適に使用される。 The dosage form of the viable bacterial preparation produced by the method of the present invention may be a preparation produced by compression molding a raw material for preparation containing viable bacteria and excipients. For example, tablets, pills, troches Solid preparations such as pills and chewable agents. Among them, the method of the present invention is suitably used for the production of tablets containing live bacteria as an active ingredient.
以下実施例を示してさらに詳しく説明を行うが、本発明はこれによりなんら制限されるものではない。本実施例中、「％」は、特に断らない限り「質量％」を意味する。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. In this example, “%” means “% by mass” unless otherwise specified.
本実施例中、生菌数は、錠剤を粉砕した後、日本薬局方外医薬品規格ラクトミン、ビフィズス菌、耐性乳酸菌の定量法に記載の方法に準拠して測定した。
錠剤の強度は、錠剤強度破壊測定器（富山産業社製、商品名「錠剤強度破壊測定器」）により測定した。
崩壊試験は、第十五改正日本薬局方 崩壊試験法に記載の方法に従って行なった。
乾燥減量は、第十五改正日本薬局方 乾燥減量試験法に記載の方法に従って測定した。
In this example, the viable cell count was measured in accordance with the method described in the Quantitative Methods for Japanese Pharmacopoeia Standards for Lactamine, Bifidobacteria and Resistant Lactic Acid Bacteria after crushing tablets.
The strength of the tablet was measured with a tablet strength breaking measuring device (trade name “Tablet strength breaking measuring device” manufactured by Toyama Sangyo Co., Ltd.).
The disintegration test was conducted according to the method described in the Fifteenth Amendment Japanese Pharmacopoeia Disintegration Test Method.
The loss on drying was measured according to the method described in the 15th Amendment Japanese Pharmacopoeia Drying Loss Test Method.
＜実施例１＞
下記表１に示した処方にて各原料を秤量し、流動層造粒機ＦＬＯ３００（商品名、フロイント産業社製）で造粒末を得た。この造粒末をスクリーン径１．５ｍｍφのパワーミル（昭和技研工業社製）で処理して整粒末を得た。この整粒末に、滑沢剤（ステアリン酸Ｍｇ及びタルク）と乳酸菌末（ビオフェルミン製薬社製、「局外規 耐性乳酸菌」）を添加した処方（１）と、処方（１）にさらにアメ粉（林原社製）、デキストリン、及び沈降炭酸Ｃａを３０％添加した処方（２）にて混合末を製造した。処方（１）及び処方（２）の組成を、表２に示す。
<Example 1>
Each raw material was weighed according to the formulation shown in Table 1 below, and a granulated powder was obtained with a fluidized bed granulator FLO300 (trade name, manufactured by Freund Sangyo Co., Ltd.). This granulated powder was processed with a power mill (made by Showa Giken Kogyo Co., Ltd.) having a screen diameter of 1.5 mmφ to obtain a sized powder. To this sized powder, a lubricant (Mg stearate and talc) and a lactic acid bacterium powder (Biofermin Pharmaceutical Co., Ltd., “external regulation resistant lactic acid bacterium”) were added, and candy powder was further added to the formulation (1). (Made by Hayashibara Co., Ltd.), dextrin, and a mixed powder was produced with a prescription (2) to which precipitated carbonic acid carbonate 30% was added. Table 2 shows the compositions of Formula (1) and Formula (2).
比較として、従来の処方（比較処方）の混合末を、以下に示した方法により作製した。すなわち、表３に示した処方にて各原料を秤量し、流動層造粒機ＦＬＯ３００（商品名、フロイント産業社製）で造粒末を得た。この造粒末をスクリーン径１．５ｍｍφのパワーミル（昭和技研工業社製）で処理して整粒末を得た。この整粒末に、滑沢剤（ステアリン酸Ｍｇ及びタルク）と乳酸菌末（ビオフェルミン製薬社製、「局外規 耐性乳酸菌」）を表４に示した処方で添加した。 For comparison, a mixed powder of a conventional formulation (comparative formulation) was prepared by the method shown below. That is, each raw material was weighed according to the formulation shown in Table 3, and a granulated powder was obtained using a fluidized bed granulator FLO300 (trade name, manufactured by Freund Corporation). This granulated powder was processed with a power mill (made by Showa Giken Kogyo Co., Ltd.) having a screen diameter of 1.5 mmφ to obtain a sized powder. Lubricants (Mg stearate and talc) and lactic acid bacteria powder (Biofermin Pharmaceutical Co., Ltd., “Externally-resistant lactic acid bacteria”) were added to this sized powder in the formulation shown in Table 4.
