JP2018199630A - Intragastric retentivity tablet - Google Patents
Intragastric retentivity tablet Download PDFInfo
- Publication number
- JP2018199630A JP2018199630A JP2017104040A JP2017104040A JP2018199630A JP 2018199630 A JP2018199630 A JP 2018199630A JP 2017104040 A JP2017104040 A JP 2017104040A JP 2017104040 A JP2017104040 A JP 2017104040A JP 2018199630 A JP2018199630 A JP 2018199630A
- Authority
- JP
- Japan
- Prior art keywords
- tablet
- gallate
- acid
- cellulose derivative
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 239000001913 cellulose Substances 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 32
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- 235000005487 catechin Nutrition 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 30
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- 238000005187 foaming Methods 0.000 claims abstract description 16
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 14
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Abstract
Description
本発明は、胃内滞留性錠剤に関する。 The present invention relates to a gastroretentive tablet.
経口投与された薬物の消化管内の吸収は主に下部消化管において行なわれる。例えば固形剤の場合、その崩壊速度が薬物の吸収の律速となる。そこで、薬物の吸収を調節する手段、例えば、持続的吸収製剤では主として製剤の硬度を種々変えることによって製剤の崩壊速度を調節し、消化管吸収を持続させる方法が用いられている。また、製剤から薬物が溶出する速度を調節する方法で吸収を調節する方法も用いられている。 Absorption of orally administered drugs is mainly carried out in the lower gastrointestinal tract. For example, in the case of a solid preparation, its disintegration rate is the rate-limiting factor for drug absorption. Therefore, means for adjusting the absorption of a drug, for example, a method of maintaining the digestive tract absorption by adjusting the disintegration rate of the preparation by changing the hardness of the preparation in various ways, for example, in the sustained absorption preparation. In addition, a method of adjusting absorption by a method of adjusting the rate at which the drug is eluted from the preparation is also used.
最近、新しい薬物輸送系として胃内滞留製剤が開発され、いくつか提案されている。
例えば、薬物含有製剤部分が膨潤性製剤部分に埋設され、全体が被膜で被覆されている胃内浮遊型薬物徐放性固形剤（特許文献１参照）、均一に分散した水溶性薬物を含有する非崩壊性の生態適合性素材の内層、該内層の周囲を含む水を通さない内層の膨潤を制御しうる生体適合性素材の外層からなる柱状製剤（特許文献２参照）が知られている。
Recently, a gastroretentive formulation has been developed as a new drug delivery system and several proposals have been made.
For example, the drug-containing preparation part is embedded in the swellable preparation part, and the whole is covered with a film, and the gastric floating drug sustained release solid preparation (see Patent Document 1) contains a uniformly dispersed water-soluble drug. A columnar preparation (see Patent Document 2) comprising an inner layer of a non-disintegrating biocompatible material and an outer layer of a biocompatible material capable of controlling the swelling of the inner layer that is impermeable to water including the periphery of the inner layer is known.
胃内膨潤製剤としてはさらに、胃液を吸収して体積を膨張させ、胃幽門通過を遅らせるもの（特許文献３）が公知である。この発明は、二層の構造を有する錠剤で、薬物層と膨潤層からなり、膨潤層が胃内で水分によって膨潤して体積が増加することで錠剤の幽門通過を遅らせる製剤である。 Further, as an intragastric swelling preparation, one that absorbs gastric juice to expand its volume and delays passage through the stomach pylorus is known (Patent Document 3). The present invention is a tablet comprising a drug layer and a swollen layer, which has a bilayer structure, and the swollen layer swells with moisture in the stomach to increase the volume, thereby delaying the passage of the tablet through the pylorus.
また、製剤を消化管粘膜に付着させて滞留時間を長くする提案がある。特許文献４には、ポリグリセリン脂肪酸エステルおよび／または脂質と薬効成分とを含むマトリックス粒子の少なくとも表層近傍に、粘性物質が分散しており、常温で固体の消化管粘膜付着性マトリックスからなる製剤が記載されている。この発明は、製剤の外層に水により粘性が発現し、消化管粘膜に対して付着性を示すとポリマーやポリエチレングリコールをコーティングし、内層に薬物とそれを含むマトリック構造を形成させ、付着後緩やかに薬剤が放出されるようにした製剤である。 There is also a proposal to increase the residence time by attaching the preparation to the gastrointestinal mucosa. Patent Document 4 discloses a preparation comprising a gastrointestinal mucoadhesive matrix that is solid at room temperature and has a viscous substance dispersed at least in the vicinity of the surface layer of matrix particles containing polyglycerin fatty acid ester and / or lipid and medicinal component. Have been described. In this invention, when the outer layer of the drug product develops viscosity with water and adheres to the gastrointestinal mucosa, it is coated with a polymer or polyethylene glycol, and the inner layer forms a drug and a matrix structure containing the drug. It is a formulation in which the drug is released.
