JPWO2007111375A1 - Orally rapidly disintegrating tablets - Google Patents
Orally rapidly disintegrating tablets Download PDFInfo
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- JPWO2007111375A1 JPWO2007111375A1 JP2008507527A JP2008507527A JPWO2007111375A1 JP WO2007111375 A1 JPWO2007111375 A1 JP WO2007111375A1 JP 2008507527 A JP2008507527 A JP 2008507527A JP 2008507527 A JP2008507527 A JP 2008507527A JP WO2007111375 A1 JPWO2007111375 A1 JP WO2007111375A1
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- tablet
- starch
- weight
- crystalline cellulose
- rapidly disintegrating
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/745—Bifidobacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
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- Mycology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nutrition Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Zoology (AREA)
- Physiology (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
有用菌、結晶セルロース・軽質無水ケイ酸（結晶セルロースと少量の軽質無水ケイ酸をスラリー状で混合後、噴霧乾燥法にて製造される賦形剤）及びデンプン含有糖類（デンプン粉末、デンプン造粒物、デンプン・乳糖造粒混合物等）の混合末を乾燥状態で圧縮成形し、錠剤硬度が約３０Ｎ〜６０Ｎ、水分含量が３．２重量％以下の錠剤とすることによって、打錠安定性及び保存安定性の高いビフィズス菌又は乳酸菌等の有用菌の口腔内速崩壊性錠剤が得られる。Useful bacteria, crystalline cellulose and light anhydrous silicic acid (excipient manufactured by spray drying after mixing crystalline cellulose and a small amount of light anhydrous silicic acid) and starch-containing saccharides (starch powder, starch granulation) Compression, and a tablet having a tablet hardness of about 30 N to 60 N and a moisture content of 3.2% by weight or less. Intraoral rapidly disintegrating tablets of useful bacteria such as bifidobacteria or lactic acid bacteria having high storage stability can be obtained.
Description
本発明は、口腔内の唾液の存在下又は少量の水の存在下において速やかに崩壊する口腔内速崩壊性錠剤に関し、更に詳しくは、有用菌を含有し、長期間の保存安定性にも優れた口腔内速崩壊性錠剤に関する。 The present invention relates to an orally rapidly disintegrating tablet that rapidly disintegrates in the presence of saliva in the oral cavity or in the presence of a small amount of water, and more particularly contains useful bacteria and is excellent in long-term storage stability. The present invention relates to an orally rapidly disintegrating tablet.
ヒトの腸内には腸内細菌が存在しており、最近では腸管全体には１００兆個もの腸内細菌がいると言われ、腸内細菌叢を形成している。腸内細菌にはビフィズス菌や乳酸菌などの有用菌又は善玉菌と大腸菌やウェルシュ菌などの悪玉菌とがあり、これらの細菌のバランスが保たれてヒトに有用な働きをもたらしている。このバランスが乱れると栄養成分の分解、消化、吸収、免疫、感染防御、老化などに影響を与え、腸内細菌叢のバランス維持がヒトの健康に深く関わっていることが近年知られてきている。腸内細菌叢の乱れは、ストレスや食生活の乱れ、疲労、睡眠不足などの現代人がよく陥る状況が原因となるだけではなく、加齢も腸内細菌叢が乱れる原因となる等、誰にでも起こりうる症状である。
腸内細菌叢のバランスを改善するために、ビフィズス菌等の生菌製剤が医療用医薬品、一般医薬品又はサプリメントとして散剤、錠剤、カプセル剤などの形で患者に提供されている。
口腔内崩壊性錠剤は、高齢者、小児など嚥下能力が低い患者又は一般の成人でも、服用場所を選ばず、水無しで服用可能な製剤としてその開発が望まれており、既にそのような製剤は幾つか開発されている。このような製剤を開示する公知文献として、（１）薬物、糖類、糖類の粒子表面が湿る程度の水分を含む混合物を打錠し、乾燥させる方法（特開平５−２７１０５４号公報参照）により製造される錠剤、（２）薬物、水溶性賦形剤及び非晶質糖類を圧縮成型後、エージングさせる方法（特開平１１−１２１６１号公報参照）により製造される錠剤、（３）薬物、乳糖、結晶セルロース及び軽質無水ケイ酸を一定の比率で含有し、更にクロスポピドン等の崩壊剤を含有することを特徴とする錠剤（特開２０００−２７３０３８号公報参照）が知られている。
更に、（４）日本薬学会第１２４年会において「結晶セルロース・軽質無水ケイ酸（商品名プロソルブ）の製剤への応用（２）」において、結晶セルロース、軽質無水ケイ酸の生菌製剤への応用処方が示されており、結晶セルロース・軽質無水ケイ酸は低い打錠圧での製剤化が可能であり、打錠時の生菌数のロスを減らすことが可能であったこと及びこのときの錠剤の崩壊時間は約１．５〜２分であったことが示されている。
しかしながら、これらの公知文献には有用菌を含有する口腔内崩壊性錠剤は明示されていない。即ち、（１）の錠剤は湿潤した混合物を打錠するため、水分に不安定な有用菌には適用することが難しく、（２）の錠剤は一定の温度、湿度の条件下で裸錠をエージングさせる必要があり、これは錠剤の乾燥減量を増大させ、有用菌の保存安定性が低下するという欠点がある。（３）の錠剤は本発明とは錠剤の組成が異なるうえ、本発明で用いられる結晶セルロース・軽質無水ケイ酸は使用されていないうえ、有用菌製剤及びその保存安定性に関しては何ら記載されていない。また、（４）には、結晶セルロース・軽質無水ケイ酸をビフィズス菌等有用菌に応用した例が示されており、打錠時の生菌数のロスを減らすことが可能であることも示されている。しかしながら、（４）には、得られた生菌製剤の保存安定性や速崩壊性の記載はない。Intestinal bacteria are present in the human intestine, and recently, it is said that there are 100 trillion intestinal bacteria in the entire intestinal tract, forming an intestinal flora. Intestinal bacteria include useful bacteria such as bifidobacteria and lactic acid bacteria, or good bacteria and bad bacteria such as Escherichia coli and Clostridium perfringens, and these bacteria are balanced to bring about useful functions for humans. In recent years, it has been known that maintaining this balance of the intestinal microflora is deeply related to human health by affecting the breakdown, digestion, absorption, immunity, infection defense, and aging of nutrients when this balance is disturbed. . Disturbance of the intestinal microflora is not only caused by the situation that modern people often fall into, such as stress, eating habits, fatigue, lack of sleep, etc. It is a symptom that can occur even in Japan.
