JP2021066715A - Method for producing particle containing imidafenacin and use thereof - Google Patents
Method for producing particle containing imidafenacin and use thereof Download PDFInfo
- Publication number
- JP2021066715A JP2021066715A JP2019195266A JP2019195266A JP2021066715A JP 2021066715 A JP2021066715 A JP 2021066715A JP 2019195266 A JP2019195266 A JP 2019195266A JP 2019195266 A JP2019195266 A JP 2019195266A JP 2021066715 A JP2021066715 A JP 2021066715A
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- Prior art keywords
- imidafenacin
- particles
- powder
- tablet
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000002245 particle Substances 0.000 title claims abstract description 106
- SQKXYSGRELMAAU-UHFFFAOYSA-N imidafenacin Chemical compound CC1=NC=CN1CCC(C(N)=O)(C=1C=CC=CC=1)C1=CC=CC=C1 SQKXYSGRELMAAU-UHFFFAOYSA-N 0.000 title claims abstract description 94
- 229950005396 imidafenacin Drugs 0.000 title claims abstract description 93
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 65
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- 238000001035 drying Methods 0.000 claims abstract description 11
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 39
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- 239000004480 active ingredient Substances 0.000 claims description 27
- 238000000576 coating method Methods 0.000 claims description 23
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- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 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
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、イミダフェナシンを含む粒子の製造方法に関する。また、本発明は、該粒子を用いて、イミダフェナシンを有効成分とする錠剤及び口腔内崩壊錠の製造方法に関する。本発明は、類縁物質の発生を抑制する方法に関する。 The present invention relates to a method for producing particles containing imidafenacin. The present invention also relates to a method for producing a tablet containing imidafenacin as an active ingredient and an orally disintegrating tablet using the particles. The present invention relates to a method for suppressing the generation of related substances.
イミダフェナシンは、下記の構造式で示される化合物であり、その化学名は、4-(2-メチル-1H-イミダゾール-1-イル)-2,2-ジフェニルブタンアミドである。イミダフェナシンは、膀胱におけるアセチルコリンの遊離抑制作用及び膀胱平滑筋の収縮抑制作用を有し、過活動膀胱の治療に用いられる。 Imidafenacin is a compound represented by the following structural formula, and its chemical name is 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutaneamide. Imidafenacin has an effect of suppressing the release of acetylcholine in the bladder and an effect of suppressing the contraction of bladder smooth muscle, and is used for the treatment of overactive bladder.
イミダフェナシンを有効成分として含む医薬組成物は、種々の方法により製造されている。これらの製法は、イミダフェナシンの溶液や懸濁液などの液体を用いる製法と、イミダフェナシンの粉体を用いる製法とに大別される。例えば特許文献１には、イミダフェナシンの溶液を、賦形剤及び結合剤を含む粉末に添加する撹拌造粒により、イミダフェナシンを含む粒子を調製し、この粒子と錠剤用添加物とを混合して得た粉末を圧縮成型して、イミダフェナシンを含む錠剤を製造したことが記載されている。特許文献２には、イミダフェナシンの10〜1600倍散粉末と錠剤用添加物とを混合し、得られた混合粉末を圧縮成型して、イミダフェナシンを含む錠剤を製造したことが記載されている。特許文献２では、特許文献１とは異なり、造粒を行わず、直打法(直接粉末圧縮法)により錠剤を得ている。 Pharmaceutical compositions containing imidafenacin as an active ingredient are produced by various methods. These production methods are roughly classified into a production method using a liquid such as a solution or suspension of imidafenacin and a production method using a powder of imidafenacin. For example, in Patent Document 1, particles containing imidafenacin are prepared by stirring granulation in which a solution of imidafenacin is added to a powder containing an excipient and a binder, and these particles are mixed with an additive for tablets. It is described that the powder was compression-molded to produce a tablet containing imidaphenacin. Patent Document 2 describes that a tablet containing imidafenacin was produced by mixing a 10 to 1600-fold powder powder of imidafenacin and an additive for tablets and compress-molding the obtained mixed powder. In Patent Document 2, unlike Patent Document 1, tablets are obtained by a direct striking method (direct powder compression method) without performing granulation.