さらにまた水に浮遊性を持つ製剤が提案されている。これは胃内に浮遊させて、胃内滞留時間を延長しようとするもので、これには２つの方法があり、中空性の製剤とする場合、胃内で反応して炭酸ガスを発生し、この炭酸ガスの浮力によって胃内滞留時間を延長する場合とがある。前者の先行技術としては、特許文献５に、中心部分に空洞部を有する中空構造を有し、糖アルコール、糖、セルロース誘導体およびスターチ類から選ばれる少なくとも１の賦形剤並びに疎水効果を示す成分を含む、水に浮遊可能である錠剤が開示されている。後者の先行技術としては、特許文献６に二酸化炭素を一時的に製剤中にとどめておく手段として、ヒドロキシプロピルセルロースやヒドロキシプロピルメチルセルロースなどで、炭酸カルシウムなどの炭酸ガス発生手段と薬物を含む組成物をコーティングする技術が記載されている。
このように胃内滞留製剤のために様々な技術が提案されているが、いずれも一長一短があり、必ずしも満足できるものがない。
Furthermore, a preparation having water buoyancy has been proposed. This is intended to float in the stomach and extend the residence time in the stomach. There are two methods for this, and when making a hollow preparation, it reacts in the stomach to generate carbon dioxide, In some cases, the buoyancy of the carbon dioxide gas extends the residence time in the stomach. As the former prior art, Patent Document 5 discloses a component having a hollow structure having a hollow portion in the central portion and at least one excipient selected from sugar alcohol, sugar, cellulose derivative and starch, and a hydrophobic effect A tablet that can float in water is disclosed. As the latter prior art, as a means for temporarily keeping carbon dioxide in the preparation in Patent Document 6, a composition containing a carbon dioxide generating means such as calcium carbonate and a drug such as hydroxypropylcellulose or hydroxypropylmethylcellulose. Techniques for coating are described.
As described above, various techniques have been proposed for gastroretentive preparations, but all have advantages and disadvantages and are not always satisfactory.
本発明は、胃内浮遊性錠剤であって、胃内にあって８０分以上の胃内浮遊性を有する胃内滞留性錠剤を提供することを課題とする。 An object of the present invention is to provide a gastric buoyant tablet that is in the stomach and has gastric buoyancy of 80 minutes or more.
前記課題に鑑み、本発明者は鋭意検討を行なった結果、薬物を胃内に滞留させるために浮遊性を付与した錠剤にあっては、胃内の条件で錠剤の最外殻層に、錠剤内で発生する炭酸ガスを保持し、さらに胃液によって破壊されない構成が必要であることに着目し鋭意検討した結果、胃内浮遊性錠剤に必要な新たな構成を見出し、発明をなした。 In view of the above-mentioned problems, the present inventors have conducted intensive studies. As a result, in the case of a tablet provided with floatability in order to retain the drug in the stomach, the tablet is applied to the outermost shell layer of the tablet under the conditions in the stomach. As a result of diligent research paying attention to the need for a structure that retains the carbon dioxide gas generated in the gas and is not destroyed by gastric juice, the inventors have found a new structure necessary for a gastric buoyant tablet and made an invention.
すなわち本発明は、以下の構成からなる。
（１）発泡成分と薬剤を含む錠剤を、セルロース誘導体を含む組成物でコーティングした錠剤であって、前記発泡成分と薬剤を含む錠剤及び／又は前記セルロース誘導体を含む組成物がタンニンを含むことを特徴とする錠剤。
（２）発泡成分と薬剤を含む錠剤を、セルロース誘導体を含む組成物でコーティングした錠剤であって、前記セルロース誘導体を含む組成物がタンニンを含むことを特徴とする錠剤。
（３）発泡成分と薬剤を含む錠剤を、セルロース誘導体を含む組成物でコーティングした錠剤であって、前記発泡成分と薬剤を含む錠剤がタンニンを含むことを特徴とする錠剤。
（４）タンニンがカテキン類である（１）〜（３）のいずれかに記載の錠剤。
（５）タンニンが没食子酸及び／又はタンニン酸である（１）〜（３）のいずれかに記載の錠剤。
（６）カテキン類がガレート基を有するカテキン類（ガレート体）である（４）に記載の錠剤。
（７）カテキン類がカテキンガレート、ガロカテキンガレート、エピカテキンガレート、エピガロカテキンガレートのいずれか１以上である（４）に記載の錠剤。
（８）タンニンが緑茶抽出物由来である（１）〜（７）のいずれかに記載の錠剤。
（９）発泡成分が炭酸水素ナトリウム、炭酸ナトリウム、炭酸カルシウム、炭酸カリウム、炭酸マグネシウム、炭酸水素カルシウム及び炭酸水素カリウムから選択される少なくとも一種又はこれらの少なくとも２種以上の混合物である（１）〜（８）のいずれかに記載の錠剤。
（１０）さらにクエン酸、酒石酸、フマル酸、コハク酸、リンゴ酸及びマレイン酸から選択される少なくとも一種以上の有機酸を含む（１）〜（９）のいずれかに記載の錠剤。
（１１）セルロース誘導体がヒドロキシプロピルメチルセルロース又はヒドロキシプロピルセルロースである（１）〜（１０）のいずれかに記載の錠剤。
That is, this invention consists of the following structures.