In order to improve the balance of the intestinal microflora, live bacteria preparations such as bifidobacteria are provided to patients in the form of powders, tablets, capsules and the like as medical drugs, general pharmaceuticals or supplements.
Orally disintegrating tablets are desired to be developed as a preparation that can be taken without water, even in patients with low swallowing ability such as elderly people, children, and general adults, and can be taken without water. Some have been developed. As a publicly known document disclosing such a preparation, (1) a method of tableting and drying a mixture containing a drug, a saccharide, and a water containing a saccharide so that the surface of the saccharide is moistened (see Japanese Patent Laid-Open No. Hei 5-27054) Tablets to be produced, (2) tablets produced by a method of aging after compression molding of drug, water-soluble excipient and amorphous sugar (see JP-A-11-12161), (3) drug, lactose There is known a tablet (see Japanese Patent Application Laid-Open No. 2000-273038) characterized by containing crystalline cellulose and light silicic acid anhydride in a certain ratio and further containing a disintegrant such as crospovidone.
Furthermore, in (4) “Application of crystalline cellulose / light anhydrous silicic acid (trade name Prosolve) (2)” at the 124th Annual Meeting of the Pharmaceutical Society of Japan Application formulas are shown, and crystalline cellulose and light silicic acid can be formulated with low tableting pressure, and it was possible to reduce the loss of viable cell count during tableting and It was shown that the disintegration time of the tablet was about 1.5-2 minutes.
However, these known literatures do not disclose orally disintegrating tablets containing useful bacteria. That is, since the tablet of (1) compresses a wet mixture, it is difficult to apply it to useful bacteria that are unstable to moisture, and the tablet of (2) is a bare tablet under constant temperature and humidity conditions. It has to be aged, which increases the loss on drying of the tablet and has the disadvantage of reducing the storage stability of useful bacteria. The tablet of (3) has a different tablet composition from that of the present invention, the crystalline cellulose and light silicic acid used in the present invention are not used, and there are no descriptions regarding useful bacterial preparations and their storage stability. Absent. In addition, (4) shows an example in which crystalline cellulose / light anhydrous silicic acid is applied to useful bacteria such as bifidobacteria, and it is shown that it is possible to reduce the loss of the number of viable bacteria during tableting. Has been. However, (4) does not describe the storage stability and quick disintegration property of the obtained viable bacterial preparation.
従って、本発明の目的は、有用菌については、口腔内で速やかに崩壊し、適度な強度を有し、通常の圧縮成型機を用いて非常に簡便な方法で製造でき、かつ含有する有用菌の長期間の保存安定性にも優れた口腔内速崩壊性錠剤を開発することにある。
本発明に従えば、有用菌、結晶セルロース・軽質無水ケイ酸及びデンプン含有糖類を含有し、水分含量が３．２重量％以下である口腔内速崩壊性錠剤が提供される。
以下に本発明の態様を記載する。
（１）有用菌がビフィズス菌又は乳酸菌である前記口腔内速崩壊性錠剤。
（２）有用菌がビフィズス菌である前記口腔内速崩壊性錠剤。
（３）結晶セルロース・軽質無水ケイ酸を、錠剤１００重量部に対して、３５〜７０重量部含有する前記口腔内速崩壊性錠剤。
（４）デンプン含有糖類を、錠剤１００重量部に対して、２５〜６０重量部含有する前記口腔内速崩壊性錠剤。
（５）錠剤１００重量部に対して、結晶セルロース・軽質無水ケイ酸を４０〜７０重量部含有し、デンプン含有糖類を３０〜６０重量部含有する前記口腔内速崩壊性錠剤。
（６）錠剤硬度が３０Ｎ〜６０Ｎである前記口腔内速崩壊性錠剤。
（７）有用菌、結晶セルロース・軽質無水ケイ酸及びデンプン含有糖類の混合末を乾燥状態で圧縮成形し、水分が３．２重量％以下の錠剤を得る口腔内速崩壊性錠剤の製造方法。Therefore, the object of the present invention is to break down rapidly in the oral cavity with useful bacteria, have an appropriate strength, can be produced by a very simple method using a normal compression molding machine, and contain useful bacteria The purpose is to develop an orally rapidly disintegrating tablet excellent in long-term storage stability.
According to the present invention, an orally rapidly disintegrating tablet containing useful bacteria, crystalline cellulose / light silicic acid anhydride and starch-containing saccharides and having a moisture content of 3.2% by weight or less is provided.
Hereinafter, embodiments of the present invention will be described.
