JP6243276B2 - Hard capsule formulation with improved acid resistance of the drug substance - Google Patents
Hard capsule formulation with improved acid resistance of the drug substance Download PDFInfo
- Publication number
- JP6243276B2 JP6243276B2 JP2014071976A JP2014071976A JP6243276B2 JP 6243276 B2 JP6243276 B2 JP 6243276B2 JP 2014071976 A JP2014071976 A JP 2014071976A JP 2014071976 A JP2014071976 A JP 2014071976A JP 6243276 B2 JP6243276 B2 JP 6243276B2
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- Prior art keywords
- drug substance
- acid resistance
- hard capsule
- mass
- substance component
- Prior art date
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- 239000007902 hard capsule Substances 0.000 title claims description 49
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Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
Description
本発明は、原薬成分の耐酸性を向上させたハードカプセル製剤に関する。さらに詳しく言うと、本発明は、耐酸性の低い原薬成分を、ヒドロキシメチルセルロース及び炭酸カルシウムとともにハードカプセルに充填して得られる、原薬成分の耐酸性を向上させたハードカプセル製剤に関する。 The present invention relates to a hard capsule formulation with improved acid resistance of a drug substance component. More specifically, the present invention relates to a hard capsule formulation having improved acid resistance of a drug substance component obtained by filling a hard capsule with hydroxymethyl cellulose and calcium carbonate with a drug substance having low acid resistance.
ビフィズス菌は、酸、水、酸素に弱く、経口摂取すると、胃酸等の消化管内の酸によってほとんどが死滅してしまうため、生菌のまま腸まで送達することが困難であった。
耐酸性の低い原薬成分を生きたまま腸までデリバリーするための方法として、近年、耐酸性のハードカプセルが用いられている。しかし、該カプセルは水分を含むとキャップとボディが分離し易くなるため、内容物の保護のためにバンドシールが必要となり、高コスト化を余儀なくされるという問題があった。
そのため、ビフィズス菌等の耐酸性が低い原薬成分を生きたまま腸まで届けることができるカプセル製剤の研究が種々行われている。
Bifidobacteria are vulnerable to acid, water, and oxygen, and when taken orally, most of them are killed by acids in the digestive tract such as gastric acid, so it is difficult to deliver them to the intestine as living bacteria.
In recent years, acid-resistant hard capsules have been used as a method for delivering a drug substance component with low acid resistance to the intestine while alive. However, when the capsule contains moisture, the cap and the body are easily separated from each other. Therefore, a band seal is required to protect the contents, and there is a problem that the cost is inevitably increased.
For this reason, various researches have been conducted on capsule preparations that can deliver drug ingredients with low acid resistance such as bifidobacteria to the intestines alive.
例えば、特許文献１には、耐酸性被膜と硬化油脂層とからなる二重膜構造の腸溶性シームレスカプセルを製造する技術が開示されている。
また、特許文献２には、ビフィズス菌を、カプセルの表面にキトサン含有層と腸溶性基剤含有層が二重コーティングされたハードカプセル内に充填して、ビフィズス菌を大腸まで失活させずにデリバリーする技術が開示されている。
しかしながら、特許文献１に記載の方法は、専用の製造設備や工程を必要とし、高コスト化は避けられないという問題があった。また、特許文献２に記載の方法は、カプセルのコーティングに長時間（４〜５時間）を費やす必要があり、やはり高コスト化は避けられないという問題があった。
For example, Patent Document 1 discloses a technique for producing an enteric seamless capsule having a double membrane structure composed of an acid-resistant coating and a hardened oil / fat layer.
Patent Document 2 discloses that bifidobacteria are delivered in a hard capsule in which a chitosan-containing layer and an enteric base-containing layer are double-coated on the surface of the capsule without inactivating the bifidobacteria to the large intestine. Techniques to do this are disclosed.
However, the method described in Patent Document 1 requires a dedicated manufacturing facility and process, and there is a problem that high cost is inevitable. In addition, the method described in Patent Document 2 needs to spend a long time (4 to 5 hours) for coating the capsule, and there is a problem that cost increase is unavoidable.
