JP2006063030A - Method for producing tablets with low content - Google Patents
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Abstract
【課題】投与量が少ない薬物について、簡便な方法で、薬効成分の含量均一性が確保され、かつ、崩壊性、溶出性、成型性の優れた錠剤の製造方法を開発する。
【解決手段】低含量の薬効成分を含有する錠剤の製造において、薬効成分を含有する溶液を撹拌下の賦形剤に滴下または噴霧により添加し、均一に混合せしめた後乾燥して得られた粉末に、さらに造粒乳糖を加えて均一に混合した粉末を打錠することによる第１４改正日本薬局方規定の含量均一性試験における判定値が１５％未満である含量均一性、成型性、崩壊性、溶出性が改良された錠剤の製造方法。[PROBLEMS] To develop a method for producing a tablet with a small dose, which is a simple method that ensures the uniformity of the content of medicinal ingredients and is excellent in disintegration, dissolution and moldability.
In the production of a tablet containing a low content of medicinal ingredients, a solution containing medicinal ingredients is added dropwise to an agitated excipient by dropping or spraying, and mixed and then dried. Content uniformity, moldability, disintegration with a judgment value of less than 15% in the content uniformity test of the 14th revised Japanese Pharmacopoeia by tableting a powder that is further mixed with granulated lactose and mixed uniformly with the powder For producing tablets with improved properties and dissolution properties.
Description
本発明は、極めて少ない量の薬効成分が均一に配合され、かつ、成型性、崩壊性に優れた錠剤の製造方法に関する。 The present invention relates to a method for producing a tablet in which an extremely small amount of a medicinal component is uniformly blended and is excellent in moldability and disintegration.
錠剤は、薬効成分および添加剤を含む混合物を、円盤形、楕円形などに圧縮成型したもので、一錠当たりの薬効成分の含有量が正確であること、薬効成分の発現部位（胃、腸など）を調節することが可能であること、調剤がし易いこと、あるいは大量生産が可能で経済的であること、など多くの利点を有していることから、経口投与用製剤として最も多用されている製剤である。その製法としては、薬効成分や添加剤の物性によって、通常、直接粉末圧縮法、乾式顆粒圧縮法あるいは湿式顆粒圧縮法の３法から適した製法が選ばれて錠剤とされる。これらいずれの製法においても、薬効成分と各種添加剤をそれぞれ篩過したのち、両者を混合する操作を経て調製され、薬効成分の多くは、その混合操作の過程で、１錠剤中の成分含量に応じて所定量となるように倍散作業が行われる。 Tablets are compression-molded mixtures containing medicinal ingredients and additives into discs, ovals, etc., and the content of medicinal ingredients per tablet is accurate, and the site where the medicinal ingredients appear Etc.), it is easy to prepare, or mass production is possible and economical. It is a formulation. As the production method, depending on the physical properties of the medicinal ingredients and additives, a suitable production method is usually selected from the direct powder compression method, dry granule compression method or wet granule compression method to form a tablet. In any of these production methods, the medicinal ingredients and various additives are respectively sieved and then prepared through an operation of mixing the two. In response, the doubling work is performed so that a predetermined amount is obtained.
錠剤は、上述のとおり、最も多用されている経口投与用の固形製剤ではあるが、生物活性の高い薬効成分の場合には投与量が少なく、錠剤中に含有せしめる量が極めて少なくなって、倍散作業によっても粉体同士の混合作業であるために、極微量の薬効成分を各種の添加物と共に均一に混合することが難しく、錠剤間の成分含量にバラツキが生じ易いという問題がある。さらに、薬効成分が吸湿性の化合物である場合、あるいは、薬効成分と添加剤との組合せが悪いなどの場合には、錠剤中の薬効成分の含有量を一定に維持することが一層困難となり、歩留まりを悪くする原因になっている。 As described above, tablets are the most frequently used solid preparations for oral administration. However, in the case of medicinal ingredients with high biological activity, the dosage is small, and the amount contained in the tablet is extremely small. Since it is a mixing operation between powders even by a dusting operation, it is difficult to uniformly mix a very small amount of medicinal ingredients together with various additives, and there is a problem that the component content between tablets tends to vary. Furthermore, when the medicinal component is a hygroscopic compound, or when the combination of the medicinal component and the additive is bad, it becomes more difficult to keep the content of the medicinal component in the tablet constant, This is a cause of poor yield.