(1) The intraoral rapidly disintegrating tablet whose useful bacteria are bifidobacteria or lactic acid bacteria.
(2) The intraoral rapidly disintegrating tablet whose useful bacteria are bifidobacteria.
(3) The intraoral quick disintegrating tablet containing 35 to 70 parts by weight of crystalline cellulose / light silicic acid anhydride with respect to 100 parts by weight of the tablet.
(4) The said intraoral quick disintegrating tablet which contains 25-60 weight part of starch containing saccharides with respect to 100 weight part of tablets.
(5) The intraorally rapidly disintegrating tablet containing 40 to 70 parts by weight of crystalline cellulose / light silicic acid anhydride and 30 to 60 parts by weight of starch-containing saccharide with respect to 100 parts by weight of the tablet.
(6) The intraoral quick disintegrating tablet having a tablet hardness of 30N to 60N.
(7) A method for producing an orally rapidly disintegrating tablet by compressing a mixed powder of useful bacteria, crystalline cellulose / light silicic anhydride and starch-containing saccharide in a dry state to obtain a tablet having a moisture content of 3.2% by weight or less.
本発明者等は、上記課題を解決すべく検討を重ねた結果、有用菌に結晶セルロース、軽質無水ケイ酸及びデンプン含有糖類を配合したものは、通常の打錠機により比較的低い打錠圧で打錠することにより、口腔内で速やかに崩壊し、適度な強度を有し、かつ有用菌の打錠時の死滅率が少なく、しかも長期間の保存安定性にも優れた口腔内速崩壊性錠剤が得られることを見出した。本発明は、この様な知見に基づき更に研究を重ねることにより完成された。
本発明で用いられる有用菌はヒトの消化活動に有用なものであればいずれでも良い。ビフィズス菌類（Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｌｏｎｇｕｍ、Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｉｎｆａｎｔｉｓ、Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｂｉｆｉｄｕｍ、Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｂｒｅｖｅなど）、乳酸菌類（Ｌａｃｔｏｂａｃｉｌｌｕｓ ｃａｓｅｉ、Ｌａｃｔｏｂａｃｉｌｌｕｓ ｇａｓｓｅｒｉ、Ｌａｃｔｏｂａｃｉｌｌｕｓ ａｃｉｄｏｐｈｉｌｕｓ、Ｓｔｒｅｐｔｏｃｏｃｃｕｓ ｆａｅｃａｌｉｓ、Ｓｔｒｅｐｔｏｃｏｃｃｕｓ ｔｈｅｒｍｏｐｈｉｌｕｓなど）を挙げることができる。好ましくは、ビフィズス菌、特にビフィドバクテリウム・ロンガム（Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｌｏｎｇｕｍ）やビフィドバクテリウム・インファンティス（Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｉｎｆａｎｔｉｓ）などのビフィズス菌を挙げることができる。有用菌は、適宜、２種又はそれ以上を配合して使用することもできる。
本発明で用いる有用菌は、例えば生菌粉末、凍結乾燥品等の形態のものを用いることができる。その配合量は錠剤１００重量部に対して、０．０３〜３０重量部とすることができ、より良好な成形性を得るためには０．１〜２０重量部、とりわけ０．５〜１０重量部とすることが好ましい。配合菌数は特に限定しないが、その有効性から考えて生菌が１０５〜１０１０個／錠であり、好ましくは１０６〜１０９個／錠である。
本発明で用いる有用菌は、有用菌に悪影響を及ぼさない医薬品、健康食品等の他の有効成分と組み合わせて使用することもできる。
本発明で用いる結晶セルロース、軽質無水ケイ酸は結晶セルロースと少量の軽質無水ケイ酸をスラリー状で混合後、噴霧乾燥法にて製造される賦形剤であり、特許第３３００３６４号にその製造方法が示されている。このものは、ＪＲＳ ＰＨＡＲＭＡ社より「プロソルブ（ＰＲＯＳＯＬＶ）」（登録商標）として市販されているものを使用することができる。結晶セルロース・軽質無水ケイ酸は、錠剤１００重量部に対して、約３５〜７０重量部、好ましくは４０〜７０重量部使用される。
本発明で用いるデンプン含有糖類は、少なくともデンプンを含有するものであればよく、デンプンのみでもよいし、デンプンと１種類又はそれ以上の他の糖類を適宜の割合で単に混合したものでも良いし、それらを造粒したものでもよい。本発明ではデンプン含有糖類として、通常、デンプンを４０重量部以上、好ましくは７０重量部以上含むものが使用される。デンプン含有糖類の造粒方法としては特に制限はないが、噴霧乾燥、攪拌造粒、流動層造粒、押し出し造粒等が挙げられる。デンプンは特に由来を問わない。例えばトウモロコシデンプン、小麦デンプン、馬鈴薯デンプンなどが挙げられる。また他の糖類としては、例えば乳糖、ラクツロース、白糖、麦芽糖、粉飴、ブドウ糖、果糖、マルチトール、マンニトール、ソルビトール、キシリトール、エリスリトールなどが挙げられる。
デンプン含有糖類の使用量は、デンプン含有糖類に含まれるデンプンの含有量等により異なるが、通常、錠剤１００重量部に対して２５〜６０重量部使用される。例えば、デンプン含有糖類としてデンプンと乳糖を約７：３の割合で含有するデンプン・乳糖造粒混合物を用いた場合は、錠剤１００重量部に対して、約２５〜６０重量部、好ましくは３０〜６０重量部使用される。
本発明の錠剤は、所望により、錠剤の製造に一般的に使用されている種々の添加剤を配合しても良い。そのような添加剤は、単独又は適宜の割合で混合して使用しても良い。添加剤としては、例えば崩壊剤、結合剤、酸味剤、発泡剤、人工甘味料、矯味剤、香料、流動化剤、滑沢剤、着色剤、安定化剤、賦形剤などが挙げられる。