このような状況下で、本発明は、耐酸性の低い原薬成分を生菌末のまま腸まで送達することができ、しかも、複雑な製造設備や工程を必要とせず、低コストで製造することが可能なハードカプセル製剤を提供することを課題とする。 Under such circumstances, the present invention can deliver the drug substance component with low acid resistance to the intestine as a live bacterial powder, and does not require complicated production equipment and processes, and can be produced at low cost. It is an object of the present invention to provide a hard capsule preparation that can be used.
本発明者らは、耐酸性の低い原薬成分を、ヒドロキシプロピルセルロース（ＨＰＣ）及び炭酸カルシウムとともに、ハードカプセル内に充填することにより、複雑な製造設備や工程を必要とせず、低ｐＨ環境でも原薬成分の生存性を大幅に向上でき、生菌のまま腸まで送達することができるハードカプセル製剤を得ることができることを見出し、本発明を完成させた。
また、ハードカプセルとして耐酸性のハードカプセルを用いることや、ＨＰＣ及び炭酸カルシウムの他に、乳蛋白消化物や硬化油脂をハードカプセルに充填することにより、さらに生菌の残存率が高くなることを見出し、本発明を完成させた。
The present inventors fill the hard capsules with a drug substance having low acid resistance together with hydroxypropylcellulose (HPC) and calcium carbonate, so that complicated manufacturing facilities and processes are not required, and even in a low pH environment. It was found that the viability of the drug component can be greatly improved, and a hard capsule preparation that can be delivered to the intestine as a living bacterium can be obtained, and the present invention has been completed.
In addition, by using acid-resistant hard capsules as hard capsules, and filling hard capsules with milk protein digests and hardened oils and fats in addition to HPC and calcium carbonate, it has been found that the survival rate of viable bacteria is further increased. Completed the invention.
すなわち、本発明は、以下のハードカプセル製剤を提供するものである。
（１）耐酸性の低い原薬成分と、ヒドロキシプロピルセルロース及び炭酸カルシウムとがハードカプセルに充填されたことを特徴とする、原薬成分の耐酸性を向上させたハードカプセル製剤。
（２）ハードカプセルが、耐酸性ハードカプセルであることを特徴とする前記（１）記載の原薬成分の耐酸性を向上させたハードカプセル製剤。
（３）さらに、乳蛋白消化物が充填されたことを特徴とする、前記（１）または（２）記載の原薬成分の耐酸性を向上させたハードカプセル製剤。
（４）さらに、硬化油脂が充填されたことを特徴とする、前記（１）〜（３）のいずれかに記載の原薬成分の耐酸性を向上させたハードカプセル製剤。
（５）耐酸性の低い原薬成分が、ビフィズス菌生菌末または乳酸菌生菌末であることを特徴とする前記（１）〜（４）のいずれかに記載の原薬成分の耐酸性を向上させたハードカプセル製剤。
（６）耐酸性の低い原薬成分が、ビフィズス菌生菌末であることを特徴とする前記（５）記載の原薬成分の耐酸性を向上させたハードカプセル製剤。
That is, the present invention provides the following hard capsule formulations.
(1) A hard capsule formulation with improved acid resistance of the drug substance component, wherein the drug substance component having low acid resistance, hydroxypropyl cellulose and calcium carbonate are filled in a hard capsule.
(2) The hard capsule formulation having improved acid resistance of the drug substance component according to (1), wherein the hard capsule is an acid-resistant hard capsule.
(3) The hard capsule preparation with improved acid resistance of the drug substance component according to (1) or (2), further filled with a milk protein digest.
(4) The hard capsule formulation with improved acid resistance of the drug substance component according to any one of (1) to (3), further filled with a hardened fat.
(5) The acid resistance of the drug substance component according to any one of (1) to (4) above, wherein the drug substance component having low acid resistance is Bifidobacterium live powder or lactic acid bacteria live powder. Improved hard capsule formulation.
(6) The hard capsule preparation with improved acid resistance of the drug substance component according to (5) above, wherein the drug substance component with low acid resistance is a live Bifidobacterium powder.
本発明によれば、特別な製造設備や製造工程を必要とせず、原薬成分の生存性を大幅に向上させ、原薬成分を死滅させずに生菌の状態で腸まで送達することができる製剤が得られる。 According to the present invention, it is possible to deliver to the intestine in a state of viable bacteria without significantly reducing the viability of the drug substance component without requiring any special production equipment or production process and without killing the drug substance component. A formulation is obtained.