上記処方（１）、（２）及び従来の処方（比較処方）の混合末をそれぞれ用いて、打錠機ＡＱＵＡＲＩＵＳ３（菊水製作所社製、以下、打錠にはこの機械を用いた）を用いて、硬度６０〜７０Ｎの錠剤を得るのに必要な打錠圧を調べた。 Using the mixed powders of the above formulas (1) and (2) and the conventional formula (comparative formula), respectively, using a tableting machine AQUARIUS3 (manufactured by Kikusui Seisakusho Co., Ltd., hereinafter, this machine was used for tableting). The tableting pressure required to obtain tablets with a hardness of 60 to 70 N was examined.
処方（１）及び（２）の製造における上記整粒末を製造するために必要な造粒時間は、７０分であった。これに対して、従来の処方の造粒に必要な時間は、１００分であった。従って、上記整粒末の製造においては、従来よりも造粒に必要な時間を短縮することができた。 The granulation time required for producing the above sized powder in the production of the formulations (1) and (2) was 70 minutes. In contrast, the time required for granulation of the conventional formulation was 100 minutes. Therefore, in the production of the above sized powder, the time required for granulation can be shortened as compared with the conventional method.
また、従来の処方では、打錠機ＡＱＵＡＲＩＵＳ３（菊水製作所社製）を用いて、硬度６０〜７０Ｎの錠剤を得るのに約３６ｋＮ／ｃｍ２の打錠圧を必要とし、含有菌の打錠間生残率（錠剤中の生菌数／混合末中の生菌数×１００）は約２０％であった。処方（１）を用いて硬度６０〜７０Ｎの錠剤を得る際には、約２２ｋＮ／ｃｍ２の打錠圧が必要であり、含有菌の打錠間生残率は４０％であった（図１）
処方（２）を用いて硬度６０〜７０Ｎの錠剤を得る際には、１４ｋＮ／ｃｍ２の打錠圧で打錠することにより、このような強度の錠剤を得ることができ、このときの含有菌の打錠間生残率は７０％であった（図１）。
In addition, the conventional formulation requires a tableting pressure of about 36 kN / cm 2 to obtain tablets with a hardness of 60 to 70 N using a tableting machine AQUARIUS3 (manufactured by Kikusui Seisakusho Co., Ltd.). The survival rate (viable bacteria count in tablets / viable bacteria count in mixed powder × 100) was about 20%. When a tablet having a hardness of 60 to 70 N was obtained using the formulation (1), a tableting pressure of about 22 kN / cm 2 was required, and the survival rate between the tablets of the contained bacteria was 40% (Fig. 1)
When a tablet having a hardness of 60 to 70 N is obtained using the formulation (2), a tablet having such strength can be obtained by tableting with a tableting pressure of 14 kN / cm 2. The survival rate of the bacteria during tableting was 70% (FIG. 1).
さらに、従来の処方の混合末を約３６ｋＮ／ｃｍ２の打錠圧で打錠して得られた錠剤（比較錠剤）、処方（１）の混合末を約２２ｋＮ／ｃｍ２の打錠圧で打錠して得られた錠剤（錠剤１）、及び処方（２）の混合末を１４ｋＮ／ｃｍ２の打錠圧で打錠して得られた錠剤（錠剤２）について、崩壊試験を行なった。錠剤１及び２の崩壊時間は、両錠剤ともに約５分であり、比較錠剤の崩壊時間１５分と比較して、非常に良好な崩壊性を示した（図２）。 Furthermore, conventional tableting pressure on a tablet with a tablet obtained by mixing powder of about 36kN / cm 2 of formulation (comparative tablets) at tableting pressure mixed powder of about 22Kn / cm 2 of formulation (1) A disintegration test was conducted on the tablet (tablet 1) obtained by tableting and tablet (tablet 2) obtained by tableting the mixed powder of the formulation (2) with a tableting pressure of 14 kN / cm 2 . . The disintegration time of tablets 1 and 2 was about 5 minutes for both tablets, and showed very good disintegration compared to the disintegration time of 15 minutes for the comparative tablet (FIG. 2).