一般に、口腔内速崩壊性錠剤では所望の崩壊性を持たせるために、通常、崩壊剤を配合する。これらの崩壊剤として、例えばクロスポピドン、低置換ヒドロキシプロピルセルロース、カルメロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム等が挙げられる。なかでもクロスポピドンが汎用されている。しかし、本発明の口腔内速崩壊性錠剤は崩壊剤を配合しなくとも、口腔内で速やかに崩壊する。
本発明の口腔内速崩壊性錠剤の製造は、有用菌、結晶セルロース・軽質無水ケイ酸及びデンプン含有糖類に所望により他の添加剤を加えたものを乾燥状態で圧縮成形し、水分が３．２重量％以下の錠剤を得ることにより行われる。本発明において有用菌等の添加物の粒子径は特に限定されないが、粒子が小さいものを用いた方が服用感に優れたものが得られる。また、所望により有用菌を除く他の添加物は、湿式造粒工程を経た後乾燥したものを用いてもよい。この場合、結晶セルロース・軽質無水ケイ酸、デンプン含有糖類等を常法により混合した後、噴霧乾燥、攪拌造粒、流動層造粒、押し出し造粒等の処理が行われる。圧縮成形は一般に錠剤の成形に使用される装置が利用され、例えばロータリー式打錠機などを用いることができる。
本発明では、打錠時に有用菌が死滅するのを避けるため、打錠圧は比較的低めに設定し、しかも錠剤が破損することがない硬度が得られるように打錠することが好ましい。打錠圧は、通常、約１トン以下が好ましい。
かくして得られる本発明の口腔内速崩壊性錠剤は口腔内で崩壊性があり、適度な錠剤硬度を示す。口腔内での崩壊時間は通常５〜５０秒、好ましくは５〜４０秒、更に好ましくは５〜３０秒である。また、錠剤硬度は、流通過程において錠剤が破損することのない強度で、かつ崩壊時間が短い錠剤が得られるようにするため、好ましくは、約３０Ｎ〜６０Ｎ、更に好ましくは、約３０Ｎ〜５０Ｎの硬度を有する。
錠剤中の水分含量は有用菌の長期間の保存安定性に著しく影響を与える。このため、本発明では口腔内速崩壊性錠剤の水分含量はできるだけ少なくする必要がある。本発明では、水分含量は３．２重量％以下、好ましくは２．５重量％以下に保たれる。また、錠剤の保管は、通常、乾燥剤を入れたガラス瓶に錠剤を入れて保存する、アルミ包材で錠剤を完全に密閉するＳＰ包装等が好ましい。
服用方法としては、（１）本錠剤を口に含み、水なしで唾液により口腔内で錠剤を崩壊させて、そのまま服用する方法、（２）本錠剤を口に含み、更に少量の水も含み、口腔内で崩壊させて服用する方法、（３）水と共に本錠剤を口に含み、そのまま服用する方法、あるいは（４）本錠剤を水で崩壊させた後で服用する方法が挙げられる。本発明の口腔内速崩壊性錠剤は（ａ）水なしで服用する機会が多い場合、（ｂ）錠剤を飲み込むことが困難な患者が服用する場合、（ｃ）同時に多くの薬剤を服用する必要の多い場合、又は（ｄ）通常の錠剤では喉に詰まらせてしまう恐れのある高齢者や子供が服用する場合、などに特に有効に利用できる。As a result of repeated studies to solve the above-mentioned problems, the inventors of the present invention blended crystalline cellulose, light anhydrous silicic acid and starch-containing saccharides with useful bacteria. Oral fast disintegration that disintegrates quickly in the oral cavity, has moderate strength, has a low kill rate when tableting useful bacteria, and has excellent long-term storage stability It was found that a sex tablet was obtained. The present invention was completed by further research based on such findings.
Any useful bacteria may be used in the present invention as long as they are useful for human digestive activity. Bifidobacterium fungi (Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium bifidum, etc. Bifidobacterium breve), lactic acid bacteria (Lactobacillus casei, Lactobacillus gasseri, Lactobacillus acidophilus, Streptococcus faecalis, etc. Streptococcus thermophilus) can be exemplified. Preferably, Bifidobacterium, especially Bifidobacterium longum (Bifidobacterium longum) and Bifidobacterium infantis (Bifidobacterium infantis), etc. can be mentioned. Useful bacteria can be used in combination of two or more kinds as appropriate.
Useful bacteria used in the present invention can be in the form of, for example, live bacteria powder, lyophilized product, or the like. The blending amount can be 0.03 to 30 parts by weight with respect to 100 parts by weight of the tablet, and 0.1 to 20 parts by weight, particularly 0.5 to 10 parts by weight, in order to obtain better moldability. Part. The number of mixed bacteria is not particularly limited, but in view of its effectiveness, the number of viable bacteria is 10 5 to 10 10 cells / tablet, preferably 10 6 to 10 9 cells / tablet.
The useful bacteria used in the present invention can be used in combination with other active ingredients such as pharmaceuticals and health foods that do not adversely affect the useful bacteria.
