JP5713544B2 - Imidafenacin-containing intraoral rapidly disintegrating tablets - Google Patents
Imidafenacin-containing intraoral rapidly disintegrating tablets Download PDFInfo
- Publication number
- JP5713544B2 JP5713544B2 JP2009178073A JP2009178073A JP5713544B2 JP 5713544 B2 JP5713544 B2 JP 5713544B2 JP 2009178073 A JP2009178073 A JP 2009178073A JP 2009178073 A JP2009178073 A JP 2009178073A JP 5713544 B2 JP5713544 B2 JP 5713544B2
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- JP
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- Prior art keywords
- imidafenacin
- coated
- tablet
- methacrylate copolymer
- tocopherol
- Prior art date
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Description
本発明は、イミダフェナシンを有効成分として含有する口腔内速崩錠に関する。 The present invention relates to an intraoral quick-disintegrating tablet containing imidafenacin as an active ingredient.
イミダフェナシンは、ムスカリン受容体Ｍ３及びＭ１拮抗作用を有する化合物であり（特許文献１）、過活動膀胱治療薬として提供される（非特許文献１）。イミダフェナシンを主成分とする製剤処方としては、イミダフェナシンを含有する経口固形製剤や、経皮吸収剤などが知られている（特許文献２、３）。
特許文献２は、イミダフェナシン製剤が光に不安定なため、酸化チタン及び三二酸化鉄を含むコーティング液で錠剤を被覆することで光安定化を図ることが記載されている。
また、特許文献３及び４には、徐放性の経口型製剤を開示されている。しかしながら、イミダフェナシンの造粒物中にアミノアルキルメタアクリレートコポリマーＥ又はトコフェロールを配合することについては知られていない。
Imidafenacin is a compound having a muscarinic receptor M3 and M1 antagonistic action (Patent Document 1) and is provided as a therapeutic agent for overactive bladder (Non-Patent Document 1). As pharmaceutical formulations containing imidafenacin as a main component, oral solid preparations containing imidafenacin, transdermal absorption agents, and the like are known (Patent Documents 2 and 3).
Patent Document 2 describes that imidafenacin preparations are unstable to light, so that light stabilization is achieved by coating tablets with a coating solution containing titanium oxide and iron sesquioxide.
Patent Documents 3 and 4 disclose sustained-release oral preparations. However, it is not known to incorporate aminoalkyl methacrylate copolymer E or tocopherol in the imidafenacin granulation.
一方、患者のＱＯＬ（Ｑｕａｌｉｔｙ ｏｆ Ｌｉｆｅ）の改善を目的に、製剤学的工夫を凝らした製剤開発が盛んであり、口腔内速崩錠は最も多く開発されている製剤である。口腔内速崩錠は、口腔内の少量の唾液でも瞬時に崩壊することから、服用が容易であり、通常の錠剤では嚥下が困難な高齢者や小児に最適な製剤である。また水なしで服用できるため服用の場所や時間が制限されない利点も有する。 On the other hand, for the purpose of improving QOL (Quality of Life) of patients, formulation development with pharmacological ingenuity has been actively conducted, and intraoral rapidly disintegrating tablets are the most frequently developed formulations. Intraoral rapidly disintegrating tablets are easy to take because even a small amount of saliva in the mouth disintegrates instantly, and are the best preparations for the elderly and children who are difficult to swallow with ordinary tablets. Moreover, since it can be taken without water, it has the advantage that the place and time for taking are not limited.
しかし、口腔内速崩錠は、崩壊性を保持したまま錠剤を酸化チタン・三二酸化鉄コーティングすることは難しく、光安定なイミダフェナシン含有口腔内速崩錠についてはこれまで報告がない。 However, it is difficult to coat the tablet with titanium oxide / iron sesquioxide while maintaining the disintegration property, and there has been no report on a light-stable imidafenacin-containing intraoral quick-disintegrating tablet.
本発明は、光安定性に優れ、かつ、製造工程分解物の少ないイミダフェナシン含有口腔内速崩錠を提供する。 The present invention provides an imidafenacin-containing intraoral quick-disintegrating tablet that is excellent in light stability and has few manufacturing process degradation products.
本発明者らは、イミダフェナシンを造粒し、非セルロース系コーティング剤で被覆することにより光安定性が向上することを見出していた(PCT/JP2009/51651)。
しかし、この造粒およびコーティング工程において、有効成分であるイミダフェナシンの分解物が生じるという課題が発生した。そこで、該分解物を低減すべく検討を行い、本発明を完成するに至った。
The present inventors have found that light stability is improved by granulating imidafenacin and coating it with a non-cellulosic coating agent (PCT / JP2009 / 51651).
However, in this granulation and coating process, a problem that a decomposition product of imidafenacin, which is an active ingredient, occurs. Therefore, studies have been made to reduce the decomposition products, and the present invention has been completed.
すなわち、本発明は、トコフェロール、トコフェロール誘導体およびアクリル系重合体からなる群より選ばれる１種又は２種以上をイミダフェナシンとともに造粒して得られる顆粒を、非セルロース系コーティング剤で被覆し、圧縮成型することを特徴とする口腔内速崩錠に関する。 That is, the present invention covers a granule obtained by granulating one or more selected from the group consisting of tocopherol, a tocopherol derivative and an acrylic polymer together with imidafenacin with a non-cellulosic coating agent, and compression molding. The present invention relates to an intraoral quick disintegrating tablet.
本発明により、口腔内崩壊性及び光安定性に優れ、かつ、錠剤中の製造工程分解物の少ないイミダフェナシン含有口腔内速崩錠の提供が可能となった。 According to the present invention, it is possible to provide an imidafenacin-containing intraoral rapidly disintegrating tablet which is excellent in oral disintegration and light stability and has few manufacturing process degradation products in a tablet.
以下に本発明について詳細に説明するが、本件明細書において口腔内速崩錠とは、口腔内で唾液の存在下、咀嚼無しに約９０秒、好ましくは約６０秒、更に好ましくは４０秒より短い時間で崩壊する固形医薬製剤をいう。 Hereinafter, the present invention will be described in detail. In the present specification, an intraoral quick-disintegrating tablet means, in the presence of saliva in the oral cavity, about 90 seconds without chewing, preferably about 60 seconds, more preferably from 40 seconds. A solid pharmaceutical preparation that disintegrates in a short time.