(1) A tablet comprising a tablet containing a foaming component and a drug coated with a composition containing a cellulose derivative, wherein the tablet containing the foaming component and the drug and / or the composition containing the cellulose derivative contains tannin. Features tablets.
(2) A tablet obtained by coating a tablet containing an effervescent component and a drug with a composition containing a cellulose derivative, wherein the composition containing the cellulose derivative contains tannin.
(3) A tablet obtained by coating a tablet containing an effervescent component and a drug with a composition containing a cellulose derivative, wherein the tablet containing the effervescent component and the drug contains tannin.
(4) The tablet according to any one of (1) to (3), wherein the tannin is a catechin.
(5) The tablet according to any one of (1) to (3), wherein the tannin is gallic acid and / or tannic acid.
(6) The tablet according to (4), wherein the catechins are catechins having a gallate group (gallate body).
(7) The tablet according to (4), wherein the catechin is one or more of catechin gallate, gallocatechin gallate, epicatechin gallate, and epigallocatechin gallate.
(8) The tablet according to any one of (1) to (7), wherein the tannin is derived from a green tea extract.
(9) The foaming component is at least one selected from sodium bicarbonate, sodium carbonate, calcium carbonate, potassium carbonate, magnesium carbonate, calcium bicarbonate and potassium bicarbonate, or a mixture of at least two of these (1) to The tablet according to any one of (8).
(10) The tablet according to any one of (1) to (9), further comprising at least one organic acid selected from citric acid, tartaric acid, fumaric acid, succinic acid, malic acid and maleic acid.
(11) The tablet according to any one of (1) to (10), wherein the cellulose derivative is hydroxypropylmethylcellulose or hydroxypropylcellulose.
本発明により、新たに浮遊性胃内滞留型の錠剤が提供される。本発明の錠剤は、酸耐久性を有する錠剤であり、胃内滞留時間が延長されるため、持続型製剤や胃内で吸収される薬剤の製剤として有用である。 According to the present invention, a new buoyant gastric retention tablet is provided. The tablet of the present invention is an acid-durable tablet and has a prolonged gastric residence time, so that it is useful as a continuous preparation or a preparation of a drug absorbed in the stomach.
本発明は、発泡成分と薬剤を含む錠剤をセルロース誘導体とカテキン類からなる組成物でコーティングした錠剤に係る発明である。
本発明の錠剤について具体的に説明する。
The present invention relates to a tablet in which a tablet containing an effervescent component and a drug is coated with a composition comprising a cellulose derivative and catechins.
The tablet of the present invention will be specifically described.
本発明において、胃内滞留型錠剤とは、経口服用された錠剤が胃内に長時間滞留し、含有される薬剤を持続的に放出する錠剤をいう。そして本発明の錠剤は、胃内において水分又は胃内の酸と反応して二酸化炭素を発生させ、この二酸化炭素が錠剤内にとどまることによって浮力が生じて錠剤が胃液の上面に浮遊し、幽門から排出されない状態を維持できる。なお、本発明でいう胃内で浮遊する状態とは、日本薬局方に定める崩壊性試験において、第１液を用いた崩壊性試験において、錠剤が液面に浮遊して４０分以上崩壊しない状態をいう。 In the present invention, the gastroretentive tablet refers to a tablet in which a tablet taken orally stays in the stomach for a long time and releases the contained drug continuously. The tablet of the present invention reacts with moisture or acid in the stomach to generate carbon dioxide in the stomach, and the carbon dioxide stays in the tablet to generate buoyancy, so that the tablet floats on the upper surface of the gastric juice, and the pylorus The state where it is not discharged from can be maintained. In the present invention, the state of floating in the stomach refers to a state in which the tablet floats on the liquid surface and does not disintegrate for more than 40 minutes in the disintegration test defined in the Japanese Pharmacopoeia. Say.
崩壊性試験に用いる第１液は胃液のモデルとして設定された試験液であって、その構成は、塩化ナトリウム２．０ｇに塩酸７．０ｍｌおよび水を加えて１０００ｍｌとした溶液である。この液は無色透明で、そのｐＨは約１．２である。
錠剤がこの溶液に崩壊せず、なおかつ溶液と反応し、二酸化炭素ガスを発生させる。さらに二酸化炭素が錠剤内にとどまり、浮力を発生させるためには、錠剤にコーティングを行ってコーティング層を形成する。コーティング層は水分又は塩酸を通過させ、さらに炭酸ガスを通過させない特性を有することが必要である。
The first liquid used in the disintegration test is a test liquid set as a model of gastric juice, and the composition thereof is a solution made up to 2.0 ml of sodium chloride and 1000 ml by adding 7.0 ml of hydrochloric acid and water. This liquid is colorless and transparent, and its pH is about 1.2.