Crystalline cellulose and light anhydrous silicic acid used in the present invention are excipients manufactured by spray drying after mixing crystalline cellulose and a small amount of light anhydrous silicic acid in a slurry state. It is shown. This thing can use what is marketed as a "PROSOLV" (trademark) from JRS PHARMA company. The crystalline cellulose / light anhydrous silicic acid is used in an amount of about 35 to 70 parts by weight, preferably 40 to 70 parts by weight, based on 100 parts by weight of the tablet.
The starch-containing saccharide used in the present invention only needs to contain at least starch, may be starch alone, or may be a simple mixture of starch and one or more other saccharides in an appropriate ratio, Those obtained by granulation may be used. In the present invention, as starch-containing saccharides, those containing 40 parts by weight or more, preferably 70 parts by weight or more of starch are usually used. The method for granulating the starch-containing saccharide is not particularly limited, and examples thereof include spray drying, stirring granulation, fluidized bed granulation, and extrusion granulation. The origin of starch is not particularly limited. Examples thereof include corn starch, wheat starch, and potato starch. Examples of other saccharides include lactose, lactulose, sucrose, maltose, flour, glucose, fructose, maltitol, mannitol, sorbitol, xylitol, and erythritol.
The amount of starch-containing saccharide used varies depending on the content of starch contained in the starch-containing saccharide, etc., but is usually 25-60 parts by weight per 100 parts by weight of the tablet. For example, when a starch / lactose granulation mixture containing starch and lactose in a ratio of about 7: 3 is used as the starch-containing saccharide, it is about 25-60 parts by weight, preferably 30-30 parts per 100 parts by weight of the tablet. 60 parts by weight are used.
If desired, the tablet of the present invention may be blended with various additives generally used in tablet production. Such additives may be used alone or in admixture at an appropriate ratio. Examples of the additive include a disintegrant, a binder, a sour agent, a foaming agent, an artificial sweetener, a flavoring agent, a flavoring agent, a fluidizing agent, a lubricant, a coloring agent, a stabilizer, and an excipient.
In general, a disintegrating agent is usually blended in an intraoral rapidly disintegrating tablet in order to have a desired disintegrating property. Examples of these disintegrants include crospovidone, low-substituted hydroxypropyl cellulose, carmellose calcium, croscarmellose sodium, and carboxymethyl starch sodium. Among them, crospopidone is widely used. However, the rapidly disintegrating tablet in the oral cavity of the present invention rapidly disintegrates in the oral cavity without blending a disintegrant.
The intraoral rapidly disintegrating tablet of the present invention is produced by compression-molding a useful bacterium, crystalline cellulose, light anhydrous silicic acid and starch-containing saccharides with other additives as desired, and having a moisture content of 3. This is done by obtaining a tablet of 2% by weight or less. In the present invention, the particle diameter of the additive such as useful bacteria is not particularly limited, but the use of a particle having a small particle provides a superior feeling of dosing. Moreover, what was dried after passing through a wet granulation process may be used for the other additive except a useful microbe depending on necessity. In this case, crystalline cellulose, light anhydrous silicic acid, starch-containing saccharides, and the like are mixed by a conventional method, and then treatments such as spray drying, stirring granulation, fluidized bed granulation, and extrusion granulation are performed. For compression molding, an apparatus generally used for tablet formation is used. For example, a rotary tableting machine or the like can be used.
In the present invention, in order to avoid the killing of useful bacteria at the time of tableting, it is preferable to set the tableting pressure to be relatively low and to perform tableting so as to obtain a hardness that does not damage the tablet. The tableting pressure is usually preferably about 1 ton or less.
The intraoral rapidly disintegrating tablet of the present invention thus obtained is disintegratable in the oral cavity and exhibits an appropriate tablet hardness. The disintegration time in the oral cavity is usually 5 to 50 seconds, preferably 5 to 40 seconds, and more preferably 5 to 30 seconds. The tablet hardness is preferably about 30 N to 60 N, and more preferably about 30 N to 50 N in order to obtain a tablet with a strength that does not break the tablet in the distribution process and a short disintegration time. Has hardness.
The water content in tablets significantly affects the long-term storage stability of useful bacteria. For this reason, in the present invention, it is necessary to reduce the water content of the rapidly disintegrating tablet in the oral cavity as much as possible. In the present invention, the water content is kept at 3.2 wt% or less, preferably 2.5 wt% or less. In addition, for storage of tablets, it is usually preferable to store the tablets in a glass bottle containing a desiccant, such as SP packaging in which the tablets are completely sealed with an aluminum packaging material.
As a method of taking, (1) the tablet is contained in the mouth, the tablet is disintegrated in the oral cavity with saliva without water, and taken as it is, (2) the tablet is contained in the mouth, and a small amount of water is also contained. (3) A method of taking this tablet together with water in the mouth and taking it as it is, or (4) A method of taking this tablet after it is disintegrated with water. The intraoral rapidly disintegrating tablet of the present invention (a) When there are many opportunities to take without water, (b) When a patient who is difficult to swallow the tablet, (c) It is necessary to take many drugs at the same time It can be used particularly effectively in cases where there are a lot of cases, or (d) when an elderly person or a child who is likely to clog the throat with a normal tablet.