本発明の口腔内速崩錠に使用される有効成分であるイミダフェナシンは、膀胱に選択的な抗コリン作用を有する頻尿・尿失禁治療薬である４−（２−メチル−１−イミダゾリル）−２，２−ジフェニルブチルアミドである。 Imidafenacin, which is an active ingredient used in the intraoral quick-disintegrating tablet of the present invention, is 4- (2-methyl-1-imidazolyl)-, which is a therapeutic agent for pollakiuria and urinary incontinence having a selective anticholinergic action on the bladder. 2,2-diphenylbutyramide.
トコフェロールまたはトコフェロール誘導体としては、ｄｌ−α―トコフェロール（ビタミンＥ）、ｄ−σ―トコフェロール、トコフェロール酢酸エステル、トコフェロールリン酸エステル、トコフェロール硫酸エステル、トコフェロールグリコシルエステルやそれらの塩が挙げられる。トコフェロールの含有量は、イミダフェナシン含有顆粒中、０．００５質量％以上が好ましく、さらに好ましくは０．０１質量％以上、より好ましくは０．０５〜１０質量％、特に好ましくは０．０８〜５質量％である。 Examples of the tocopherol or tocopherol derivative include dl-α-tocopherol (vitamin E), d-σ-tocopherol, tocopherol acetate, tocopherol phosphate, tocopherol sulfate, tocopherol glycosyl ester and salts thereof. The content of tocopherol is preferably 0.005% by mass or more, more preferably 0.01% by mass or more, more preferably 0.05 to 10% by mass, particularly preferably 0.08 to 5% by mass in the imidafenacin-containing granule. %.
アクリル系重合体は、酸性ポリマー(モノマー単位中にカルボキシル基を含むもので主に腸溶性コーティングに用いられる)、中性ポリマー(モノマー単位中にメタクリル酸エステルを含むもので被膜の透過性が高く主に徐放性製剤に用いられる)、塩基性ポリマー(モノマー単位中にアミノ基を含むもので主に胃溶性コーティングに用いられる)に分類することができる。アクリル系重合体の例としては、アクリル酸エチル・メタクリル酸メチルコポリマー、アミノアルキルメタアクリレートコポリマーＥ、アミノアルキルメタアクリレートコポリマーＲＳ、メタアクリル酸コポリマーＬ、メタアクリル酸コポリマーＬＤ、メタアクリル酸コポリマーＳが挙げられるが、工程分解物低減の点からアミノアルキルメタアクリレートコポリマーＥを使用することが好ましい。アミノアルキルメタアクリレートコポリマーＥとしては、オイドラギットＥ１００（Rohm GmbH ＆ Co.KG）、オイドラギットＥＰＯ（Rohm GmbH ＆ Co.KG）が挙げられる。アクリル系重合体の含有量は、イミダフェナシン含有顆粒中、０．０５質量％以上が好ましく、さらに好ましくは０．１質量％以上、より好ましくは０．５〜２０質量％、特に好ましくは２〜１０質量％である。 Acrylic polymers are acidic polymers (which contain carboxyl groups in monomer units and are mainly used for enteric coating), neutral polymers (those that contain methacrylate esters in monomer units and have high film permeability). Mainly used for sustained-release preparations) and basic polymers (containing amino groups in monomer units and mainly used for gastric coating). Examples of acrylic polymers include ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S. Although mentioned, it is preferable to use aminoalkyl methacrylate copolymer E from the point of reduction of process decomposition products. Examples of the aminoalkyl methacrylate copolymer E include Eudragit E100 (Rohm GmbH & Co. KG) and Eudragit EPO (Rohm GmbH & Co. KG). The content of the acrylic polymer is preferably 0.05% by mass or more, more preferably 0.1% by mass or more, more preferably 0.5 to 20% by mass, particularly preferably 2 to 10% in the imidafenacin-containing granule. % By mass.
本発明の口腔内速崩錠は、イミダフェナシンをトコフェロール、トコフェロール誘導体およびアクリル系重合体からなる群より選ばれる１種又は２種以上とともに造粒した顆粒を使用することを特徴とする。
イミダフェナシン含有顆粒は、乾式造粒法や、攪拌造粒法、押出造粒法、流動層造粒法、転動流動層造粒法、噴霧造粒法などの造粒方法により容易に製造することができる。これらの造粒法は、当業者に自明である。
造粒法としては、好ましくは、流動層造粒法や転動流動層造粒法が好適に挙げられる。造粒物の平均粒径は、後述する方法により測定した場合に、0.1〜350μmであることが好ましく、さらに好ましくは50〜200μmである。
イミダフェナシン含有顆粒は、本発明の効果を大きく損なわない限り、トコフェロール、トコフェロール誘導体、アクリル系重合体以外の成分を配合することができる。光安定性の点から造粒物中に配合する賦形剤は、澱粉が好ましく、さらに好ましくは部分アルファ化デンプンである。
また、イミダフェナシン含有顆粒は、医薬品成分の安定性、錠剤の製造容易性の点から造粒後乾燥することもできる。乾燥法は、医薬品製剤の製造に使用可能な方法であれば特に限定はない。
The intraoral quick-disintegrating tablet of the present invention is characterized by using granules obtained by granulating imidafenacin with one or more selected from the group consisting of tocopherol, a tocopherol derivative and an acrylic polymer.
Imidafenacin-containing granules can be easily produced by granulation methods such as dry granulation, agitation granulation, extrusion granulation, fluidized bed granulation, rolling fluidized bed granulation, spray granulation Can do. These granulation methods are obvious to those skilled in the art.
Preferred examples of the granulation method include a fluidized bed granulation method and a rolling fluidized bed granulation method. The average particle size of the granulated product is preferably 0.1 to 350 μm, more preferably 50 to 200 μm, when measured by the method described later.