生物活性が高く一回当たりの投与量が少ない薬物としては、メストラノール、エチニルエストラジオールなどの卵胞ホルモン剤、あるいは、骨そしょう症の治療剤として用いられている活性ビタミンＤ3 などがある。これら薬物の一回当たりの投与量は、０．２５〜３５μｇ程度で、錠剤１錠当たりの含有量は極めて微量でなければならない。
一方で、錠剤における薬効成分の含量均一性試験の判定値は１５％未満と規定されており（第１４改正日本薬局方）、特に、生物活性が高い薬物について上述の倍散法による製造法によって判定値を満たす錠剤を得るためには、厳重な生産管理のもとで行わなければならず、極めて効率の悪いものとなっている。
さらに、錠剤は、判定値１５％未満の規定に合致するだけでなく、体内での崩壊性および薬効成分の溶出速度と生体内利用性から、また生産性のうえからも、適切な添加剤を選択し製剤化が容易に行える方法でなければならない。
Examples of drugs having high biological activity and small dose per dose include follicular hormone agents such as mestranol and ethinyl estradiol, and active vitamin D 3 used as a therapeutic agent for osteoporosis. The dosage per one of these drugs is about 0.25 to 35 μg, and the content per tablet must be extremely small.
On the other hand, the judgment value of the content uniformity test of medicinal ingredients in tablets is defined as less than 15% (14th revised Japanese Pharmacopoeia), especially for drugs with high biological activity by the above-mentioned production method by the doubling method In order to obtain a tablet satisfying the judgment value, it must be performed under strict production control, which is extremely inefficient.
Furthermore, tablets not only meet the criteria of less than 15% of the judgment value, but also contain appropriate additives for disintegration in the body, dissolution rate and bioavailability of medicinal ingredients, and productivity. The method must be easy to select and formulate.
上述のメストラノールやエチニルエストラジオールのような生物活性が高く、投与量が極めて少ない薬物は、錠剤中の含量が極めて少なくなり、倍散によって、判定値１５％未満の規格を確保することが難しい。本発明者は、上記の判定値を満たす錠剤を得るべく、撹拌造粒法、押出造粒法あるいは流動層造粒法など各種の方法によって製剤化を試みたが、一応の規格内にある錠剤を得ることができても、造粒粉末の特性により成型性が悪く、かつ、錠剤の強度（硬度）に問題が生じ、崩壊性と薬効成分の溶出特性などの物性を満足する錠剤を安定して得ることが困難であった。
このような状況下において、本発明の目的は、投与量が少ない薬物について、直接粉末圧縮法に準じた方法で、手間がかからず、判定値が１５％未満という規定を満たし、崩壊性、溶出性に問題がなく、しかも、生産性の高い錠剤の製造方法を開発することにある。
A drug having a high biological activity such as mestranol or ethinylestradiol and having a very small dose has a very small content in the tablet, and it is difficult to ensure a standard with a judgment value of less than 15% by trituration. The present inventor tried to formulate by various methods such as agitation granulation method, extrusion granulation method or fluidized bed granulation method in order to obtain a tablet satisfying the above judgment value. Even if it can be obtained, the moldability is poor due to the characteristics of the granulated powder, and there is a problem in the strength (hardness) of the tablet, and the tablets satisfying physical properties such as disintegration and dissolution characteristics of medicinal ingredients are stabilized. It was difficult to obtain.
Under such circumstances, the object of the present invention is to reduce the dose of a drug in accordance with the direct powder compression method, which does not take time and satisfies the rule that the judgment value is less than 15%, The purpose is to develop a method for producing tablets with no problem in dissolution and high productivity.