以下に実施例、比較例を示し、本発明を詳しく説明するが、本発明はこれらに限定されるものではない。錠剤の物性（硬度、崩壊時間及び有用菌安定性試験）は下記試験法により測定した。
尚、以下の実施例、比較例で使用したビフィズス菌粉末は、ビフィドバクテリウム・ロンガム（Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｌｏｎｇｕｍ）とビフィドバクテリウム・インファンティス（Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｉｎｆａｎｔｉｓ）を培養した後、凍結乾燥処理を施して得られた粉末で、約１×１０１０個／ｇの生菌を有するものである。
（１）硬度試験
錠剤硬度計（ＦＵＪＩＷＡＲＡ）を用いて測定した。試験は１０回行い、その平均値を示した。
（２）崩壊試験
日本薬局方による崩壊試験により評価した。試験は崩壊試験器（富山産業（株））を用い、補助板なしで測定した。試験液は水（３７℃）を用いた。試験は６錠について行い、その平均値を示した。
（３）口腔内崩壊時間測定
口腔内の唾液のみで錠剤が崩壊するまでの時間を測定した。試験は３回行い、その平均値を示した。
（４）保存安定性試験
各錠剤をアルミ包装後、温度４０℃、７５％相対湿度下に１週間又は２週間保存した。その間の菌数の減少はビフィドバクテリウム鑑別用培地（馬脱繊維血液添加）を用いて平板塗抹法により測定した。保存前の生菌数と保存後の生菌数よりビフィズス菌の生存率を求めた。
実施例１〜３
ビフィズス菌粉末、結晶セルロース・軽質無水ケイ酸（プロソルブ９０、ＪＲＳ ＰＨＡＲＭＡ製）、デンプン含有糖類（トウモロコシデンプン、トウモロコシデンプン造粒品、トウモロコシデンプン・乳糖造粒混合物（トウモロコシデンプン：乳糖（重量比）＝７０：２９）のいずれか１種）を混合後、ステアリン酸Ｍｇを添加、再混合し、打錠用末とした。ロータリー式打錠機（ＰＩＣＣＯＲＡ、ＲＩＶＡ．Ｓ．Ａ製）を用いて、糖衣型の杵で１錠２８０ｍｇ、９ｍｍφ、硬度が約４０Ｎとなるように打錠した。得られた錠剤について崩壊試験及び口腔内崩壊時間の測定を行った。その結果を表１に示した。
実施例４及び比較例１
ビフィズス菌粉末、結晶セルロース・軽質無水ケイ酸（プロソルブ９０、ＪＲＳ ＰＨＡＲＭＡ製）、トウモロコシデンプン・乳糖造粒混合物を混合後、ステアリン酸Ｍｇを添加、再混合し、打錠用末とした。ロータリー式打錠機（ＰＩＣＣＯＲＡ、ＲＩＶＡ．Ｓ．Ａ製）を用いて、糖衣型の杵で１錠２８０ｍｇ、９ｍｍφ、硬度が約４０Ｎとなるように打錠した。得られた錠剤について保存安定性試験（保存期間２週間）を行った。その結果を表２に示した。
比較例２及び３
ビフィズス菌粉末、結晶セルロース（アビセルＰＨ１０１、旭化成（株））、マンニトール、乳糖、軽質無水ケイ酸、クロスポピドン（コリドンＣＬ、ＢＡＳＦ社製）を混合後、ステアリン酸Ｍｇを添加、再混合し打錠用末とした。ロータリー式打錠機（ＰＩＣＣＯＲＡ、ＲＩＶＡ．Ｓ．Ａ製）を用いて、糖衣型の杵で１錠２８０ｍｇ、９ｍｍφ、硬度が約４０Ｎとなるように打錠した。得られた錠剤について崩壊試験、口腔内崩壊時間測定および保存安定性試験（保存期間１週間）を行った。その結果を表３に示した。
実施例５並びに比較例４及び５
ビフィズス菌粉末、結晶セルロース・軽質無水ケイ酸（プロソルブ９０、ＪＲＳ ＰＨＡＲＭＡ製）、トウモロコシデンプン、トウモロコシデンプン・乳糖造粒混合物を混合後、ステアリン酸Ｍｇを添加、再混合し、打錠用末とした。ロータリー式打錠機（ＰＩＣＣＯＲＡ、ＲＩＶＡ．Ｓ．Ａ製）を用いて、糖衣型の杵で１錠２８０ｍｇ、９ｍｍφ、硬度が約３０〜４０Ｎとなるように打錠した。錠剤の乾燥減量は２．２〜７．３重量％のものを製造した。得られた錠剤について崩壊試験、口腔内崩壊時間測定および保存安定性試験（保存期間１週間）を行った。その結果を表４に示した。
実施例６〜９及び比較例６
ビフィズス菌粉末、結晶セルロース・軽質無水ケイ酸（プロソルブ９０、ＪＲＳ ＰＨＡＲＭＡ製）、トウモロコシデンプン・乳糖造粒混合物を混合後、ステアリン酸Ｍｇを添加、再混合し、打錠用末とした。ロータリー式打錠機（ＰＩＣＣＯＲＡ、ＲＩＶＡ．Ｓ．Ａ製）を用いて、糖衣型の杵で１錠２８０ｍｇ、９ｍｍφ、硬度が約３０、４０、５０、６０Ｎとなるように打錠した。得られた錠剤について崩壊試験、口腔内崩壊時間測定を行った。その結果を表５に示した。
実施例１０〜１２及び比較例７〜９
ビフィズス菌粉末、結晶セルロース・軽質無水ケイ酸（プロソルブ９０、ＪＲＳ ＰＨＡＲＭＡ製）、トウモロコシデンプン・乳糖造粒混合物を混合後、ステアリン酸Ｍｇを添加、再混合し、打錠用末とした。ロータリー式打錠機（ＰＩＣＣＯＲＡ、ＲＩＶＡ．Ｓ．Ａ製）を用いて、糖衣型の杵で１錠２８０ｍｇ、９ｍｍφ、硬度が３０〜４０Ｎとなるように打錠した。結晶セルロース・軽質無水ケイ酸の配合量は錠剤中に約９〜８７重量部、トウモロコシデンプン・乳糖造粒混合物も錠剤中に約９〜８７重量部含有する錠剤を製造した。得られた錠剤について崩壊試験、口腔内崩壊時間測定、打錠安定性試験、保存安定性試験を行った。その結果を表６に示した。
また、結晶セルロース・軽質無水ケイ酸が９．６重量部と少なく、デンプン含有糖類が８７重量部と多い錠剤（比較例７）では崩壊性が著しく悪くなるので好ましくない。一方、結晶セルロース・軽質無水ケイ酸が８７重量部と多くデンプン含有糖類が９．６重量部と少ない錠剤（比較例９）では保存安定性が低くなるので好ましくない。Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto. The physical properties (hardness, disintegration time and useful bacteria stability test) of the tablets were measured by the following test methods.