以下、本発明について、例を挙げながら詳しく説明する。
本発明における耐酸性の低い原薬成分は、サプリメント、健康食品、美容食品、医薬品などにおいて機能成分や有効成分として用いられ、胃酸あるいは胆汁酸等消化管から分泌される酸に対する耐性が弱い成分であれば限定されない。このような耐酸性の低い原薬成分としては、腸内での活性や代謝を期待して摂取、投与されるビフィズス菌や乳酸菌が好ましく、ビフィズス菌は特に好ましい。
Hereinafter, the present invention will be described in detail with examples.
The drug substance component with low acid resistance in the present invention is a component that is used as a functional ingredient or an active ingredient in supplements, health foods, beauty foods, pharmaceuticals, etc., and has low resistance to acids secreted from the digestive tract such as stomach acid or bile acid. There is no limitation as long as there is. As such a drug substance component having low acid resistance, bifidobacteria and lactic acid bacteria that are ingested and administered in the hope of activity and metabolism in the intestine are preferable, and bifidobacteria are particularly preferable.
本発明において、ビフィズス菌は、耐酸性が低いものであれば特に限定されず、ビフィドバクテリウム・ビフィダム、ビフィドバクテリウム・ロンガム、ビフィドバクテリウム・アドレッセンティス、ビフィドバクテリウム・ブレーべ、ビフィドバクテリウム・インファンティス等に属する株のうち、胃酸などの酸に弱いものが好適に用いられる。
また、乳酸菌も耐酸性が低いものであれば特に限定されない。このような乳酸菌の例としては、ラクトバチルス・カゼイ、ラクトバチルス・アシドフィルス等に属する株のうち、胃酸等の酸に対する耐性が弱いものが好適に用いられる。これらはｐＨ２．０では１２０分間残存するが、ｐＨ１．０ではすぐに死滅する。
本発明における原薬成分は、１種のみでも２種以上を組み合わせて用いてもよい。
In the present invention, the Bifidobacterium is not particularly limited as long as it has low acid resistance. Among strains belonging to Bifidobacterium infantis and the like, those which are sensitive to acids such as stomach acid are preferably used.
Also, lactic acid bacteria are not particularly limited as long as they have low acid resistance. As an example of such lactic acid bacteria, among strains belonging to Lactobacillus casei, Lactobacillus acidophilus, etc., those having a low resistance to acids such as gastric acid are preferably used. They remain for 120 minutes at pH 2.0, but die immediately at pH 1.0.
The drug substance components in the present invention may be used alone or in combination of two or more.
本発明においては、機能成分または有効成分としての耐酸性の低い原薬成分を、基剤成分としてのヒドロキシプロピルセルロース（ＨＰＣ）及び炭酸カルシウムと組み合わせて、ハードカプセルに充填してハードカプセル製剤を製造する。
ＨＰＣは、カプセル製剤の内容物を固めて、内容物の散逸を防止し、浸水を抑制する作用を有する。ＨＰＣとヒドロキシプロピルメチルセルロース（ＨＰＭＣ）は、共に浸水抑制作用を有し、胃酸耐性を付与する効果が期待されるが、ＨＰＣの方がＨＰＭＣに比べて浸水速度が小さく、浸水抑制効果が高い。また、ＨＰＭＣは浸水時の膨潤度が高く、膨らんだカプセル内容物がカプセルから飛び出してしまうが、ＨＰＣは浸水時にも膨潤せず、より高い胃酸耐性を付与することができる。
本発明において、ＨＰＣは、耐酸性の低い原薬成分に対して、好ましくは、３質量％〜２０質量％、さらに好ましくは、５質量％〜１５質量％、特に好ましくは、８質量％〜１０質量％の量で用いることが好ましい。
In the present invention, an active ingredient component having low acid resistance as a functional component or active ingredient is combined with hydroxypropyl cellulose (HPC) and calcium carbonate as base components, and filled into a hard capsule to produce a hard capsule preparation.