医薬品の有効成分は有機化合物であるところ、温度(熱)は、有効成分の分解に最も大きな影響を与える要因である。特許文献１では、製造した錠剤について、光に対する安定性は確認しているが、温度に対する安定性は確認していない。特許文献２では、製造した錠剤の安定性試験は行っていない。本発明者らは、特許文献１と同様に、イミダフェナシンを含む溶液を造粒液として用いる撹拌造粒によって得た粒子から錠剤を製造し、70℃での苛酷試験を行ったところ、温度に対する安定性があまり良好ではないことを見出した。また、この製法で得た錠剤では、苛酷試験を行う前の製造時点においてもイミダフェナシンの分解産物が認められた。本発明は、温度に対してより安定なイミダフェナシン含有医薬組成物を製造する方法を提供することを目的とする。 Where the active ingredient of a drug is an organic compound, temperature (heat) is the factor that has the greatest effect on the decomposition of the active ingredient. In Patent Document 1, the produced tablet has been confirmed to be stable to light, but has not been confirmed to be stable to temperature. In Patent Document 2, the stability test of the produced tablet is not performed. Similar to Patent Document 1, the present inventors produced tablets from particles obtained by stirring granulation using a solution containing imidafenacin as a granulation solution, and conducted a rigorous test at 70 ° C., and found that they were stable against temperature. I found that the sex was not very good. In addition, in the tablets obtained by this production method, a decomposition product of imidafenacin was observed even at the time of production before the harsh test. An object of the present invention is to provide a method for producing an imidafenacin-containing pharmaceutical composition that is more stable with respect to temperature.
本発明者らは、イミダフェナシンの粉末と賦形剤との混合粉末と、結合剤を含む造粒液とを用いて、湿式造粒によりイミダフェナシンを含む粒子を得て、この粒子から錠剤を製造して苛酷試験を行ったところ、温度に対する安定性が良好であることを見出して、本発明を完成した。また、得られた錠剤では、製造時点においてもイミダフェナシンの分解産物は検出されなかった。よって、本発明は、イミダフェナシンの粉末と、賦形剤とを混合して、混合粉末を得る工程と、前記混合粉末と、結合剤を含む溶液又は懸濁液とを用いて、湿式造粒により、イミダフェナシンを含む粒子を得る工程と、前記粒子を乾燥させる工程とを含む、イミダフェナシンを含む粒子の製造方法を提供する。 The present inventors obtained particles containing imidafenacin by wet granulation using a mixed powder of imidafenacin powder and an excipient and a granulating solution containing a binder, and produced tablets from these particles. As a result of conducting a rigorous test, the present invention was completed by finding that the stability with respect to temperature was good. In addition, no degradation product of imidafenacin was detected in the obtained tablets even at the time of production. Therefore, in the present invention, a step of mixing an imidaphenacin powder and an excipient to obtain a mixed powder, and using the mixed powder and a solution or suspension containing a binder are used for wet granulation. The present invention provides a method for producing particles containing imidaphenacin, which comprises a step of obtaining particles containing imidaphenacin and a step of drying the particles.
本発明は、イミダフェナシンの粉末と、賦形剤とを混合して、混合粉末を得る工程と、前記混合粉末と、結合剤を含む溶液又は懸濁液とを用いて、湿式造粒により、イミダフェナシンを含む粒子を得る工程と、前記粒子を乾燥させる工程と、乾燥させた前記粒子と、錠剤用添加物とを混合して、打錠用粉末を得る工程と、前記打錠用粉末を圧縮成型して錠剤を得る工程とを含む、イミダフェナシンを有効成分とする錠剤の製造方法を提供する。 In the present invention, imidafenacin is obtained by mixing a powder of imidafenacin and an excipient to obtain a mixed powder, and by wet granulation using the mixed powder and a solution or suspension containing a binder. A step of obtaining particles containing the above, a step of drying the particles, a step of mixing the dried particles with a tablet additive to obtain a tableting powder, and a compression molding of the tableting powder. Provided is a method for producing a tablet containing imidaphenacin as an active ingredient, which comprises a step of obtaining a tablet.