The tablet does not disintegrate into this solution and still reacts with the solution to generate carbon dioxide gas. Furthermore, in order for carbon dioxide to remain in the tablet and generate buoyancy, the tablet is coated to form a coating layer. The coating layer needs to have a property of allowing moisture or hydrochloric acid to pass therethrough and not allowing carbon dioxide gas to pass therethrough.
コーティング層は、水溶性セルロース誘導体とカテキン類からなる組成物によって形成する。またグリセリンや糖アルコールなどの可塑剤を配合しても良い。水溶性セルロース誘導体としては、ヒドロキシプロピルメチルセルロースやヒドロキシプロピルセルロースが好ましい。
コーティング層には、このセルロース誘導体とカテキン類を含有させる。カテキン類は、カテキンガレート、ガロカテキンガレート、エピカテキンガレート、エピガロカテキンガレートなどのガレート基を持つものでなければならない。水の存在下では、セルロース誘導体とガレート基を持つカテキンが重合し、不溶体を生成する。不溶化したコーティング層は、風船のようにその内部に気体を閉じ込めて膨らむことができるので、錠剤内部より発生する二酸化炭素を保持し、錠剤に浮力を発生させることができる。錠剤１粒当たり、セルロース誘導体は２〜１０ｍｇ、好ましくは３〜６ｍｇが望ましい。またコーティング層に配合するカテキンは錠剤１粒当たり１〜４ｍｇが望ましい。カテキンが４ｍｇより多いと不溶化したコーティング層の柔軟性が不足し、ガスを閉じ込めたまま膨らむことができずに被膜に亀裂が入るので浮遊することが出来ない。また１ｍｇより少ないと不溶体を生成する前に水溶性セルロース誘導体の被膜が溶けてしまい浮遊することが出来ない。
また、カテキン類はコーティング層中ではなく、錠剤内部に配合しても良い。その場合、１０質量％以上のカテキンが必要となる。カテキンを錠剤内部のみに配合することで、コーティング液の調製溶媒にエタノールを使用しなくてもコーティングが可能となり、加工費用を抑えることができる。
The coating layer is formed by a composition comprising a water-soluble cellulose derivative and catechins. Moreover, you may mix | blend plasticizers, such as glycerol and sugar alcohol. As the water-soluble cellulose derivative, hydroxypropylmethylcellulose and hydroxypropylcellulose are preferable.
The coating layer contains this cellulose derivative and catechins. The catechins must have a gallate group such as catechin gallate, gallocatechin gallate, epicatechin gallate, and epigallocatechin gallate. In the presence of water, catechin having a cellulose derivative and a gallate group is polymerized to form an insoluble material. Since the insolubilized coating layer can swell by trapping gas inside like a balloon, it can hold carbon dioxide generated from the inside of the tablet and generate buoyancy in the tablet. The cellulose derivative is desirably 2 to 10 mg, preferably 3 to 6 mg per tablet. The catechin blended in the coating layer is preferably 1 to 4 mg per tablet. When the amount of catechin is more than 4 mg, the insolubilized coating layer is not flexible enough to swell while confining the gas, and the coating is cracked and cannot float. On the other hand, when the amount is less than 1 mg, the water-soluble cellulose derivative film dissolves before the insoluble material is formed, and cannot float.
Further, catechins may be blended inside the tablet, not in the coating layer. In that case, 10 mass% or more of catechin is required. By blending catechin only inside the tablet, coating can be performed without using ethanol as a solvent for preparing the coating solution, and processing costs can be reduced.
水溶性セルロース誘導体とカテキンによるコーティング被膜は、水中で不溶化した後も親水性を保っており、水や水に溶解した薬剤はコーティング被膜を自由に出入りすることができる。胃内の水分や胃液は不溶化したコーティング被膜を通過して錠剤内部へ浸透し、錠剤中に含有されている発泡成分の炭酸水素ナトリウム、炭酸ナトリウム、炭酸カルシウム、炭酸カリウム、炭酸マグネシウム、炭酸水素カルシウム及び炭酸水素カリウムと反応して二酸化炭素を発生させる。また、クエン酸、酒石酸、フマル酸、コハク酸、リンゴ酸及びマレイン酸などの有機酸が溶解して強い酸性となって前記の発泡成分からの炭酸ガス発生を促進する。 The coating film made of a water-soluble cellulose derivative and catechin maintains hydrophilicity even after insolubilization in water, and water or a drug dissolved in water can freely enter and leave the coating film. Moisture and gastric juice in the stomach pass through the insolubilized coating film and penetrate into the tablet, and the foaming ingredients sodium bicarbonate, sodium carbonate, calcium carbonate, potassium carbonate, magnesium carbonate, calcium bicarbonate contained in the tablet And reacts with potassium bicarbonate to generate carbon dioxide. In addition, organic acids such as citric acid, tartaric acid, fumaric acid, succinic acid, malic acid and maleic acid dissolve and become strongly acidic, promoting the generation of carbon dioxide from the foaming component.