本発明者らは、上記課題を解決するため、倍散法に拠らない製剤化方法について鋭意検討を行ったところ、薬効成分を含む低濃度の溶液を、撹拌下の賦形剤に滴下もしくは噴霧により均一に添加し、これを乾燥した後、造粒乳糖を加えて、さらによく混合して得られた粉末を錠剤に成型することによって、薬効成分含量が均一で、かつ、成型性も優れていることを見出し、本発明をなすに至った。
すなわち、本発明は、極めて少ない量の薬効成分を含有する錠剤の製造法であって、薬効成分を含有する溶液を撹拌下の賦形剤に滴下または噴霧により全体に均一に添加し、充分混合した後、乾燥した粉末に、賦形剤として造粒乳糖を加えて均一に混合した粉末を成型することを特徴とする第１４改正日本薬局方規定の含量均一性試験における判定値が１５％未満である、薬効成分含量が均一、かつ、成型性が優れた錠剤の製造方法を提供するものである。
In order to solve the above-mentioned problems, the present inventors diligently studied a formulation method that does not rely on the trituration method, and dropped or dropped a low-concentration solution containing a medicinal ingredient into an agitated excipient. Add uniformly by spraying, dry it, add granulated lactose and mix the powder obtained by mixing well into tablets, the content of medicinal ingredients is uniform and the moldability is also excellent The present inventors have found that the present invention has been made.
That is, the present invention is a method for producing a tablet containing a very small amount of a medicinal ingredient, and a solution containing the medicinal ingredient is uniformly added to the stirring excipient by dripping or spraying and mixed thoroughly. After that, the determination value in the content uniformity test of the 14th revision Japanese Pharmacopoeia characterized by adding granulated lactose as an excipient to the dried powder and uniformly mixing it is less than 15% The present invention provides a method for producing a tablet having a uniform medicinal content and excellent moldability.
本発明の薬効成分の溶液を賦形剤に加えて均一に混合した後、追加の賦形剤として造粒乳糖を加えて成型する直接粉末圧縮法に準じた格別の技術を要しない方法によって、極めて少ない量の薬効成分が均一、かつ、一定量配合された錠剤を高い歩留まりで得ることができる。 After adding the solution of the medicinal component of the present invention to the excipient and mixing uniformly, a method that does not require any special technique according to the direct powder compression method in which granulated lactose is added and molded as an additional excipient, A tablet containing a very small amount of a medicinal component in a uniform and constant amount can be obtained with a high yield.
以下、本発明について詳細に説明する。
本発明の錠剤の製造法が適用される薬物は、特に限定されないが、生物活性が高く、投与量が少ない薬物で、代表的には、プロスタグランジン誘導体、活性型ビタミンＤ3 、副腎皮質ホルモン剤、男性ホルモン剤、メストラノール、エチニルエストラジオールなどの卵胞ホルモン剤やプロゲステロン、ノルエチステロンなどの黄体ホルモン剤、あるいは、それらの混合ホルモン剤などである。混合ホルモン剤としては、男性ホルモンと卵胞ホルモンとの配合剤、経口避妊薬としてのピルに用いられる卵胞ホルモンや黄体ホルモンとの配合剤などが挙げられる。なお、一方の薬物が投与量（含量）の多い配合剤にも適用することが可能である。
Hereinafter, the present invention will be described in detail.
The drug to which the tablet production method of the present invention is applied is not particularly limited, but is a drug having a high biological activity and a small dose, and is typically a prostaglandin derivative, active vitamin D 3 , adrenocortical hormone Agents, male hormone agents, follicular hormone agents such as mestranol and ethinyl estradiol, progesterone and progesterone and norethosterone progesterone agents, or mixed hormone agents thereof. Examples of the mixed hormone agent include a combination agent of male hormone and follicular hormone, a combination agent of follicular hormone and luteinizing hormone used for pills as an oral contraceptive. Note that one drug can be applied to a combination drug with a large dose (content).