The bifidobacteria powder used in the following examples and comparative examples was cultured after bifidobacterium longum and bifidobacterium infantis were lyophilized. The obtained powder has about 1 × 10 10 cells / g of live bacteria.
(1) Hardness test It measured using the tablet hardness meter (FUJIWARA). The test was performed 10 times and the average value was shown.
(2) Disintegration test It evaluated by the disintegration test by a Japanese pharmacopoeia. The test was carried out using a disintegration tester (Toyama Sangyo Co., Ltd.) without an auxiliary plate. Water (37 ° C.) was used as the test solution. The test was conducted on 6 tablets and the average value was shown.
(3) Oral disintegration time measurement The time until the tablet disintegrates with only saliva in the oral cavity was measured. The test was performed 3 times and the average value was shown.
(4) Storage stability test Each tablet was packaged in aluminum, and then stored for 1 week or 2 weeks at a temperature of 40 ° C and 75% relative humidity. During this period, the decrease in the number of bacteria was measured by a plate smearing method using a Bifidobacterium discrimination medium (with horse defibrinated blood added). The viability of bifidobacteria was determined from the number of viable bacteria before storage and the number of viable bacteria after storage.
Examples 1-3
Bifidobacteria powder, crystalline cellulose / light anhydrous silicic acid (Prosolv 90, manufactured by JRS PHARMA), starch-containing saccharide (corn starch, corn starch granulated product, corn starch / lactose granulated mixture (corn starch: lactose (weight ratio)) = After mixing any one of 70:29), Mg stearate was added and mixed again to obtain a tableting powder. Using a rotary tableting machine (PICCORA, manufactured by RIVA.SA), tableting was performed with a sugar-coated scissors so that one tablet was 280 mg, 9 mmφ, and the hardness was about 40N. The disintegration test and the oral disintegration time were measured for the obtained tablets. The results are shown in Table 1.
Example 4 and Comparative Example 1
Bifidobacteria powder, crystalline cellulose / light anhydrous silicic acid (Prosolv 90, manufactured by JRS PHARMA), corn starch / lactose granulation mixture were mixed, and then Mg stearate was added and mixed again to obtain a tableting powder. Using a rotary tableting machine (PICCORA, manufactured by RIVA.SA), tableting was performed with a sugar-coated scissors so that one tablet was 280 mg, 9 mmφ, and the hardness was about 40N. The obtained tablets were subjected to a storage stability test (storage period 2 weeks). The results are shown in Table 2.
Comparative Examples 2 and 3
Bifidobacteria powder, crystalline cellulose (Avicel PH101, Asahi Kasei Co., Ltd.), mannitol, lactose, light anhydrous silicic acid, crospovidone (Collidon CL, manufactured by BASF) are added, Mg stearate is added, mixed again, and tableted It was used. Using a rotary tableting machine (PICCORA, manufactured by RIVA.SA), tableting was performed with a sugar-coated scissors so that one tablet was 280 mg, 9 mmφ, and the hardness was about 40N. The obtained tablets were subjected to a disintegration test, an oral disintegration time measurement, and a storage stability test (storage period of 1 week). The results are shown in Table 3.
Example 5 and Comparative Examples 4 and 5
Bifidobacteria powder, crystalline cellulose / light anhydrous silicic acid (Prosolv 90, manufactured by JRS PHARMA), corn starch, corn starch / lactose granulation mixture were mixed, and then Mg stearate was added and mixed again to obtain a tableting powder. . Using a rotary tableting machine (PICCORA, manufactured by RIVA.SA), tableting was performed with a sugar-coated scissors so that one tablet was 280 mg, 9 mmφ, and the hardness was about 30 to 40 N. Tablets with a loss on drying of 2.2 to 7.3% by weight were produced. The obtained tablets were subjected to a disintegration test, an oral disintegration time measurement, and a storage stability test (storage period of 1 week). The results are shown in Table 4.
Examples 6 to 9 and Comparative Example 6
Bifidobacteria powder, crystalline cellulose / light anhydrous silicic acid (Prosolv 90, manufactured by JRS PHARMA), corn starch / lactose granulation mixture were mixed, and then Mg stearate was added and mixed again to obtain a tableting powder. Using a rotary tableting machine (PICCORA, manufactured by RIVA.SA), tableting was performed with a sugar-coated scissors so that one tablet was 280 mg, 9 mmφ, and the hardness was about 30, 40, 50, 60 N. The obtained tablets were subjected to a disintegration test and an oral disintegration time measurement. The results are shown in Table 5.