＜実施例２＞
実施例１で製造した造粒後整粒末（表１）に、アメ粉、デキストリン、及び沈降炭酸Ｃａ混合物（未造粒原料）を、該混合物の添加率がそれぞれ１５、３０、及び４５％となるように添加し、さらにそれぞれに滑沢剤と乳酸菌末を添加して、生菌含有組成物を調製した。表５に、各生菌含有組成物の組成を示す。このとき、各処方の乾燥減量はほぼ同等であった（表５）。これらの生菌含有組成物の７５μｍ以下の微粒子の含有量を、第十五改正日本薬局方 粒度測定法 ふるい分け法により測定した。また、これら混合末（生菌含有組成物）について、硬度６０〜７０Ｎの錠剤を得るのに必要な打錠圧を検討した。その結果、図３に示すように、アメ粉、デキストリン及び沈降炭酸Ｃａ混合物の添加率（未造粒原料添加率）が増えるほど、生菌含有組成物中の７５μｍ以下の微粒子の含有量が増加するにもかかわらず、添加率０％以外は、いずれの添加率においても、生菌含有組成物を１４ｋＮ／ｃｍ２の打錠圧で打錠して硬度６０〜７０Ｎの錠剤を得ることができ、このときの含有菌の打錠間生残率はいずれも７０％であった。そして製造された硬度６０〜７０Ｎの錠剤の崩壊時間はいずれも５分であった。これらの結果を、表６に示す。
<Example 2>
A mixture of candy powder, dextrin, and precipitated carbonic acid carbonate (ungranulated raw material) was added to the post-granulated sized powder (Table 1) produced in Example 1, and the addition ratio of the mixture was 15, 30, and 45%, respectively. Then, a lubricant and a lactic acid bacterium powder were added to each to prepare a viable cell-containing composition. Table 5 shows the composition of each viable bacteria-containing composition. At this time, the loss on drying of each formulation was almost the same (Table 5). The content of fine particles of 75 μm or less of these viable bacteria-containing compositions was measured by a fifteenth revised Japanese Pharmacopoeia particle size measurement method sieving method. Moreover, the tableting pressure required in order to obtain the tablet of hardness 60-70N was examined about these mixed powders (viable microbe containing composition). As a result, as shown in FIG. 3, the content of fine particles of 75 μm or less in the viable cell-containing composition increases as the addition rate of the mixture of candy powder, dextrin and precipitated carbonic acid Ca (non-granulated raw material addition rate) increases. Nevertheless, at any addition rate except for the addition rate of 0%, the viable bacteria-containing composition can be tableted with a tableting pressure of 14 kN / cm 2 to obtain tablets with a hardness of 60 to 70 N. In this case, the survival rate between tableting of the contained bacteria was 70%. And the disintegration time of the manufactured tablet with hardness 60-70N was all 5 minutes. These results are shown in Table 6.
＜実施例３＞
実施例１の処方（２）から、滑沢剤と菌末を除いた以外は、実施例１の処方（２）と同様にして混合末を製造した。この混合末の乾燥減量は３．３％であった。この混合末を６０℃にて２時間乾燥させた後、滑沢剤、及び乳酸菌末と混合して、乾燥減量２％以下の混合末を得た（混合末、滑沢剤及び乳酸菌末の配合比は、上記表２の処方（２）と同じにした）。これらの混合末それぞれを打錠したところ、乾燥減量２％以下の混合末は、乾燥減量３．３％の混合末とほぼ同等の１４ｋＮ／ｃｍ２の打錠圧で打錠することができ、また含有菌の生残率もほぼ同等の７０％であった。結果を図４に示す。
<Example 3>
A mixed powder was produced in the same manner as the formulation (2) of Example 1 except that the lubricant and the fungus powder were removed from the formulation (2) of Example 1. The loss on drying of this mixed powder was 3.3%. This mixed powder was dried at 60 ° C. for 2 hours, and then mixed with a lubricant and lactic acid bacteria powder to obtain a mixed powder having a loss on drying of 2% or less (mixed powder, lubricant and powder of lactic acid bacteria) The ratio was the same as the prescription (2) in Table 2 above). When each of these mixed powders was tableted, a mixed powder having a loss on drying of 2% or less can be tableted with a tableting pressure of 14 kN / cm 2 which is substantially equivalent to a mixed powder having a loss on drying of 3.3%. In addition, the survival rate of the contained bacteria was almost equal to 70%. The results are shown in FIG.