HPC hardens the contents of the capsule preparation, prevents the contents from escaping, and has the action of suppressing flooding. Both HPC and hydroxypropylmethylcellulose (HPMC) have a water-inhibiting action and are expected to provide gastric acid resistance. However, HPC has a lower water-infiltration rate and a higher water-inhibiting effect than HPMC. In addition, HPMC has a high degree of swelling during water immersion, and the swelled capsule contents pop out of the capsule, but HPC does not swell even during water immersion and can impart higher gastric acid resistance.
In the present invention, HPC is preferably 3% by mass to 20% by mass, more preferably 5% by mass to 15% by mass, and particularly preferably 8% by mass to 10% by mass with respect to the drug substance component having low acid resistance. It is preferably used in an amount of mass%.
炭酸カルシウムは、胃酸を中和させ、酸性で消化力の強いペプシンの作用を消滅、低下させる作用を有する。本発明においては、炭酸カルシウムをＨＰＣと組み合わせて用いることにより、耐酸性の低い原薬成分の耐酸性を向上させることができる。
本発明において、炭酸カルシウムは、耐酸性の低い原薬成分に対して、好ましくは、０．５質量％〜１０質量％の量、さらに好ましくは、１質量％〜５質量％、特に好ましくは、３質量％〜５質量％の量で用いることが好ましい。
Calcium carbonate has the effect of neutralizing gastric acid and eliminating or reducing the action of acidic and highly digestible pepsin. In the present invention, by using calcium carbonate in combination with HPC, the acid resistance of the drug substance component having low acid resistance can be improved.
In the present invention, the calcium carbonate is preferably 0.5% by mass to 10% by mass, more preferably 1% by mass to 5% by mass, particularly preferably based on the drug substance component having low acid resistance. It is preferably used in an amount of 3% by mass to 5% by mass.
本発明は、耐酸性の低い原薬成分とともにＨＰＣと炭酸カルシウムを用いることを特徴とするが、ハードカプセルとして耐酸性のハードカプセルを用いることがさらに好ましい。耐酸性のハードカプセルは、製剤への浸水を抑制することができ、健康食品や医薬等の機能成分や有効成分を胃酸等の酸から保護するために使用できるものであればよく、バンドシールはなくてもよい。このような耐酸性を有するハードカプセルとしては、ＣＡＰＳＵＧＥＬ社製のＤＲｃａｐｓ等を特に好ましい例として挙げることができる。 The present invention is characterized by using HPC and calcium carbonate together with a drug substance component having low acid resistance, and it is more preferable to use an acid resistant hard capsule as the hard capsule. The acid-resistant hard capsule can be used as long as it can suppress water immersion in the preparation and can be used to protect functional ingredients and active ingredients such as health foods and medicines from acids such as stomach acid. May be. As a hard capsule having such acid resistance, DRcaps manufactured by CAPSUGEL can be cited as a particularly preferable example.
本発明においては、基剤成分として、上記の他に、乳蛋白消化物を用いることが好ましい。乳蛋白消化物としては、低ｐＨ環境下で凝固する性質を有し、浸水を抑制する性質を有するものであれば特に限定されない。このような乳蛋白消化物としては、森永乳業社製のＧＦＲ−Ｐｏｗｄｅｒ（Ｎ）等を特に好ましい例として挙げることができる。
本発明において、乳蛋白消化物は、耐酸性の低い原薬成分に対して、１０質量％〜３０質量％の量で用いることが好ましく、１５質量％〜２０質量％の量で用いることが特に好ましい。
In the present invention, it is preferable to use a milk protein digest in addition to the above as the base component. The milk protein digest is not particularly limited as long as it has a property of coagulating in a low pH environment and a property of suppressing water immersion. As such a milk protein digest, GFR-Powder (N) manufactured by Morinaga Milk Industry Co., Ltd. can be mentioned as a particularly preferred example.
In the present invention, the milk protein digest is preferably used in an amount of 10% by mass to 30% by mass, particularly 15% by mass to 20% by mass, based on the drug substance having low acid resistance. preferable.
また、本発明においては、基剤成分として、ＨＰＣと炭酸カルシウムの他に、硬化油脂を用いることが好ましい。硬化油脂は、製剤中への浸水を抑制する作用を有し、サプリメント、機能性食品、医薬品において使用できるものであれば限定されない。
硬化油脂は、耐酸性の低い原薬成分に対して、２０質量％〜４０質量％の量で用いることが好ましく、２０質量％〜３０質量％の量で用いることが特に好ましい。
Moreover, in this invention, it is preferable to use hardened fats and oils other than HPC and calcium carbonate as a base component. Hardened fats and oils are not limited as long as they have an action of suppressing water immersion in the preparation and can be used in supplements, functional foods, and pharmaceuticals.