The imidafenacin-containing granule can contain components other than tocopherol, a tocopherol derivative, and an acrylic polymer as long as the effects of the present invention are not significantly impaired. From the viewpoint of light stability, the excipient to be blended in the granulated product is preferably starch, more preferably partially pregelatinized starch.
Further, imidafenacin-containing granules can be dried after granulation from the viewpoint of the stability of pharmaceutical ingredients and the ease of production of tablets. The drying method is not particularly limited as long as it is a method that can be used for producing a pharmaceutical preparation.
イミダフェナシン含有顆粒は、光安定化のため非セルロース系コーティング剤で被覆する。本発明で使用できる非セルロース系コーティング剤としては、水溶性コーティング剤でも、疎水性コーティング剤でも、胃溶性コーティング剤でも、また、腸溶性コーティング剤であってもよい。
水溶性コーティング剤としては、例えば、ポビドンなどのｐＨ非依存性コーティング剤が好適に挙げられる。
また、疎水性コーティング剤としては、例えば、ステアリルアルコールや、アンモニオメタクリレート・コポリマーなどが好適に挙げられる。
胃溶性コーティング剤としては、例えば、アミノアルキルメタクリレートコポリマーＥや、ポリビニルアセタールジエチルアミノアセテートなどが好適に挙げられる。
腸溶性コーティング剤としては、メタクリル酸コポリマー（Ｌ、Ｓ）などが好適に挙げられる。
なお、これらコーティング剤による被覆は、光安定性を向上させる目的から三二酸化鉄や酸化チタンとともに行ってもよい
被覆顆粒中のコーティング剤の含有量は、特に制限はないが、好ましくは被覆前造粒物１質量部に対して、例えば、約０．００１〜１０質量部、さらに好ましくは、約０．０１〜１質量部、特に好ましくは、約０．０５〜０．５質量部である。
また、コーティング剤を使用した被覆法は、医薬品製剤の製造に使用可能な方法であれば特に限定はない。
Imidafenacin-containing granules are coated with a non-cellulosic coating agent for light stabilization. The non-cellulosic coating agent that can be used in the present invention may be a water-soluble coating agent, a hydrophobic coating agent, a gastric coating agent, or an enteric coating agent.
Suitable water-soluble coating agents include, for example, pH-independent coating agents such as povidone.
Suitable examples of the hydrophobic coating agent include stearyl alcohol and ammonio methacrylate copolymer.
Preferable examples of the gastric coating agent include aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate.
As an enteric coating agent, a methacrylic acid copolymer (L, S) etc. are mentioned suitably.
The coating with these coating agents may be carried out together with iron sesquioxide or titanium oxide for the purpose of improving light stability. The content of the coating agent in the coated granules is not particularly limited, but is preferably pre-coated. For example, the amount is about 0.001 to 10 parts by mass, more preferably about 0.01 to 1 part by mass, and particularly preferably about 0.05 to 0.5 part by mass with respect to 1 part by mass of the granules.
Moreover, the coating method using a coating agent will not be specifically limited if it is a method which can be used for manufacture of a pharmaceutical formulation.
本発明の口腔内速崩錠は、被覆イミダフェナシン含有顆粒と組合せて、賦形剤及び崩壊剤が使用される。
ここで使用される賦形剤は、医薬品製剤の製造に使用可能なものであれば特に限定はなく適宜使用することができる。このような賦形剤としては、例えば、医薬品添加物事典［日本医薬品添加剤協会、薬事日報社（２００７年）］に記載されているものを好適に使用することができる。例えば、賦形剤としては、乳糖や、ブドウ糖などの糖類、Ｄ−ソルビトールや、マンニトールなどの糖アルコール類、結晶セルロースなどのセルロース類、部分アルファ化デンプン、トウモロコシデンプンなどの澱粉類などを好適に挙げることができる。賦形剤としては、好ましくは糖アルコールである。
In the intraoral quick-disintegrating tablet of the present invention, an excipient and a disintegrant are used in combination with the coated imidafenacin-containing granule.
The excipient used here is not particularly limited as long as it can be used in the production of pharmaceutical preparations, and can be used as appropriate. As such an excipient, for example, those described in the Pharmaceutical Additives Encyclopedia [Japan Pharmaceutical Additives Association, Yakuji Nipposha (2007)] can be preferably used. For example, as the excipient, lactose, sugars such as glucose, sugar alcohols such as D-sorbitol, mannitol, celluloses such as crystalline cellulose, starches such as partially pregelatinized starch, and corn starch are preferably used. Can be mentioned. The excipient is preferably a sugar alcohol.
本発明で使用される崩壊剤としては、医薬品製剤の製造に使用可能なものであれば特に限定はなく、各種の崩壊剤が使用できる。このような崩壊剤としては、例えば、医薬品添加物事典［日本医薬品添加剤協会、薬事日報社（２００７年）］に記載されているものを適宜使用できる。崩壊剤としては、例えば、カルボキシメチルセルロースカルシウムや、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、メチルセルロースなどのセルロース類、クロスポビドンなどを使用することができ、速やかな崩壊性及び飲用のし易さ（口当たりのよさ）の点からクロスポビドンを使用することが好ましい。崩壊剤の配合量は、錠剤中１〜１０質量％が好ましく、さらに好ましくは２〜６質量％である。 The disintegrant used in the present invention is not particularly limited as long as it can be used for production of a pharmaceutical preparation, and various disintegrants can be used. As such a disintegrating agent, for example, those described in Pharmaceutical Additives Encyclopedia [Japan Pharmaceutical Additives Association, Yakuji Nipposha (2007)] can be used as appropriate. As the disintegrant, for example, carboxymethylcellulose calcium, celluloses such as low-substituted hydroxypropylcellulose, croscarmellose sodium, methylcellulose, crospovidone, etc. can be used, and rapid disintegration and easy drinking. It is preferable to use crospovidone from the viewpoint of (taste). 1-10 mass% is preferable in a tablet, and, as for the compounding quantity of a disintegrating agent, More preferably, it is 2-6 mass%.