本発明は、菌の生存率が高く、硬度が高く、かつ崩壊性が良好な生菌製剤を製造することができるため、医薬品の製造に有用である。 INDUSTRIAL APPLICABILITY The present invention is useful for producing a pharmaceutical product because it can produce a viable bacterial preparation having a high survival rate of bacteria, high hardness and good disintegration.
Claims (10)
（２）該顆粒と、二糖類、多糖類及び炭酸カルシウムを含有する粉体組成物（ＩＩ）と、生菌とを混合して生菌含有組成物を得る工程、及び、
（３）該生菌含有組成物を打錠圧１０〜２０ｋＮ／ｃｍ２で圧縮成形する工程、
を含み、工程（２）における粉体組成物（ＩＩ）の配合量が、顆粒１質量部に対して０．１５〜１．０質量部であることを特徴とする生菌製剤の製造方法。 (1) A step of granulating the excipient composition (I) containing starch to obtain granules,
(2) A step of mixing the granules, a powder composition (II) containing disaccharides, polysaccharides and calcium carbonate with viable bacteria to obtain a viable bacteria-containing composition; and
(3) a step of compression-molding the viable cell-containing composition at a tableting pressure of 10 to 20 kN / cm 2 ;
And the blending amount of the powder composition (II) in the step (2) is 0.15 to 1.0 part by mass with respect to 1 part by mass of the granule.
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| JP2016193894A (en) * | 2015-04-01 | 2016-11-17 | 京都薬品工業株式会社 | Viable cell-containing preparation |
| JP2017508754A (en) * | 2014-03-06 | 2017-03-30 | リサーチ インスティチュート アット ネイションワイド チルドレンズ ホスピタル | Probiotic formulations and methods for use |
| KR101914919B1 (en) | 2017-09-08 | 2019-01-14 | 롯데칠성음료주식회사 | A liquid formulation of live lactic acid bacteria and drink containing them |
| US10624934B2 (en) | 2014-03-06 | 2020-04-21 | Research Institute At Nationwide Children's Hospital | Prebiotic formulations |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2017508754A (en) * | 2014-03-06 | 2017-03-30 | リサーチ インスティチュート アット ネイションワイド チルドレンズ ホスピタル | Probiotic formulations and methods for use |
| JP2018087248A (en) * | 2014-03-06 | 2018-06-07 | リサーチ インスティチュート アット ネイションワイド チルドレンズ ホスピタル | Probiotic formulations and methods for use |
| US10369176B2 (en) | 2014-03-06 | 2019-08-06 | Research Institute At Nationwide Children's Hospital | Probiotic formulations and methods for use |
| US10624934B2 (en) | 2014-03-06 | 2020-04-21 | Research Institute At Nationwide Children's Hospital | Prebiotic formulations |
| US11452748B2 (en) | 2014-03-06 | 2022-09-27 | Research Institute at Nation Children's Hospital | Probiotic formulations and methods for use |
| US11497780B2 (en) | 2014-03-06 | 2022-11-15 | Research Institute At Nationwide Children's Hospital | Prebiotic formulations |
| CN104248731A (en) * | 2014-09-29 | 2014-12-31 | 洛阳御平国生物科技有限公司 | Formula for treating child anorexia |
| JP2016193894A (en) * | 2015-04-01 | 2016-11-17 | 京都薬品工業株式会社 | Viable cell-containing preparation |
| KR101914919B1 (en) | 2017-09-08 | 2019-01-14 | 롯데칠성음료주식회사 | A liquid formulation of live lactic acid bacteria and drink containing them |
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