本発明に用いる水溶性セルロース誘導体としてヒドロキシプロピルセルロース又はヒドロキシプロピルメチルセルロースが好ましいことは上記のとおりである。
ヒドロキシプロピルセルロース（以下「ＨＰＣ」）は、セルロースの水酸基を酸化プロピレンでエーテル化することで得られ、多数のヒドロキシプロピル基（−ＯＣＨ２ＣＨ（ＯＨ）ＣＨ３）を持つ。１グルコースあたりの置換された水酸基の平均数は置換度（ｄｅｇｒｅｅ ｏｆ ｓｕｂｓｔｉｔｕｔｉｏｎ，ＤＳ）として表され、これは最大３である。しかしヒドロキシプロピル基にも水酸基が含まれるため、反応途中にここもエーテル化される。そのため、１グルコースあたりのヒドロキシプロピル基の数であるモル置換度（ｍｏｌｅｓ ｏｆ ｓｕｂｓｔｉｔｕｔｉｏｎ，ＭＳ）は３より大きくなる。ＨＰＣは食品添加物又は医薬品の賦形剤として市販されている。
食品添加物として市販されているＨＰＣとしては、例えば日本曹達株式会社製のセルニーＳＳＬ（分子量４０，０００）、セルニーＳＬ（分子量１００，０００）、セルニーＬ（分子量１４０，０００）、セルニーＭ（分子量６２０，０００）、セルニーＨ（分子量９１０，０００）を例示することができる。本発明においてはセルニーＳＳＬまたはＳＬ、Ｌが好ましく、特に好ましくはセルニーＳＳＬを使用することが好ましい。
As described above, hydroxypropylcellulose or hydroxypropylmethylcellulose is preferable as the water-soluble cellulose derivative used in the present invention.
Hydroxypropyl cellulose (hereinafter “HPC”) is obtained by etherifying a hydroxyl group of cellulose with propylene oxide, and has a number of hydroxypropyl groups (—OCH 2 CH (OH) CH 3 ). The average number of substituted hydroxyl groups per glucose is expressed as the degree of substitution (DS), which is a maximum of three. However, since the hydroxypropyl group also contains a hydroxyl group, it is etherified during the reaction. Therefore, the molar substitution degree (moles of substitution, MS), which is the number of hydroxypropyl groups per glucose, is larger than 3. HPC is commercially available as a food additive or pharmaceutical excipient.
As HPC marketed as a food additive, for example, Selney SSL (molecular weight 40,000), Selney SL (molecular weight 100,000), Selney L (molecular weight 140,000), Selney M (molecular weight) manufactured by Nippon Soda Co., Ltd. 620,000), Celny H (molecular weight 910,000). In the present invention, Cerney SSL or SL, L is preferred, and it is particularly preferred to use Cerney SSL.
本発明に用いるヒドロキシプロピルメチルセルロース（以下「ＨＰＭＣ」）は、メチルセルロースにヒドロキシプロポキシル基を導入したセルロースエーテルであり、水溶性のセルロース誘導体である。ＨＰＭＣは薬物の徐放性基材として知られている。本発明の目的に適したＨＰＭＣは、医薬品の賦形剤や食品添加物用としても市販されている。このようなＨＰＭＣとしては、信越化学工業株式会社製のＨＰＭＣ メトローズ ＳＥ０６、メトローズ ＳＥ５０、メトローズ ＮＥ１００、メトローズ ＳＦＥ４００、メトローズ ＮＥ４０００、メトローズ ＳＦＥ４０００を例示することができる。 Hydroxypropyl methylcellulose (hereinafter “HPMC”) used in the present invention is a cellulose ether in which a hydroxypropoxyl group is introduced into methylcellulose, and is a water-soluble cellulose derivative. HPMC is known as a sustained-release base for drugs. HPMCs suitable for the purposes of the present invention are also commercially available for pharmaceutical excipients and food additives. Examples of such HPMCs include HPMC Metroles SE06, Metroles SE50, Metroles NE100, Metrows SFE400, Metrows NE4000, and Metrows SFE4000 manufactured by Shin-Etsu Chemical Co., Ltd.