The hardened fat is preferably used in an amount of 20% by mass to 40% by mass, particularly preferably 20% by mass to 30% by mass, based on the drug substance component having low acid resistance.
本発明のハードカプセル製剤の製造方法は、限定されず、公知の方法により製造することができる。すなわち、機能成分または有効成分と基剤成分を常法により配合してカプセル内容物を調製し、それを常法によりハードカプセルに充填する方法により製造することができる。
ハードカプセルの内容物としては、耐酸性の低い原薬成分と上記基剤成分の他、許容される任意の原材料を任意の配合量で用いることができる。すなわち、ハードカプセルの内容物は、耐酸性の低い原薬成分以外の機能成分や有効成分を含んでいてもよく、その種類や配合量は特に限定されない。また、ハードカプセルの内容物は、上記基剤成分以外の任意の基剤成分を任意の配合量で含有することができる。
The manufacturing method of the hard capsule formulation of this invention is not limited, It can manufacture by a well-known method. That is, it can be produced by a method in which a functional ingredient or an active ingredient and a base ingredient are blended by a conventional method to prepare a capsule content and filled into a hard capsule by a conventional method.
As the contents of the hard capsule, in addition to the drug substance component having low acid resistance and the above base component, any acceptable raw material can be used in any compounding amount. That is, the contents of the hard capsule may contain functional components and active ingredients other than the drug substance component having low acid resistance, and the type and blending amount are not particularly limited. Moreover, the contents of the hard capsule can contain any base component other than the above base component in any amount.
本発明のハードカプセル製剤において用いることができるその他の基剤成分としては、賦形剤や滑沢剤等を挙げることができ、その種類は通常許容されるものであればよい。 Examples of other base components that can be used in the hard capsule preparation of the present invention include excipients and lubricants.
賦形剤としては、例えば、セルロース、乳糖、白糖、ブドウ糖、Ｄ−マンニトール、粉末還元麦芽糖水あめ、マルチトール、キシリトール、エリスリトール、Ｄ−ソルビトール、マルトース、デンプンおよびデンプン誘導体、アスパルテーム、グリチルリチン酸およびその塩、サッカリンおよびその塩、ステビアおよびその塩、スクラロース、アセスルファムカリウム、リン酸水素カルシウム、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、メチルセルロース、デキストリン、デンプンおよびデンプン誘導体、グァーガム、アラビアゴム、トラガント、アルギン酸およびその塩、プルラン、カラギーナン、ゼラチン、寒天、カルボキシビニルポリマー、カルメロースナトリウム、デンプン、カルボキシメチルスターチナトリウム、カルメロースナトリウム、低置換度ヒドロキシプロピルセルロース等が挙げられる。その中でも、デンプンは好ましい。これらの賦形剤は、１種または２種以上を適宜組み合わせて、任意の配合量で用いることができる。 Examples of the excipient include cellulose, lactose, sucrose, glucose, D-mannitol, powdered reduced maltose starch syrup, maltitol, xylitol, erythritol, D-sorbitol, maltose, starch and starch derivatives, aspartame, glycyrrhizic acid and salts thereof , Saccharin and its salts, stevia and its salts, sucralose, acesulfame potassium, calcium hydrogen phosphate, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, dextrin, starch and starch derivatives, guar gum, gum arabic, tragacanth, alginic acid and its salts, pullulan , Carrageenan, gelatin, agar, carboxyvinyl polymer, carmellose sodium, starch, carboxymethyl starch natri Arm, carmellose sodium, low-substituted hydroxypropylcellulose and the like. Among these, starch is preferable. These excipients can be used alone or in appropriate combination of two or more.
また、滑沢剤としては、例えば、ステアリン酸カルシウム、ステアリン酸マグネシウム、タルク、水素添加植物油等が挙げられ、その中でもステアリン酸カルシウムは好ましい。これらの滑沢剤は、１種または２種以上を適宜組み合わせて任意の配合量で用いることができる。 Examples of the lubricant include calcium stearate, magnesium stearate, talc, hydrogenated vegetable oil, and the like, among which calcium stearate is preferable. These lubricants can be used alone or in any combination of two or more.