本発明の口腔内速崩錠は、必要により医薬品製剤の製造に使用可能な添加物を配合することができる。具体的には、医薬品添加物事典［日本医薬品添加剤協会、薬事日報社（２００７年）］に記載されているものを使用でき、例えば、滑沢剤としてステアリン酸及びその金属塩類、並びにタルク、軽質無水ケイ酸、含水二酸化ケイ素、ショ糖脂肪酸エステル等、甘味剤として糖類、糖アルコール類、アスパルテーム、サッカリン及びその塩類、グリチルリチン酸及びその塩類、ステビア、並びにアセスルファムカリウム等、嬌味剤としてクエン酸、クエン酸ナトリウム、コハク酸、酒石酸及びフマル酸等、着色剤として三二酸化鉄、黄色三二酸化鉄、カラメル、リボフラビン及びアルミニウムレーキ等、香料としてメントール及びオレンジ油等が挙げられる。 The intraoral quick-disintegrating tablet of the present invention can be blended with additives that can be used in the production of pharmaceutical preparations as necessary. Specifically, those described in the Pharmaceutical Additives Encyclopedia [Japan Pharmaceutical Additives Association, Yakuji Nipposha (2007)] can be used, for example, stearic acid and its metal salts as lubricants, talc, Light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester, etc., saccharides, sugar alcohols, aspartame, saccharin and salts thereof, glycyrrhizic acid and salts thereof, stevia, acesulfame potassium, etc. Sodium citrate, succinic acid, tartaric acid, fumaric acid, and the like, iron sesquioxide, yellow sesquioxide, caramel, riboflavin, aluminum lake, and the like as coloring agents, and menthol and orange oil as fragrances.
本発明の口腔内速崩錠の調製において、被覆イミダフェナシン含有顆粒は、賦形剤及び崩壊剤を含有する組成物（イミダフェナシン含有顆粒以外の成分）と混合される。賦形剤及び崩壊剤を含有する組成物の量は、被覆イミダフェナシン含有顆粒１質量部に対して、例えば、１〜５０質量部、好ましくは、３〜２５質量部が好適である。
被覆イミダフェナシン含有顆粒と、賦形剤及び崩壊剤を含有する組成物との混合は、例えば、Ｖ字型混合機や、ダイヤモンドミキサー、ドラムミキサー等の装置において、行うことができる。
このように調製された混合物は、次いで、圧縮成形されて、本発明の口腔内速崩錠が調製される。
In the preparation of the intraoral rapidly disintegrating tablet of the present invention, the coated imidafenacin-containing granules are mixed with a composition containing an excipient and a disintegrant (components other than imidafenacin-containing granules). The amount of the composition containing the excipient and the disintegrant is, for example, 1 to 50 parts by mass, preferably 3 to 25 parts by mass with respect to 1 part by mass of the coated imidafenacin-containing granule.
Mixing of the coated imidafenacin-containing granule with a composition containing an excipient and a disintegrant can be performed, for example, in an apparatus such as a V-shaped mixer, a diamond mixer, or a drum mixer.
The mixture thus prepared is then compression molded to prepare the intraoral rapidly disintegrating tablet of the present invention.
圧縮成形は、例えば、ロータリー打錠機などの打錠機で好適に行うことができる。但し、本発明の口腔内速崩錠の形状は、本発明の効果を損なうものでなければ特に限定はされない。例えば、中抜き、多角形及び凹型などの特殊な形状にすることができる。また、錠剤の舌の上での接触面積を増やし、口腔内水分を迅速に錠剤内部へ浸透させ、口腔内速崩壊性を高めるために、錠厚を薄く、錠径を大きくした扁平状の錠剤に成形することもできる。
圧縮成形における圧力は、例えば、３００〜２０００ｋｇ、好ましくは、６００〜１０００ｋｇが好適であり、室温、６０％ＲＨにて行うことができる。
The compression molding can be suitably performed with a tableting machine such as a rotary tableting machine. However, the shape of the intraoral quick disintegrating tablet of the present invention is not particularly limited as long as the effect of the present invention is not impaired. For example, special shapes such as hollows, polygons, and concave shapes can be used. In addition, a flat tablet with a thin tablet thickness and a large tablet diameter to increase the contact area of the tablet on the tongue, rapidly penetrate the oral cavity into the tablet, and increase the rapid disintegration of the oral cavity. It can also be formed into.
The pressure in compression molding is, for example, 300 to 2000 kg, preferably 600 to 1000 kg, and can be performed at room temperature and 60% RH.
以下に、本発明の実施例、比較例、比較試験を挙げて、さらに具体的に本発明を説明する。 Hereinafter, the present invention will be described more specifically with reference to examples, comparative examples and comparative tests of the present invention.
イミダフェナシン含有造粒物及びコーティング顆粒の評価方法
［粒度分布測定］篩式粒度分布測定器（ATM、ソニックシフター）にて、目開き７５、１０６、１５０、１８０、２１２、３５５μｍの篩を用いて測定した。
また、粒度分布測定より平均粒子径（50%径）を算出した。
口腔内速崩壊錠の評価方法
［硬度試験］錠剤硬度計(岡田精工社製)を用いて測定した。試験は５錠で行い、その平均値を示す。
［崩壊試験］崩壊試験機(富山産業社製)を用いて測定した。試験は６錠で行い、その平均値を示す。試験液は水を用い、錠剤が完全に崩壊し溶解するまでの時間を測定した。
Evaluation method of imidafenacin-containing granulated product and coated granule [Particle size distribution measurement] Measured with sieve type particle size distribution measuring device (ATM, Sonic Shifter) using sieves with openings of 75, 106, 150, 180, 212, 355 μm did.
The average particle size (50% size) was calculated from the particle size distribution measurement.
Evaluation method of intraoral rapidly disintegrating tablet [Hardness test] The hardness was measured using a tablet hardness tester (Okada Seiko Co., Ltd.). The test is performed with 5 tablets, and the average value is shown.
[Disintegration test] Measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.). The test is performed with 6 tablets, and the average value is shown. The test solution was water, and the time until the tablet completely disintegrated and dissolved was measured.