本発明に用いるカテキン類とは、緑茶ポリフェノールのうちフラバン−３−オール骨格を有するカテキン類で、（−）−エピガロカテキンガレート（ＥＧＣＧ）、（−）−エピカテキンガレート（ＥＣＧ）、（−）−エピガロカテキン（ＥＧＣ）、（−）−エピカテキン（ＥＣ）、（−）−ガロカテキンガレート（ＧＣＧ）、（−）−カテキンガレート（ＣＧ）、（±）−ガロカテキン（ＧＣ）及び（±）−カテキン（Ｃ）等の分子種を含むがこれらに限定されない。本明細書においてガレート基を有するカテキン類とは、（−）−エピガロカテキンガレート（ＥＧＣＧ）、（−）−エピカテキンガレート（ＥＣＧ）、（−）−カテキンガレート（ＣＧ）および（−）−ガロカテキンガレート（ＧＣＧ）等の分子種を含むがこれらに限定されない。本明細書においてガレート基を有しないカテキン類とは、（−）−エピガロカテキン（ＥＧＣ）、（−）−エピカテキン（ＥＣ）、（±）−ガロカテキン（ＧＣ）及び（±）−カテキン（Ｃ）等の分子種を含むがこれらに限定されない。またカテキン類は、精製されたものであっても良いし、緑茶から抽出された粗精製物である緑茶エキスであっても良い。緑茶エキスは、ツバキ科植物・チャの芽葉を原料として抽出されたエキスをいう。一般には緑茶を原料として、水で又はアルコールで抽出し、乾燥したものが市販されている。緑茶エキスは水抽出物が好ましい。本発明においては市販の緑茶エキスを使用することができる。
なお緑茶エキス又は緑茶抽出物としてはネキシラ（株）「グリーンティ抽出物ＥＧＣＧ４０」、三井農林（株）「ポリフェノン」（ポリフェノン７０Ａ）、（株）伊藤園「テアフラン」（テアフラン９０Ｓ）、太陽化学（株）「サンフェノン」（サンフェノン９０Ｓ）などの市販品がある。
本発明に使用するに適したガレート基を有するカテキンの量はＨＰＬＣ法で定量することができる。
またカテキン以外のガレート基を持つ化合物である没食子酸及び／又はタンニン酸であっても同様の効果を発揮する。
The catechins used in the present invention are catechins having a flavan-3-ol skeleton among green tea polyphenols, and (−)-epigallocatechin gallate (EGCG), (−)-epicatechin gallate (ECG), (− ) -Epigallocatechin (EGC), (−)-epicatechin (EC), (−)-gallocatechin gallate (GCG), (−)-catechin gallate (CG), (±) -gallocatechin (GC) and ( Including but not limited to molecular species such as ±) -catechin (C). In this specification, catechins having a gallate group are (−)-epigallocatechin gallate (EGCG), (−)-epicatechin gallate (ECG), (−)-catechin gallate (CG) and (−) —. Including but not limited to molecular species such as gallocatechin gallate (GCG). In the present specification, catechins having no gallate group include (−)-epigallocatechin (EGC), (−)-epicatechin (EC), (±) -gallocatechin (GC) and (±) -catechin ( Including but not limited to molecular species such as C). The catechins may be refined or green tea extract that is a crude product extracted from green tea. Green tea extract refers to an extract extracted from camellia plants and tea buds. Generally, green tea is used as a raw material, extracted with water or alcohol and dried. The green tea extract is preferably a water extract. In the present invention, a commercially available green tea extract can be used.
In addition, as green tea extract or green tea extract, Nexilla Co., Ltd. “Green Tea Extract EGCG40”, Mitsui Norin Co., Ltd. “Polyphenone” (Polyphenone 70A), ITO EN Co., Ltd. “Theafran” (Teafranc 90S), Taiyo Kagaku Co., Ltd. ) There are commercially available products such as “Sunphenon” (Sunphenon 90S).
The amount of catechin having a gallate group suitable for use in the present invention can be quantified by HPLC.
Moreover, even if it is a gallic acid and / or tannic acid which are compounds with gallate groups other than catechin, the same effect is exhibited.
本発明に使用する発泡成分の炭酸水素ナトリウム、炭酸ナトリウム、炭酸カルシウム、炭酸カリウム、炭酸マグネシウム、炭酸水素カルシウム及び炭酸水素カリウムは、食品や医薬品の原料として市販されているものであれば使用可能である。またホタテ貝殻末（ホタテ末）やボーンカルシウム（骨粉）のような炭酸カルシウムを主成分とする食品原料も使用可能である。発泡成分は、コーティング前の素錠当たり１〜１０質量％、好ましくは３〜５質量％配合する。 The foaming component sodium bicarbonate, sodium carbonate, calcium carbonate, potassium carbonate, magnesium carbonate, calcium bicarbonate and potassium bicarbonate used in the present invention can be used as long as they are commercially available as raw materials for foods and pharmaceuticals. is there. In addition, food ingredients mainly composed of calcium carbonate such as scallop shell powder (scallop powder) and bone calcium (bone meal) can be used. A foaming component is mix | blended 1-10 mass% with respect to the uncoated tablet before coating, Preferably it is 3-5 mass%.