本発明のハードカプセル製剤の用途は特に限定されず、サプリメント、医薬品、健康食品、美容食品、飼料などに使用することができる。また、原薬成分とＨＰＣ及び炭酸カルシウムとの組み合わせは、それらが固まって存在していれば原薬成分に耐酸性を付与することができるため、ハードカプセル以外に、錠剤や固形化食品（ブロック状に固めた顆粒等）などの形態をとることも可能である。 The use of the hard capsule preparation of the present invention is not particularly limited, and can be used for supplements, pharmaceuticals, health foods, beauty foods, feeds, and the like. In addition, the combination of the drug substance component with HPC and calcium carbonate can impart acid resistance to the drug substance component if they are solidified. It is also possible to take a form such as hardened granules.
以下、実施例、試験例及び比較例を挙げて本発明をさらに具体的に説明するが、これらは単なる例示であって、本発明を限定するものではない。
（実施例１〜４及び比較例１〜４）
＜試験サンプル調製方法＞
表１及び表２に示す原材料のうち、ステアリン酸カルシウム以外の原料を量り取り、Ｖ型混合器（筒井理化学器械社製：ミクロ型透視式混合器）で１０分間混合した後、ステアリン酸カルシウムを加え、５分間混合し、カプセル充填用内容物を得た。次いで、カプセル充填機（Ｆｅｔｏｎ ｉｎｔｅｒｎａｔｉｏｎａｌ社製：ＣＡＰＳＵＬＥ ＦＩＬＬＥＲ＆ＬＯＡＤＥＲ）を使用し、１カプセル当り２６０ｍｇの内容物を充填し試験サンプル（実施例１〜４及び比較例１〜４）を調製した。
EXAMPLES Hereinafter, although an Example, a test example, and a comparative example are given and this invention is demonstrated further more concretely, these are only illustrations and do not limit this invention.
(Examples 1-4 and Comparative Examples 1-4)
<Test sample preparation method>
Of the raw materials shown in Table 1 and Table 2, raw materials other than calcium stearate were weighed and mixed for 10 minutes with a V-type mixer (manufactured by Tsutsui Rika Instruments Co., Ltd .: micro-type fluoroscopic mixer), and then calcium stearate was added. The contents for capsule filling were obtained by mixing for 5 minutes. Next, using a capsule filling machine (manufactured by Feton international: CAPSULE FILLER & LOADER), 260 mg of the content was filled per capsule to prepare test samples (Examples 1 to 4 and Comparative Examples 1 to 4).
表１に示される実施例１〜４及び表２に示される比較例１〜４において用いる原材料の詳細は下記の通りである。
（機能成分）
・ビフィズス菌末（１）（森永乳業社製：高濃度ビフィズス菌末ＢＢ５３６−ＥＸ）生菌末
・ビフィズス菌末（２）（森永乳業社製：森永ビフィズス菌末Ｂ−３−ＥＸ）生菌末
・Ｎ−アセチルグルコサミン(焼津水産化学工業社製：マリンスウィート（Ｒ）ＹＳＫ）
（賦形剤）
・ヒドロキシプロピルセルロース（日本曹達社製：セルニーＨ微粉）
・炭酸カルシウム（キューピー社製：カルホープ）
・乳蛋白消化物（森永乳業社製：ＧＦＲ−Ｐｏｗｄｒ（Ｎ））
・硬化油脂（川研ファインケミカル社製：ラブリワックス−１０２Ｈ）
・デンプン（松谷化学工業社製：松谷乾燥殺菌コーンスターチ）
（滑沢剤）
・ステアリン酸カルシウム（堺化学工業社製：食品添加物ステアリン酸カルシウム）
（カプセル）
・耐酸性ハードカプセル（ＣＡＰＳＵＧＥＬ社製：ＤＲｃａｐｓ）
・非耐酸性ハードカプセル（ＣＡＰＳＵＧＥＬ社製：Ｖｃａｐｓ）
Details of the raw materials used in Examples 1 to 4 shown in Table 1 and Comparative Examples 1 to 4 shown in Table 2 are as follows.