また、実施例、比較例に使用される添加物を以下に示した。
1．商品名スターチ1500G（日本カラコン）: 部分α化デンプン
2．商品名dl-α-トコフェロール（BASF）
3．商品名オイドラギットEPO及びE100（Rohm GmbH & Co. KG）：アミノアルキルメタアクリレートコポリマーＥ
4．商品名コリドン90F（BASF）：ポビドン
5．商品名ステアリン酸マグネシウム植物性（太平化学産業）
6．商品名ペアリトール（ROQUETTE JAPAN）：Ｄ―マンニトール
7．商品名コリドンCL-F（BASF）：クロスポビドン
8．商品名カープレックス#67（DSLジャパン）：含水二酸化ケイ素
Moreover, the additive used for an Example and a comparative example was shown below.
1． Product name Starch 1500G (Nihon Colorcon): Partially pregelatinized starch
2． Product name dl-α-Tocopherol (BASF)
3． Product name Eudragit EPO and E100 (Rohm GmbH & Co. KG): aminoalkyl methacrylate copolymer E
Four. Product name Kollidon 90F (BASF): Povidone
Five. Product name Magnesium stearate vegetable (Taihei Chemical Industry)
6． Product name Pairitol (ROQUETTE JAPAN): D-mannitol
7． Product name Kollidon CL-F (BASF): Crospovidone
8． Product name Carplex # 67 (DSL Japan): Hydrous silicon dioxide
実施例１
イミダフェナシン２５．０ｇ、dl-α-トコフェロール５．０ｇ、コリドン９０F（BASF）１２．５ｇを精製水９８３．０ｇ、エタノール１４７４．５ｇの混液に溶解した。スターチ１５００G（日本カラコン）４９５７．５ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量７５〜８５g／min、噴霧空気圧０．３MPa、給気温度７０℃）、イミダフェナシン含有造粒物得た（平均粒子径：１２４〜１４１μｍ）。別に、オイドラギットEPO（Rohm GmbH & Co. KG）７５０ｇ、ステアリン酸マグネシウム植物性（太平化学産業）３７５ｇを精製水４５５０ｇ、エタノール６８２５ｇの混液に溶解した。イミダフェナシン含有造粒物３７５０ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量７５〜８５ｇ／ｍｉｎ、噴霧空気圧０．３MPa、給気温度８０℃）、コーティング顆粒を得た（平均粒子径：１０１〜１０４μｍ）。
さらに、このコーティング顆粒２６００ｇ、ペアリトール（ROQUETTE JAPAN）１４６４０ｇ、コリドンCL-F（BASF）５４０ｇ及びカープレックス#67（DSLジャパン）４０ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）１８０ｇを加え混合後、ロータリー打錠機を用いて打錠圧８．５ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度４．７ｋｇ(n=５)、崩壊時間１４秒(n=６)を示した。
Example 1
25.0 g of imidafenacin, 5.0 g of dl-α-tocopherol, and 12.5 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 983.0 g of purified water and 1474.5 g of ethanol. 4957.5g of starch 1500G (Nihon Colorcon) was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid volume 75-85g / min, spraying air pressure 0 .3 MPa, supply air temperature 70 ° C.), and imidafenacin-containing granulated product was obtained (average particle size: 124 to 141 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 4550 g of purified water and 6825 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 75 to 85 g / min, spraying air pressure 0.3 MPa, (Air supply temperature 80 ° C.) and coating granules were obtained (average particle size: 101 to 104 μm).
Furthermore, after mixing 2600g of this coated granule, 14640g of Pearitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8.5 kN using a rotary tableting machine. The obtained tablet had a hardness of 4.7 kg (n = 5) and a disintegration time of 14 seconds (n = 6).
実施例２
イミダフェナシン２５．０ｇ、オイドラギットEPO（Rohm GmbH & Co. KG）１２５ｇ及びステアリン酸マグネシウム植物性（太平化学産業）６２．５ｇを精製水９１５ｇ、エタノール１３７２．５ｇの混液に溶解した。スターチ１５００G（日本カラコン）４７８７．５ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１００g／min、噴霧空気圧０．３MPa、給気温度７０℃）、イミダフェナシン含有造粒物を得た。別に、オイドラギットEPO（Rohm GmbH & Co. KG）９４０ｇ、ステアリン酸マグネシウム植物性（太平化学産業）４７０ｇを精製水５７０２．８ｇ、エタノール８５５４．２ｇの混液に溶解した。イミダフェナシン含有造粒物４７００ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１００ｇ／ｍｉｎ、噴霧空気圧０．３MPa、給気温度８０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒２６００ｇ、ペアリトール（ROQUETTE JAPAN）１４６４０ｇ、コリドンCL-F（BASF）５４０ｇ及びカープレックス#67（DSLジャパン）４０ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）１８０ｇを加え混合後、ロータリー打錠機を用いて打錠圧８．６ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．６ｋｇ(n=５)、崩壊時間１２秒(n=６)を示した。
Example 2
25.0 g of imidafenacin, 125 g of Eudragit EPO (Rohm GmbH & Co. KG) and 62.5 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 915 g of purified water and 1372.5 g of ethanol. 4787.5g of starch 1500G (Nihon Colorcon) was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa) A supply temperature of 70 ° C.) and an imidafenacin-containing granulated product was obtained. Separately, 940 g of Eudragit EPO (Rohm GmbH & Co. KG) and 470 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 5702.8 g of purified water and 8554.2 g of ethanol. 4700 g of imidafenacin-containing granulated product is charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution is coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply At a temperature of 80 ° C.) to obtain coated granules.
Furthermore, after mixing 2600g of this coated granule, 14640g of Pearitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8.6 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.6 kg (n = 5) and a disintegration time of 12 seconds (n = 6).