Examples 10-12 and Comparative Examples 7-9
Bifidobacteria powder, crystalline cellulose / light anhydrous silicic acid (Prosolv 90, manufactured by JRS PHARMA), corn starch / lactose granulation mixture were mixed, and then Mg stearate was added and mixed again to obtain a tableting powder. Using a rotary tableting machine (PICCORA, manufactured by RIVA.SA), tableting was performed with a sugar-coated scissors so that one tablet was 280 mg, 9 mmφ, and the hardness was 30 to 40N. Tablets containing about 9 to 87 parts by weight of crystalline cellulose / light silicic acid anhydride and about 9 to 87 parts by weight of the corn starch / lactose granulation mixture were produced. The obtained tablets were subjected to a disintegration test, an oral disintegration time measurement, a tableting stability test, and a storage stability test. The results are shown in Table 6.
Further, a tablet (Comparative Example 7) having a small amount of crystalline cellulose / light silicic acid anhydride of 9.6 parts by weight and a large amount of starch-containing saccharides of 87 parts by weight is not preferable because the disintegration property is significantly deteriorated. On the other hand, a tablet (Comparative Example 9) containing 87 parts by weight of crystalline cellulose / light anhydrous silicic acid and 9.6 parts by weight of starch-containing saccharide is not preferable because the storage stability is low.
本発明の口腔内速崩壊性錠剤は適度な強度を有しつつ、口腔内での優れた崩壊性を示し、有用菌の優れた打錠安定性と保存安定性を有している。従って、高齢者、小児など嚥下能力が低い患者又は一般の成人でも服用場所を選ばず、水無しで服用可能な錠剤として、腸内細菌叢のバランスの乱れの改善、又は腸内細菌叢のバランスの維持を望む患者に提供することができる。 The rapidly disintegrating tablet in the oral cavity of the present invention exhibits an excellent disintegrating property in the oral cavity while having an appropriate strength, and has excellent tableting stability and storage stability of useful bacteria. Therefore, even in patients with low swallowing ability, such as elderly people and children, or general adults, as a tablet that can be taken without water, improving the disturbance of intestinal flora balance, or balancing intestinal flora Can be provided to patients who wish to maintain the above.
Claims (8)
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| JP2008507527A JP5100634B2 (en) | 2006-03-24 | 2007-03-23 | Orally rapidly disintegrating tablets |
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| JP2006083857 | 2006-03-24 | ||
| JP2008507527A JP5100634B2 (en) | 2006-03-24 | 2007-03-23 | Orally rapidly disintegrating tablets |
| PCT/JP2007/057007 WO2007111375A1 (en) | 2006-03-24 | 2007-03-23 | Intraorally rapidly disintegrating tablet |
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| JPWO2007111375A1 true JPWO2007111375A1 (en) | 2009-08-13 |
| JP5100634B2 JP5100634B2 (en) | 2012-12-19 |
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| KR (1) | KR101470483B1 (en) |
| CN (1) | CN101410127B (en) |
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| JP6983407B2 (en) * | 2015-07-07 | 2021-12-17 | 東亜薬品工業株式会社 | Bacterial fast-disintegrating tablet containing bacteria |
| EP4135670A1 (en) * | 2020-04-17 | 2023-02-22 | Evelo Biosciences, Inc. | Solid dosage forms with improved disintegration profiles |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH0441434A (en) * | 1990-06-07 | 1992-02-12 | Asahi Breweries Ltd | Lactobacillus tablet provided with enteric coating |
| JPH054926A (en) * | 1991-06-27 | 1993-01-14 | Dainippon Pharmaceut Co Ltd | Enteral useful bacterium-containing sugar-coated tablet |
| JP3069458B2 (en) * | 1992-01-29 | 2000-07-24 | 武田薬品工業株式会社 | Orally disintegrating tablet and production method thereof |
| US5585115A (en) * | 1995-01-09 | 1996-12-17 | Edward H. Mendell Co., Inc. | Pharmaceutical excipient having improved compressability |
| JP3591801B2 (en) * | 1997-06-19 | 2004-11-24 | 田辺製薬株式会社 | Manufacturing method of oral disintegrating preparation |
| EP0931543B1 (en) * | 1997-12-19 | 2002-03-20 | MERCK PATENT GmbH | Multilayered tablet comprising probiotic microorganisms such as lactobacilli or bifidobacteria |
| JP4063386B2 (en) * | 1998-01-29 | 2008-03-19 | キッセイ薬品工業株式会社 | Rapid-release oral pharmaceutical composition |
| JP2000063289A (en) * | 1998-08-20 | 2000-02-29 | Morinaga Milk Ind Co Ltd | Pharmaceutical preparation containing physiologically active substance |
| JP2001122785A (en) * | 1999-10-22 | 2001-05-08 | Nippon Boehringer Ingelheim Co Ltd | Tablet containing brotizolam |
| ES2398910T3 (en) * | 2001-09-28 | 2013-03-22 | Tntgamble, Inc. | Contribution system for biological components |
| JP4605977B2 (en) * | 2002-06-14 | 2011-01-05 | 日本ベーリンガーインゲルハイム株式会社 | Tablets containing brotizolam |
| US20040265375A1 (en) * | 2003-04-16 | 2004-12-30 | Platteeuw Johannes J. | Orally disintegrating tablets |
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| KR101470483B1 (en) | 2014-12-08 |
| KR20080111014A (en) | 2008-12-22 |
| CN101410127B (en) | 2011-08-31 |
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| SG170766A1 (en) | 2011-05-30 |
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