(Functional ingredients)
・ Bifidobacteria powder (1) (Morinaga Milk Industry Co., Ltd .: high-concentration bifidobacterium powder BB536-EX) Live bacteria powder ・ Bifidobacteria powder (2) (Morinaga Milk Industry Co., Ltd .: Morinaga Bifidobacterium powder B-3-EX) Sue N-acetylglucosamine (Yaizu Fisheries Chemical Industries, Ltd .: Marine Sweet (R) YSK)
(Excipient)
・ Hydroxypropyl cellulose (Nippon Soda Co., Ltd .: Celny H fine powder)
・ Calcium carbonate (Culpope)
Milk protein digest (Morinaga Milk Industry Co., Ltd .: GFR-Powdr (N))
・ Hardened fats and oils (manufactured by Kawaken Fine Chemical Co., Ltd .: Lovely wax-102H)
・ Starch (Matsuya Chemical Co., Ltd .: Matsutani dry sterilized corn starch)
(lubricant)
・ Calcium stearate (manufactured by Sakai Chemical Industry Co., Ltd .: Food additive calcium stearate)
(capsule)
・ Acid resistant hard capsule (manufactured by Capsugel: DRcaps)
・ Non-acid-resistant hard capsules (CAPSUGEL: Vcaps)
実施例及び比較例における各成分の配合量は、実施例１を基準にし、各実施例２〜４及び比較例１〜４においては、各々の例で使用しない原材料の実施例１での配合量をデンプン（賦形剤）で置き換えた。すなわち、実施例３においては、乳蛋白消化物を使用していないが、実施例１での乳蛋白消化物の１粒当たりの質量である４１．６００ｍｇと、内容物調製時の仕込量である１６．０００ｇを、実施例３ではデンプンの質量とした。 The amount of each component in Examples and Comparative Examples is based on Example 1, and in Examples 2 to 4 and Comparative Examples 1 to 4, the amounts of raw materials not used in each example in Example 1 Was replaced with starch (excipient). That is, in Example 3, no milk protein digest was used, but 41.600 mg, which is the mass per grain of the milk protein digest in Example 1, and the amount charged when the contents were prepared 16.000 g was the mass of starch in Example 3.
＜試験方法＞
崩壊試験機（富山産業社製：ＮＴ−４０ＨＳ）を使用し、３７℃の日本薬局方１液（ｐＨ１．２）中でカプセルを１２０分間遊泳させた。その後カプセルを取り出し、下記方法で培養した。
すなわち、取り出したカプセル内容物を、生理食塩水を用いてサンプル調製し、ＴＯＳプロピオン酸寒天培地（ヤクルト薬品工業社製）へ混釈培養した。アネロパウチ・ケンキ（三菱ガス化学社製）を用いて嫌気状態にし、３７℃、７２時間の培養後コロニー数をカウントした。
なお、試験前の初発ビフィズス菌数は、２．０×１０１０個であった。
<Test method>
Using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd .: NT-40HS), the capsules were allowed to swim for 120 minutes in Japanese Pharmacopoeia 1 solution (pH 1.2) at 37 ° C. Thereafter, the capsule was taken out and cultured by the following method.
That is, a sample of the taken capsule contents was prepared using physiological saline, and mixed-cultured on a TOS propionic acid agar medium (manufactured by Yakult Pharmaceutical Co., Ltd.). Anaeropouch Kenki (Mitsubishi Gas Chemical Co., Ltd.) was used to make the anaerobic state, and the number of colonies after counting at 37 ° C. for 72 hours was counted.
The initial bifidobacteria count before the test was 2.0 × 10 10 .
＜試験結果＞
試験結果を表１及び表２に示す。
<Test results>
The test results are shown in Tables 1 and 2.