実施例３
イミダフェナシン２５．０ｇ、オイドラギットEPO（Rohm GmbH & Co. KG）１２５ｇ及びステアリン酸マグネシウム植物性（太平化学産業）６２．５ｇを精製水９１５ｇ、エタノール１３７２．５ｇの混液に溶解する。スターチ１５００G（日本カラコン）４７８７．５ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１００g／min、噴霧空気圧０．３MPa、給気温度７０℃）、イミダフェナシン含有造粒物を得る。別に、オイドラギットRSPO（Rohm GmbH & Co. KG）６０ｇ、ステアリン酸マグネシウム植物性（太平化学産業）３０ｇを精製水９１ｇ、エタノール８１９ｇの混液に溶解する。イミダフェナシン含有造粒物３００ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、サイドスプレー法にてこの溶液をコーティングし（噴霧液量２０ｇ／ｍｉｎ、噴霧空気圧０．１５MPa、給気温度６０℃）、コーティング顆粒を得る。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ROQUETTE JAPAN）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、単発打錠機を用いて打錠圧８００ｋｇにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製する。
Example 3
25.0 g of imidafenacin, 125 g of Eudragit EPO (Rohm GmbH & Co. KG) and 62.5 g of magnesium stearate plant (Taihei Chemical Industry) are dissolved in a mixture of 915 g of purified water and 1372.5 g of ethanol. 4787.5g of starch 1500G (Nihon Colorcon) was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa) , Supply temperature 70 ° C.), and imidafenacin-containing granulated product is obtained. Separately, 60 g of Eudragit RSPO (Rohm GmbH & Co. KG) and 30 g of magnesium stearate plant (Taihei Chemical Industry) are dissolved in a mixed solution of 91 g of purified water and 819 g of ethanol. 300 g of imidafenacin-containing granulated product is charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution is coated by the side spray method (spraying liquid amount 20 g / min, spraying air pressure 0.15 MPa, supply (Air temperature 60 ° C.) and coated granules are obtained.
Furthermore, 78.0 g of this coated granule, 439.2 g of Pearitol (ROQUETTE JAPAN), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant ( Taihei Chemical Industry) After adding 5.4 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 800 kg using a single tableting machine.
実施例４
イミダフェナシン２５．０ｇ、オイドラギットEPO（Rohm GmbH & Co. KG）１２５ｇ及びステアリン酸マグネシウム植物性（太平化学産業）６２．５ｇを精製水９１５ｇ、エタノール１３７２．５ｇの混液に溶解する。スターチ１５００G（日本カラコン）４７８７．５ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１００g／min、噴霧空気圧０．３MPa、給気温度７０℃）、イミダフェナシン含有造粒物を得る。別に、AEA（三共ライフテック）６０ｇ、ステアリン酸マグネシウム植物性（太平化学産業）３０ｇを精製水９１ｇ、エタノール８１９ｇの混液に溶解する。イミダフェナシン含有造粒物３００ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、サイドスプレー法にてこの溶液をコーティングし（噴霧液量２０ｇ／ｍｉｎ、噴霧空気圧０．２MPa、給気温度６０℃）、コーティング顆粒を得る。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ROQUETTE JAPAN）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、単発打錠機を用いて打錠圧８００ｋｇにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製する。
Example 4
25.0 g of imidafenacin, 125 g of Eudragit EPO (Rohm GmbH & Co. KG) and 62.5 g of magnesium stearate plant (Taihei Chemical Industry) are dissolved in a mixture of 915 g of purified water and 1372.5 g of ethanol. 4787.5g of starch 1500G (Nihon Colorcon) was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa) , Supply temperature 70 ° C.), and imidafenacin-containing granulated product is obtained. Separately, 60 g of AEA (Sankyo Lifetech) and 30 g of magnesium stearate plant (Taihei Chemical Industry) are dissolved in a mixed solution of 91 g of purified water and 819 g of ethanol. 300 g of imidafenacin-containing granulated product is charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution is coated by the side spray method (spraying liquid amount 20 g / min, spraying air pressure 0.2 MPa, supply (Air temperature 60 ° C.) and coated granules are obtained.
Furthermore, 78.0 g of this coated granule, 439.2 g of Pearitol (ROQUETTE JAPAN), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant ( Taihei Chemical Industry) After adding 5.4 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 800 kg using a single tableting machine.
比較例1
イミダフェナシン２５．０ｇ、コリドン９０F（BASF）１２．５ｇを精製水７３８．７５ｇ、エタノール１７２３．７５ｇの混液に溶解した。スターチ１５００G（日本カラコン）４９６２．５ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１００g／min、噴霧空気圧０．３MPa、給気温度７０℃）、イミダフェナシン含有造粒物得た（平均粒子径：１２８μｍ）。別に、オイドラギットEPO（Rohm GmbH & Co. KG）７５０ｇ、ステアリン酸マグネシウム植物性（太平化学産業）３７５ｇを精製水３４１２．５ｇ、エタノール７９６２．５ｇの混液に溶解した。イミダフェナシン含有造粒物３７５０ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１００ｇ／ｍｉｎ、噴霧空気圧０．３MPa、給気温度８０℃）、コーティング顆粒を得た（平均粒子径：１１７μｍ）。
さらに、このコーティング顆粒２６００ｇ、ペアリトール（ROQUETTE JAPAN）１４６４０ｇ、コリドンCL-F（BASF）５４０ｇ及びカープレックス#67（DSLジャパン）４０ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）１８０ｇを加え混合後、ロータリー打錠機を用いて打錠圧９ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．６ｋｇ(n=５)、崩壊時間１２秒(n=６)を示した。
Comparative Example 1
25.0 g of imidafenacin and 12.5 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 738.75 g of purified water and 1723.75 g of ethanol. Starch 1500G (Nihon Colorcon) 4962.5g was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa) , Supply temperature 70 ° C.), and imidafenacin-containing granulated product was obtained (average particle size: 128 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply The temperature was 80 ° C.) to obtain coated granules (average particle size: 117 μm).
Furthermore, after mixing 2600g of this coated granule, 14640g of Pearitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 9 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.6 kg (n = 5) and a disintegration time of 12 seconds (n = 6).