クエン酸、酒石酸、フマル酸、コハク酸、リンゴ酸及びマレイン酸などの有機酸を配合する場合は前記の発泡成分と混合し、造粒しておくと、炭酸ガスの発泡効率が上昇する。有機酸を配合する場合は、コーティング前の素錠当たり１〜５質量％、好ましくは３〜５質量％配合する。 When an organic acid such as citric acid, tartaric acid, fumaric acid, succinic acid, malic acid and maleic acid is blended and mixed with the above foaming component and granulated, the foaming efficiency of carbon dioxide gas increases. When the organic acid is blended, it is blended in an amount of 1 to 5% by mass, preferably 3 to 5% by mass, based on the uncoated tablet.
本発明の錠剤を製造する場合、目的の薬剤または生理活性成分と発泡成分、有機酸を混合し、必要に応じて各種賦形剤を添加し、常法に則って造粒後打錠成型する。 When producing the tablet of the present invention, the target drug or physiologically active ingredient, foaming ingredient and organic acid are mixed, various excipients are added as necessary, and granulation is performed after granulation according to a conventional method. .
賦形剤としては、例えば、ぶどう糖、果糖、麦芽糖、乳糖、異性化乳糖、還元乳糖、蔗糖、Ｄ−マンニトール、エリスリトール、マルチトール、キシリトール、パラチノース（登録商標）、トレハロース、ソルビトール、トウモロコシデンプン、馬鈴薯デンプン、コムギデンプン、コメデンプン、結晶セルロース、タルク、無水ケイ酸、無水リン酸カルシウム、沈降炭酸カルシウム、ケイ酸カルシウム等が挙げられ、これらの１種または２種以上適宜配合して用いてもよい。好ましくは、乳糖、Ｄ−マンニトール、トウモロコシデンプン、結晶セルロース、ケイ酸カルシウムおよび無水リン酸カルシウムである。特に好ましくは乳糖、結晶セルロースおよびケイ酸カルシウムである。 Examples of the excipient include glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose (registered trademark), trehalose, sorbitol, corn starch, potato Starch, wheat starch, rice starch, crystalline cellulose, talc, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate and the like may be mentioned, and one or more of these may be appropriately blended and used. Lactose, D-mannitol, corn starch, crystalline cellulose, calcium silicate and anhydrous calcium phosphate are preferred. Particularly preferred are lactose, crystalline cellulose and calcium silicate.
結合剤としては、例えば、ポリビニルピロリドン、メチルセルロース、ポリビニルアルコール、カルボキシメチルセルロース、部分α化デンプン、α化デンプン、アルギン酸ナトリウム、プルラン、アラビアゴム末、ゼラチン、デキストリン等が挙げられ、これらの１種または２種以上適宜配合して用いてもよい。 Examples of the binder include polyvinyl pyrrolidone, methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, dextrin and the like, one or two of these. You may mix and use a seed | species suitably.
滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、蔗糖脂肪酸エステル、フマル酸ステアリルナトリウム、ステアリン酸、タルク、ポリエチレングリコール等が挙げられ、これらの１種または２種以上適宜配合して用いてもよい。好ましくは、ステアリン酸マグネシウム、蔗糖脂肪酸エステル、ステアリン酸、ステアリン酸カルシウムおよびポリエチレングリコールである。特に好ましくはステアリン酸マグネシウム、ステアリン酸カルシウムおよび蔗糖脂肪酸エステルである。 Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like, and one or more of these may be appropriately blended and used. Also good. Preferred are magnesium stearate, sucrose fatty acid ester, stearic acid, calcium stearate and polyethylene glycol. Particularly preferred are magnesium stearate, calcium stearate and sucrose fatty acid ester.
崩壊剤としては、例えば、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、クロスポビドン、ヒドロキシプロピルスターチ、トウモロコシデンプン等が挙げられ、これらの１種または２種以上適宜配合して用いてもよい。 Examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, hydroxypropyl starch, corn starch and the like, one or two of these. You may mix and use a seed | species suitably.
錠剤を打錠成形後、カテキン類と水溶性セルロースの混合物を溶解したコーティング液をコーティングする。可塑剤としてグリセリンや糖アルコールなどを使用してよい。コーティング液の調製溶媒には、エタノール又は水エタノール混合物を使用するのが望ましい。溶媒のエタノール濃度は、セルロース誘導体が溶解でき、かつカテキン類とセルロース誘導体の不溶体が生成されないように調節する必要がある。例えば、ヒドロキシプロピルセルロースを用いる場合はエタノール９５〜１００質量％、ヒドロキシプロピルメチルセルロースを用いる場合はエタノール７０質量％溶液を使用できる。コーティングは、パンコーティング法、通気式コーティング装置による方法、流動コーティング法のいずれでも使用可能である。 After tableting, tablets are coated with a coating solution in which a mixture of catechins and water-soluble cellulose is dissolved. Glycerin or sugar alcohol may be used as a plasticizer. It is desirable to use ethanol or a water ethanol mixture as a solvent for preparing the coating solution. It is necessary to adjust the ethanol concentration of the solvent so that the cellulose derivative can be dissolved and an insoluble form of catechins and cellulose derivative is not generated. For example, when hydroxypropylcellulose is used, ethanol 95 to 100% by mass, and when hydroxypropylmethylcellulose is used, a 70% ethanol solution can be used. The coating can be performed by any of a pan coating method, a method using a ventilation type coating apparatus, and a fluid coating method.