表１に示されるビフィズス菌残数から明らかなように、ＨＰＣ及び炭酸カルシウムを用いる実施例１〜４では、ビフィズス菌生菌の残数が非常に多かった。
それに対して、表２に示されるように、ＨＰＣ、炭酸カルシウム、乳蛋白消化物、硬化油脂を含有しない比較例２では、ハードカプセルとして耐酸性ハードカプセルを用いても、ビフィズス菌生菌が完全に死滅した。また、ＨＰＣ、炭酸カルシウム、硬化油脂を含有しない比較例３においても、ビフィズス菌生菌が完全に死滅した。比較例３とカプセル内容物を同じとし、ハードカプセルとして耐酸性ハードカプセルを用いた比較例４では、ビフィズス菌生菌の残数は、比較例３に比べると多かった。
また、実施例１の処方のうち、炭酸カルシウムを用いず、その分をデンプン（賦形剤）に置き換えた比較例１では、実施例１に比べてビフィズス菌生菌の残数が著しく減少した。
As is clear from the number of remaining bifidobacteria shown in Table 1, in Examples 1 to 4 using HPC and calcium carbonate, the number of remaining bifidobacteria was very large.
On the other hand, as shown in Table 2, in Comparative Example 2 that does not contain HPC, calcium carbonate, milk protein digest, and hardened fats and oils, even when acid hard capsules are used as hard capsules, Bifidobacteria live bacteria are completely killed. did. Moreover, also in the comparative example 3 which does not contain HPC, a calcium carbonate, and hardened fats and oils, the bifidobacteria live microbe was killed completely. In Comparative Example 4 in which the capsule contents were the same as in Comparative Example 3 and acid-resistant hard capsules were used as hard capsules, the remaining number of Bifidobacteria viable bacteria was larger than that in Comparative Example 3.
In addition, in the prescription of Example 1, in Comparative Example 1 in which calcium carbonate was not used and the amount was replaced with starch (excipient), the number of remaining bifidobacteria was significantly reduced as compared with Example 1. .
これらの結果から、ビフィズス菌生菌末をＨＰＣ及び炭酸カルシウムと組み合わせて用いることにより、ビフィズス菌生菌末の耐酸性が著しく向上することが分かった。
また、実施例１と実施例２ではカプセルの内容物の処方は全く同じであるが、実施例１で耐酸性カプセルを用いることにより、さらにビフィズス菌の生菌末の耐酸性が向上することが分かった。
From these results, it was found that the acid resistance of the bifidobacteria live powder was significantly improved by using the bifidobacteria live powder in combination with HPC and calcium carbonate.
In addition, the formulation of the capsule contents is exactly the same in Example 1 and Example 2, but the acid resistance of the viable powder of Bifidobacteria can be further improved by using the acid-resistant capsule in Example 1. I understood.
本発明のハードカプセル製剤は、ビフィズス菌生菌末などの耐酸性の弱い原薬成分を死滅させずに、生きたまま腸まで送達することができ、水などに対する保存安定性にも優れているため、サプリメント、健康食品、美容食品、医薬品等の分野において広く利用できる。 The hard capsule formulation of the present invention can be delivered to the intestine alive without killing a weakly acid-resistant drug substance component such as live Bifidobacterium powder, and has excellent storage stability against water and the like. It can be widely used in the fields of supplements, health foods, beauty foods, pharmaceuticals and the like.
Claims (4)
前記耐酸性の低い原薬成分がビフィズス菌生菌末であり、
ヒドロキシプロピルセルロースの配合量が、ビフィズス菌生菌末に対して３質量％〜２０質量％であり、炭酸カルシウムの配合量が、ビフィズス菌生菌末に対して０．５質量〜１０質量％であることを特徴とする、原薬成分の耐酸性を向上させたハードカプセル製剤。 The drug substance component with low acid resistance, hydroxypropyl cellulose and calcium carbonate are filled into a hard capsule ,
The drug substance component with low acid resistance is a living Bifidobacterium powder,
The blending amount of hydroxypropyl cellulose is 3% by mass to 20% by mass with respect to the live Bifidobacterium powder, and the blending amount of calcium carbonate is 0.5% by mass to 10% by mass with respect to the Bifidobacterium live cell powder. The hard capsule formulation which improved the acid resistance of the drug substance component characterized by having.
硬化油脂の配合量が、ビフィズス菌生菌末に対して、２０質量％〜４０質量％であることを特徴とする、請求項１〜３のいずれかに記載の原薬成分の耐酸性を向上させたハードカプセル製剤。 Furthermore, it is filled with hardened oil and fat ,
4. The acid resistance of the drug substance component according to any one of claims 1 to 3, wherein the blended amount of the hardened fat is 20% by mass to 40% by mass with respect to the viable Bifidobacterium powder. Hard capsule formulation.
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