比較例２
イミダフェナシン２０．０ｇ、コリドン９０F（BASF）１０．０ｇを精製水５９１ｇ、エタノール１３７９ｇの混液に溶解した。スターチ１５００G（日本カラコン）４９７０ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１００g／min、噴霧空気圧０．３MPa、給気温度７０℃）、イミダフェナシン含有造粒物を得た（平均粒子径：１２４μｍ）。別に、オイドラギットEPO（Rohm GmbH & Co. KG）７５０ｇ、ステアリン酸マグネシウム植物性（太平化学産業）３７５ｇを精製水３４１２．５ｇ、エタノール７９６２．５ｇの混液に溶解した。イミダフェナシン含有造粒物３７５０ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１００ｇ／ｍｉｎ、噴霧空気圧０．３MPa、給気温度８０℃）、コーティング顆粒を得た（平均粒子径：１２０μｍ）。
さらに、このコーティング顆粒３２５０ｇ、ペアリトール（ROQUETTE JAPAN）１３９９０ｇ、コリドンCL-F（BASF）５４０ｇ及びカープレックス#67（DSLジャパン）４０ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）１８０ｇを加え混合後、ロータリー打錠機を用いて打錠圧９ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度４．９ｋｇ(n=５)、崩壊時間１０秒(n=６)を示した。
Comparative Example 2
20.0 g of imidafenacin and 10.0 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 591 g of purified water and 1379 g of ethanol. Charge 4970g of Starch 1500G (Nihon Colorcon) to a fluidized bed granulator (Freund Sangyo, FL-5), and coat this solution by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa, supply And an imidafenacin-containing granulated product was obtained (average particle size: 124 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply The temperature was 80 ° C.) to obtain coated granules (average particle size: 120 μm).
Further, 3250 g of this coated granule, 13990 g of Pairitol (ROQUETTE JAPAN), 540 g of Kollidon CL-F (BASF) and 40 g of Carplex # 67 (DSL Japan) were mixed, and then 180 g of magnesium stearate plant (Tahei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 9 kN using a rotary tableting machine. The obtained tablet had a hardness of 4.9 kg (n = 5) and a disintegration time of 10 seconds (n = 6).
比較例３
イミダフェナシン１６．７ｇ、コリドン９０F（BASF）８．３ｇを精製水４９３．５ｇ、エタノール１１５１．５ｇの混液に溶解した。スターチ１５００G（日本カラコン）４９７５ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１００g／min、噴霧空気圧０．３MPa、給気温度７０℃）、イミダフェナシン含有造粒物を得た（平均粒子径：１１９μｍ）。別に、オイドラギットEPO（Rohm GmbH & Co. KG）７５０ｇ、ステアリン酸マグネシウム植物性（太平化学産業）３７５ｇを精製水３４１２．５ｇ、エタノール７９６２．５ｇの混液に溶解した。イミダフェナシン含有造粒物３７５０ｇを流動層造粒機(フロイント産業製、FL-5)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１００ｇ／ｍｉｎ、噴霧空気圧０．３MPa、給気温度８０℃）、コーティング顆粒を得た（平均粒子径：１１５μｍ）。
さらに、このコーティング顆粒３９００ｇ、ペアリトール（ROQUETTE JAPAN）１３３４０ｇ、コリドンCL-F（BASF）５４０ｇ及びカープレックス#67（DSLジャパン）４０ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）１８０ｇを加え混合後、ロータリー打錠機を用いて打錠圧９ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．２ｋｇ(n=５)、崩壊時間１６秒(n=６)を示した。
Comparative Example 3
16.7 g of imidafenacin and 8.3 g of Kollidon 90F (BASF) were dissolved in a mixture of 493.5 g of purified water and 1151.5 g of ethanol. Charge 4975 g of Starch 1500G (Nihon Colorcon) into a fluidized bed granulator (Freund Sangyo, FL-5), and coat this solution by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, supply And an imidafenacin-containing granulated product was obtained (average particle size: 119 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply The temperature was 80 ° C.) to obtain coated granules (average particle size: 115 μm).
Furthermore, after mixing 3900g of this coated granule, 13340g of Pairitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 9 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.2 kg (n = 5) and a disintegration time of 16 seconds (n = 6).
試験例１
実施例１、２及び比較例１〜３のイミダフェナシン含有顆粒について純度試験を実施した。イミダフェナシン含有顆粒のスプレー終了時、乾燥終了時およびコーティング顆粒の分解物の生成量の結果を表１に示した。なお、分解物の定量は液体クロマトグラフ法（HPLC法）により評価した。
Test example 1
A purity test was performed on the imidafenacin-containing granules of Examples 1 and 2 and Comparative Examples 1 to 3. The results of the amount of imidafenacin-containing granules at the end of spraying, the end of drying, and the amount of degradation products of the coated granules are shown in Table 1. In addition, quantification of the decomposition product was evaluated by liquid chromatography (HPLC method).
HPLC法
カラム：オクタデシルシリル化シリカゲル（平均粒径5 μm，内径4.6 mm×長さ250mm） (ジーエルサイエンス株式会社 商品名Inertsil ODS-3)
A液：薄めたリン酸(1→200)にジエチルアミンを加え，pHを6.0に調整する。
B液：液体クロマトグラフィー用アセトニトリル
C液：液体クロマトグラフィー用メタノール
送液：A液，B液及びC液の混合比を変えて濃度勾配制御する。
検出器：UV
測定波長：220 nm
HPLC method column: octadecylsilylated silica gel (average particle size 5 μm, inner diameter 4.6 mm × length 250 mm) (GL Sciences Inc., trade name Inertsil ODS-3)
Liquid A: Add diethylamine to diluted phosphoric acid (1 → 200) and adjust the pH to 6.0.
Liquid B: acetonitrile for liquid chromatography
Liquid C: Methanol solution for liquid chromatography: Concentration control is performed by changing the mixing ratio of liquid A, liquid B and liquid C.
Detector: UV
Measurement wavelength: 220 nm
表１より、比較例１〜３のdl-α-トコフェロール等を配合しないイミダフェナシン含有顆粒は、分解物の生成を認められた。一方、実施例１のdl-α-トコフェロールを配合したイミダフェナシン含有顆粒および実施例２のアミノアルキルメタアクリレートコポリマーＥを配合したイミダフェナシン含有顆粒は、分解物がほとんど認められなかった。
この結果から、トコフェロールやアクリル系重合体を配合することで造粒・コーティング時の工程分解物が低減されることが確認された。
From Table 1, the imidafenacin containing granule which does not mix | blend the dl- (alpha) -tocopherol etc. of the comparative examples 1-3 recognized the production | generation of the decomposition product. On the other hand, in the imidafenacin-containing granules blended with the dl-α-tocopherol of Example 1 and the imidafenacin-containing granules blended with the aminoalkyl methacrylate copolymer E of Example 2, almost no degradation products were observed.