本発明の錠剤の製造方法において、投与量が少ない薬効成分は、賦形剤を２回に分けて使用し、その初回の賦形剤に当該薬効成分の溶液を滴下または噴霧により全体にゆきわたるように添加される。この薬効成分が加えられた混合物を均一に攪拌混合したのち、追加の賦形剤として造粒乳糖を加え、さらに攪拌混合されて錠剤に成型される。初回の賦形剤としては、乳糖、無水乳糖などのほか、結晶セルロース、ブドウ糖、ショ糖、マンニトール、ソルビトール、あるいはそれらの混合物など公知の賦形剤が用いられる。初回の賦形剤の使用量は、賦形剤全量に対して４０〜８０質量％程度が好ましく、より好ましくは、５０〜７０質量％である。また、後に加える造粒乳糖の量は１０質量％以上であり、好ましくは、１０〜３０質量％である。この造粒乳糖を用いることによって、成型性がよく、また、崩壊性に優れた錠剤を得ることができる。造粒乳糖としては、「日本薬局方第１４局」掲載の造粒乳糖が主に用いられる。 In the method for producing a tablet of the present invention, the medicinal ingredient with a small dose is used by dividing the excipient into two parts, and the solution of the medicinal ingredient is dripped or sprayed on the first excipient. To be added. After the mixture to which this medicinal component has been added is uniformly stirred and mixed, granulated lactose is added as an additional excipient, which is further stirred and mixed to form a tablet. As the initial excipient, known excipients such as lactose and anhydrous lactose, crystalline cellulose, glucose, sucrose, mannitol, sorbitol, or a mixture thereof are used. The amount of the initial excipient used is preferably about 40 to 80% by mass, and more preferably 50 to 70% by mass with respect to the total amount of the excipient. Moreover, the quantity of the granulated lactose added later is 10 mass% or more, Preferably, it is 10-30 mass%. By using this granulated lactose, a tablet having good moldability and excellent disintegration can be obtained. As the granulated lactose, granulated lactose published in “Japan Pharmacopoeia 14th Bureau” is mainly used.
また、溶剤は、薬効成分を溶解する溶媒であれば特に制限されないが、人に対して安全なエタノール、イソプロパノールが適しており、通常エタノールを用いる。
一方の投与量（錠剤への含有量）が多い薬物との配合剤については、これを最初の賦形剤に、公知の篩過・倍散による方法を適用してそれらの混合物とした後、当該含有量の極めて少ない薬物に対して本発明の製造方法が適用される。
The solvent is not particularly limited as long as it dissolves medicinal ingredients, but ethanol and isopropanol which are safe for humans are suitable, and ethanol is usually used.
For a combination with a drug with a large dose (content in a tablet), apply this to the first excipient and apply a known sieving and trituration method to make a mixture of them, The production method of the present invention is applied to a drug having a very small content.
なお、本発明の錠剤には、その特性を損なわない範囲で、通常用いられている添加剤の適量を加えることは差し支えない。例えば、トウモロコシデンプンやバレイショデンプン、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース、ポリビニルピロリドン、クロスカルメロースナトリウム、カルメロースやカルメロースナトリウム、カルメロースカルシウムなどの崩壊剤、ステアリン酸マグネシウムやショ糖脂肪酸エステルなどの滑沢剤、部分アルファー化デンプン、クロスポビドン、ポリソルベート、ヒドロキシプロピルセルロースやメチルセルロース、ヒドロキシプロピルスターチなどの結合剤、或いは各種の着色剤が所望により添加される。 It should be noted that an appropriate amount of commonly used additives may be added to the tablet of the present invention as long as the characteristics are not impaired. For example, corn starch, potato starch, partially pregelatinized starch, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, croscarmellose sodium, carmellose, carmellose sodium, carmellose calcium, etc., magnesium stearate and sucrose fatty acid ester Lubricants such as partially pregelatinized starch, crospovidone, polysorbate, binders such as hydroxypropylcellulose, methylcellulose, hydroxypropyl starch, and various colorants are added as desired.
次に、本発明を実施例によりさらに詳細に説明するが、本発明はこれらの実施例により限定されるものではない。 EXAMPLES Next, although an Example demonstrates this invention further in detail, this invention is not limited by these Examples.
［実施例１］
表１の処方により、次のようにして錠剤を製造した。賦形剤の無水乳糖と結合剤の部分アルファー化デンプンとの混合物にノルエチステロンを加え篩過・混合して、倍散とする。この混合物に転動造粒機中で撹拌混合下、エタノールに溶解したエチニルエストラジオール溶液を全体に滴下し、充分混合したのち乾燥し、さらに乳糖を加えて、均一に混合後、打錠する。賦形剤全量に対する造粒乳糖の割合は２６％である。
[Example 1]
According to the formulation shown in Table 1, tablets were produced as follows. Add norethisterone to the mixture of the anhydrous lactose excipient and the partially pregelatinized starch binder and sift through and mix to make a trituration. To this mixture, an ethinylestradiol solution dissolved in ethanol is added dropwise to the whole while stirring and mixing in a tumbling granulator, thoroughly mixed and then dried, further added with lactose, mixed uniformly, and then tableted. The ratio of granulated lactose to the total amount of excipient is 26%.