以下に実施例及び試験例を示し、本発明をさらに説明する。
１．試験用錠剤の製造
（１）素錠の製造
胃内で吸収されることが明らかになっているフェルラ酸を含有する錠剤を下記の表１の組成で製造した。
The following examples and test examples further illustrate the present invention.
1. Manufacture of test tablets (1) Manufacture of uncoated tablets Tablets containing ferulic acid, which has been shown to be absorbed in the stomach, were manufactured with the composition shown in Table 1 below.
フェルラ酸、カテキン（ネキシラ株式会社製）、ホタテ末、微粒二酸化ケイ素は、流動層造粒機（株式会社パウレック製 ＭＰ−０１）を用いて、クラスターデキストリン１５％濃度液をバインダーとして造粒した。これに賦形剤を添加し混合した後、ロータリー式打錠装置（株式会社菊水製作所製 ＶＥＬ−２）を用いて打圧１０００ｋｇｆで打錠し、直径８ｍｍ ２５０ｍｇの素錠を製造した。 Ferulic acid, catechin (manufactured by Nexira Co., Ltd.), scallop powder, and fine silicon dioxide were granulated using a fluidized bed granulator (MP-01, manufactured by POWREC Co., Ltd.) with a 15% concentration solution of cluster dextrin as a binder. After adding and mixing an excipient | filler to this, it was tableted by 1000 kgf of tableting pressures using the rotary type tableting apparatus (VEL-2 by Kikusui Seisakusho Co., Ltd.), and manufactured the uncoated tablet of diameter 8mm 250mg.
（２）コーティング
下記の表２の組成のコーティング液を調製した。
(2) Coating A coating solution having the composition shown in Table 2 below was prepared.
コーティング溶液は、７０質量％エタノール溶液を溶媒とし、表２の組成で固形分濃度８質量％に調整した。錠剤コーティング機（株式会社パウレック製 ＤＲＣ−２００）を用いて１錠当り６〜８ｍｇをコーティングした。 The coating solution was adjusted to a solid content concentration of 8% by mass with the composition shown in Table 2 using a 70% by mass ethanol solution as a solvent. 6-8 mg per tablet was coated using a tablet coating machine (DRC-200 manufactured by POWREC Co., Ltd.).
２．崩壊性試験（浮遊性試験）
上記１で調製した錠剤を用いて第１６改正日本薬局方に収載の崩壊試験１液（胃液相当）に対する崩壊性及び浮遊性を崩壊試験機により試験した。
試験液を３７±０．５℃に保ち、錠剤６粒を容器に投入し、崩壊試験機を作動させ、錠剤が浮遊する様子を観察した（表３）。実施例１、２はコーティング被膜が不溶化し、５〜９分で錠剤が膨らみ試験液表面に浮遊した。一方、比較例の錠剤のコーティング被膜は不溶化せずに剥れ、錠剤は浮遊せずに約４０分後に完全崩壊して消失した。８０分経過後に浮遊している実施例１、２の錠剤を取り出し、コーティング層を開けて内部の状態を確認したところ、錠剤は全て溶けており、試験液中に溶出していた。
崩壊試験１液による試験結果から、本発明の錠剤は胃内で８０分以上浮遊しながら被膜内部の成分を放出することが確認された。
2. Disintegration test (floating test)
Using the tablets prepared in 1 above, the disintegration property and buoyancy for disintegration test 1 liquid (corresponding to gastric juice) listed in the 16th revised Japanese Pharmacopoeia were tested with a disintegration tester.
The test liquid was kept at 37 ± 0.5 ° C., 6 tablets were put into the container, the disintegration tester was operated, and the appearance of the tablets floating was observed (Table 3). In Examples 1 and 2, the coating film became insoluble, and the tablets swelled and floated on the surface of the test solution in 5 to 9 minutes. On the other hand, the coating film of the tablet of the comparative example peeled without insolubilization, and the tablet did not float and disappeared completely after about 40 minutes. When the tablets of Examples 1 and 2 floating after 80 minutes were taken out and the coating layer was opened to check the internal state, all the tablets were dissolved and eluted in the test solution.
From the test results of the disintegration test 1 liquid, it was confirmed that the tablet of the present invention released components inside the coating while floating in the stomach for 80 minutes or more.
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| KR20210141200A (en) * | 2020-05-15 | 2021-11-23 | 이화여자대학교 산학협력단 | Coating layer comprising pullulan and manufacturing method thereof |
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