From this result, it was confirmed that the process decomposition product at the time of granulation and coating was reduced by mix | blending a tocopherol and an acrylic polymer.
参考例１
イミダフェナシン４．０ｇ、コリドン９０F（BASF）２ｇを精製水１１８．２ｇ、エタノール２７５．８ｇの混液に溶解した。スターチ１５００G（日本カラコン）３９４ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５g／min、噴霧空気圧０．１MPa、給気温度７０℃）、イミダフェナシン含有造粒物を得た。別に、オイドラギットEPO（Rohm GmbH & Co. KG）６０ｇ、ステアリン酸マグネシウム植物性（太平化学産業）３０ｇを精製水４５０ｇ、エタノール１０５０ｇの混液に溶解した。イミダフェナシン含有造粒物３００ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０ｇ／ｍｉｎ、噴霧空気圧０．１５MPa、給気温度８０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒５．２ｇ、ペアリトール（ROQUETTE JAPAN）６３．７６ｇ、コリドンCL-F（BASF）２．１６ｇ及びカープレックス#67（DSLジャパン）０．１６ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）０．７２ｇを加え混合後、単発打錠機を用いて打錠圧６７０ｋｇにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．１ｋｇ(n=５)を示した。
Reference example 1
4.0 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixture of 118.2 g of purified water and 275.8 g of ethanol. 394 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, A supply temperature of 70 ° C.) and an imidafenacin-containing granulated product was obtained. Separately, 60 g of Eudragit EPO (Rohm GmbH & Co. KG) and 30 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 450 g of purified water and 1050 g of ethanol. 300 g of imidafenacin-containing granulated product is charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution is coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.15 MPa, supply (Gas temperature 80 ° C.) and coated granules were obtained.
Further, 5.2 g of this coated granule, 63.76 g of Pearitol (ROQUETTE JAPAN), 2.16 g of Kollidon CL-F (BASF) and 0.16 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant ( Taihei Chemical Industry) After adding 0.72 g and mixing, 180 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 670 kg using a single tableting machine. The obtained tablet had a hardness of 5.1 kg (n = 5).
参考例２
イミダフェナシン４．０ｇ、コリドン９０F（BASF）２ｇを精製水１９７ｇ、エタノール１９７ｇの混液に溶解した。スターチ１５００G（日本カラコン）３９４ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５g／min、噴霧空気圧０．１MPa、給気温度５０℃）、イミダフェナシン含有造粒物を得た。
さらに、このイミダフェナシン含有造粒物２５ｇ、ペアリトール（ROQUETTE JAPAN）３７４．５ｇ、ポリプラスドンＸＬ−１０（ＩＳＰ）４５ｇ及びカープレックス#67（DSLジャパン）１ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）４．５ｇを加え混合後、ロータリー打錠機を用いて打錠圧８００ｋｇにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度４．７ｋｇ(n=５)を示した。
Reference example 2
4.0 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 197 g of purified water and 197 g of ethanol. 394 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, A supply temperature of 50 ° C.) and an imidafenacin-containing granulated product was obtained.
Further, 25 g of this imidafenacin-containing granulated product, 374.5 g of Pairitol (ROQUETTE JAPAN), 45 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan) were mixed and then mixed with magnesium stearate (Taipei). Chemical Industry) After adding 4.5 g and mixing, 180 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 800 kg using a rotary tableting machine. The obtained tablet had a hardness of 4.7 kg (n = 5).
試験例２
参考例１、２の製剤について光安定性試験を実施した。D65ランプ4500ルクス×約12日間における分解物の生成量を測定した。なお、分解物の定量は液体クロマトグラフ法（HPLC法）により評価した。
Test example 2
A photostability test was performed on the preparations of Reference Examples 1 and 2. The amount of decomposition products in D65 lamp 4500 lux x about 12 days was measured. In addition, quantification of the decomposition product was evaluated by liquid chromatography (HPLC method).
HPLC法
カラム：オクタデシルシリル化シリカゲル（平均粒径5 μm，内径4.6 mm×長さ250mm） (ジーエルサイエンス株式会社 商品名Inertsil ODS-3)
A液：薄めたリン酸(1→200)にジエチルアミンを加え、pHを6.0に調整する。
B液：液体クロマトグラフィー用アセトニトリル
C液：液体クロマトグラフィー用メタノール
送液：A液，B液及びC液の混合比を変えて濃度勾配制御する。
検出器：UV
測定波長：220 nm
参考例１の錠剤の分解物の合計は、光照射前０．０７％であったが、光照射後０．４％であった。一方、参考例２の錠剤の分解物の合計は、光照射前０％であったが、光照射後３．１％であった。
この結果から、非セルロース系コーティング剤の被覆により光安定性が向上していることが確認された。
HPLC method column: octadecylsilylated silica gel (average particle size 5 μm, inner diameter 4.6 mm × length 250 mm) (GL Sciences Inc., trade name Inertsil ODS-3)
Solution A: Diethylamine is added to diluted phosphoric acid (1 → 200) to adjust the pH to 6.0.
Liquid B: acetonitrile for liquid chromatography
Liquid C: Methanol solution for liquid chromatography: Concentration control is performed by changing the mixing ratio of liquid A, liquid B and liquid C.
Detector: UV
Measurement wavelength: 220 nm
The total degradation product of the tablet of Reference Example 1 was 0.07% before light irradiation, but was 0.4% after light irradiation. On the other hand, the total decomposition product of the tablet of Reference Example 2 was 0% before light irradiation, but was 3.1% after light irradiation.
From this result, it was confirmed that the light stability was improved by the coating of the non-cellulosic coating agent.
Claims (3)
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