［実施例２］
表２の処方により、実施例１に記載した方法に準じて錠剤を製造した。賦形剤全量に対する造粒乳糖の割合は１４％である。
[Example 2]
According to the formulation shown in Table 2, tablets were produced according to the method described in Example 1. The ratio of granulated lactose to the total amount of excipient is 14%.
［比較例１］
表３の処方により、次のようにして錠剤を製造した。賦形剤の無水乳糖と結合剤の部分アルファー化デンプンとの混合物の一部を取り、ノルエチステロンと篩過・混合して、倍散とする。この混合物に転動造粒機中で撹拌混合下、エタノールに溶解したエチニルエストラジオール溶液を滴下し、充分混合した後乾燥し、さらに残りの無水乳糖と部分アルファー化デンプンとの混合物を添加して、充分混合の後、打錠した。このものは約１０万錠あまり打錠した時点でスティッキングを起こした。
[Comparative Example 1]
According to the formulation in Table 3, tablets were produced as follows. A portion of the mixture of the anhydrous lactose excipient and the partially pregelatinized starch of the binder is taken and sieved and mixed with norethisterone to make a trituration. To this mixture, while stirring and mixing in a tumbling granulator, ethinylestradiol solution dissolved in ethanol was added dropwise, thoroughly mixed and dried, and further a mixture of remaining anhydrous lactose and partially pregelatinized starch was added, After thorough mixing, tableting was performed. This produced sticking when about 100,000 tablets were compressed.
１）含量均一性試験
薬効成分として、エチニルエストラジオールを含有する錠剤について、本発明の方法と公知の直接粉末圧縮法により製造した錠剤の含量均一性試験を行った。その結果を表４に示す。表４の結果から明らかなように、本発明の方法により得た錠剤は、公知方法による錠剤に比べて、判定値が54.667 → 3.864 と大幅な改善が認められた。
1) Content uniformity test A tablet containing ethinylestradiol as a medicinal component was subjected to a content uniformity test of tablets produced by the method of the present invention and a known direct powder compression method. The results are shown in Table 4. As is clear from the results in Table 4, the tablet obtained by the method of the present invention showed a marked improvement of 54.667 → 3.864 as compared with the tablet obtained by the known method.
２）硬度・キャッピング試験
本発明の方法による錠剤と賦形剤として造粒乳糖を用いないで成型した錠剤について、硬度・キャッピング試験を行った。その結果を表５に示す。表５から明らかなように、硬度が、2.32 (kg) → 5.11 (kg) と有意な改善効果が認められた。
2) Hardness / capping test A hardness / capping test was performed on the tablets formed by the method of the present invention and tablets formed without using granulated lactose as an excipient. The results are shown in Table 5. As is clear from Table 5, the hardness improved significantly from 2.32 (kg) to 5.11 (kg).
以上説明したように、本発明により、薬効成分の含有量の極めて少ない錠剤を、直接粉末圧縮法に準じた簡便な方法により効率よく生産することが可能となった。したがって、本発明の錠剤の製造方法は、生物活性が高く、投与量が少ない医薬品に向けた錠剤の製法として極めて利用価値が高い。
As described above, according to the present invention, it has become possible to efficiently produce tablets with a very low content of medicinal ingredients by a simple method according to the direct powder compression method. Therefore, the tablet production method of the present invention is extremely useful as a tablet production method for pharmaceutical products having high biological activity and a small dose.
Claims (5)
The manufacturing method of the tablet in any one of Claims 1-4 whose usage-amount of granulated lactose is 10 mass% or more with respect to the whole quantity.
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| Application Number | Priority Date | Filing Date | Title |
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| JP2004248485A JP4756153B2 (en) | 2004-08-27 | 2004-08-27 | Method for producing tablets with low content |
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| JP2004248485A JP4756153B2 (en) | 2004-08-27 | 2004-08-27 | Method for producing tablets with low content |
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| JP2006063030A true JP2006063030A (en) | 2006-03-09 |
| JP4756153B2 JP4756153B2 (en) | 2011-08-24 |
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| JP2004248485A Expired - Lifetime JP4756153B2 (en) | 2004-08-27 | 2004-08-27 | Method for producing tablets with low content |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010525052A (en) * | 2007-04-25 | 2010-07-22 | ザ プロクター アンド ギャンブル カンパニー | Pharmaceutical dosage form with improved vitamin D content uniformity |
| JP2016068961A (en) * | 2014-09-26 | 2016-05-09 | ノーベルファーマ株式会社 | Portable drug set |
| WO2016084493A1 (en) * | 2014-11-24 | 2016-06-02 | 株式会社ダイセル | Disintegrative particle composition including pulverized lactose or granulated lactose |
| JP2019006506A (en) * | 2018-10-09 | 2019-01-17 | ノーベルファーマ株式会社 | Portable drug set |
| WO2020218310A1 (en) | 2019-04-22 | 2020-10-29 | ニプロ株式会社 | Method for producing pharmaceutical formulation |
| JP2020193229A (en) * | 2019-02-13 | 2020-12-03 | 富士製薬工業株式会社 | Oral solid composition, production method thereof, and oral tablet obtained by the production method |
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| JPS51144722A (en) * | 1975-06-06 | 1976-12-13 | Furointo Sangyo Kk | Process for preparing granules of lactose |
| JPH07196513A (en) * | 1992-09-04 | 1995-08-01 | Akzo Nobel Nv | Pharmaceutical granules |
| JP2003081876A (en) * | 2001-09-10 | 2003-03-19 | Asahi Kasei Corp | How to mix drugs |
| WO2003099291A1 (en) * | 2002-05-29 | 2003-12-04 | Akzo Nobel N.V. | Progestagenic dosage units |
| JP2004503467A (en) * | 2000-02-29 | 2004-02-05 | ブリストル−マイヤーズ スクイブ カンパニー | Low dose entecavir formulations and uses thereof |
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|---|---|---|---|---|
| JPS51144722A (en) * | 1975-06-06 | 1976-12-13 | Furointo Sangyo Kk | Process for preparing granules of lactose |
| JPH07196513A (en) * | 1992-09-04 | 1995-08-01 | Akzo Nobel Nv | Pharmaceutical granules |
| JP2004503467A (en) * | 2000-02-29 | 2004-02-05 | ブリストル−マイヤーズ スクイブ カンパニー | Low dose entecavir formulations and uses thereof |
| JP2003081876A (en) * | 2001-09-10 | 2003-03-19 | Asahi Kasei Corp | How to mix drugs |
| WO2003099291A1 (en) * | 2002-05-29 | 2003-12-04 | Akzo Nobel N.V. | Progestagenic dosage units |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010525052A (en) * | 2007-04-25 | 2010-07-22 | ザ プロクター アンド ギャンブル カンパニー | Pharmaceutical dosage form with improved vitamin D content uniformity |
| US8703187B2 (en) | 2007-04-25 | 2014-04-22 | Warner Chilcott Company, Llc | Vitamin D content uniformity in pharmaceutical dosage forms |
| JP2016068961A (en) * | 2014-09-26 | 2016-05-09 | ノーベルファーマ株式会社 | Portable drug set |
| WO2016084493A1 (en) * | 2014-11-24 | 2016-06-02 | 株式会社ダイセル | Disintegrative particle composition including pulverized lactose or granulated lactose |
| JPWO2016084493A1 (en) * | 2014-11-24 | 2017-09-21 | 株式会社ダイセル | Disintegrating particle composition comprising ground lactose or granulated lactose |
| US10130584B2 (en) | 2014-11-24 | 2018-11-20 | Daicel Corporation | Disintegrative particle composition including pulverized lactose or granulated lactose |
| JP2019006506A (en) * | 2018-10-09 | 2019-01-17 | ノーベルファーマ株式会社 | Portable drug set |
| JP2020193229A (en) * | 2019-02-13 | 2020-12-03 | 富士製薬工業株式会社 | Oral solid composition, production method thereof, and oral tablet obtained by the production method |
| WO2020218310A1 (en) | 2019-04-22 | 2020-10-29 | ニプロ株式会社 | Method for producing pharmaceutical formulation |
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| JP4756153B2 (en) | 2011-08-24 |
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