本発明は、イミダフェナシンの粉末と、賦形剤とを混合して、混合粉末を得る工程と、前記混合粉末と、結合剤を含む溶液又は懸濁液とを用いて、湿式造粒により、イミダフェナシンを含む粒子を得る工程と、前記粒子を乾燥させる工程と、乾燥させた前記粒子と、崩壊性粒子と、錠剤用添加物とを混合して、打錠用粉末を得る工程と、前記打錠用粉末を圧縮成型して口腔内崩壊錠を得る工程とを含む、イミダフェナシンを有効成分とする口腔内崩壊錠の製造方法を提供する。 In the present invention, imidafenacin is obtained by mixing a powder of imidafenacin and an excipient to obtain a mixed powder, and by wet granulation using the mixed powder and a solution or suspension containing a binder. A step of obtaining particles containing the above, a step of drying the particles, a step of mixing the dried particles, disintegrating particles, and an additive for tablets to obtain a powder for tableting, and the step of tableting. Provided is a method for producing an orally disintegrating tablet containing imidaphenacin as an active ingredient, which comprises a step of compression-molding a powder for orally to obtain an orally disintegrating tablet.
本発明は、イミダフェナシンの粉末と賦形剤との混合粉末と、結合剤を含む溶液又は懸濁液とを用いて、湿式造粒によりイミダフェナシンを含む粒子を得て、得られた粒子を用いてイミダフェナシンを有効成分として含む錠剤を製造することにより、前記錠剤の製造過程における類縁物質の発生を抑制する方法を提供する。さらに、本発明は、イミダフェナシンの粉末と賦形剤との混合粉末と、結合剤を含む溶液又は懸濁液とを用いて、湿式造粒によりイミダフェナシンを含む粒子を得て、得られた粒子を用いてイミダフェナシンを有効成分として含む錠剤を製造することにより、前記錠剤の保存期間における類縁物質の発生を抑制する方法を提供する。 In the present invention, particles containing imidafenacin are obtained by wet granulation using a mixed powder of imidafenacin powder and an excipient and a solution or suspension containing a binder, and the obtained particles are used. Provided is a method for suppressing the generation of related substances in the manufacturing process of the tablet by producing a tablet containing imidaphenacin as an active ingredient. Furthermore, the present invention uses a mixed powder of imidazole powder and an excipient and a solution or suspension containing a binder to obtain particles containing imidazole by wet granulation, and obtains the obtained particles. Provided is a method for suppressing the generation of related substances during the storage period of the tablet by producing a tablet containing imidafenacin as an active ingredient.
本発明によれば、温度に対してより安定なイミダフェナシン含有医薬組成物を製造する方法が提供される。 According to the present invention, there is provided a method for producing an imidafenacin-containing pharmaceutical composition that is more stable with respect to temperature.
本明細書において「イミダフェナシン」との用語は、イミダフェナシン、並びにその薬学的に許容される塩及び溶媒和物を包含する。薬学的に許容される塩とは、有効成分の化合物と、ヒトを含む哺乳動物への投与が許容される有機又は無機の酸とから形成される塩をいう。そのような酸としては、例えば塩酸、メタンスルホン酸、フマル酸、リン酸などが挙げられる。薬学的に許容される溶媒和物とは、有効成分の化合物と、ヒトを含む哺乳動物への投与が許容される溶媒とから形成される固体分子をいう。そのような溶媒としては、例えば水、酢酸、エタノールなどが挙げられる。 As used herein, the term "imidafenacin" includes imidafenacin, as well as pharmaceutically acceptable salts and solvates thereof. A pharmaceutically acceptable salt is a salt formed from a compound of the active ingredient and an organic or inorganic acid that is acceptable for administration to mammals, including humans. Examples of such an acid include hydrochloric acid, methanesulfonic acid, fumaric acid, phosphoric acid and the like. A pharmaceutically acceptable solvate refers to a solid molecule formed from a compound of the active ingredient and a solvent that is acceptable for administration to mammals, including humans. Examples of such a solvent include water, acetic acid, ethanol and the like.
本実施形態のイミダフェナシンを含む粒子の製造方法(以下、「粒子の製造方法」ともいう)では、まず、イミダフェナシンの粉末と、賦形剤とを混合して、混合粉末を得る。 In the method for producing particles containing imidafenacin of the present embodiment (hereinafter, also referred to as "method for producing particles"), first, a powder of imidafenacin and an excipient are mixed to obtain a mixed powder.
イミダフェナシンの粉末と混合される賦形剤は、薬学的に許容される粉体の賦形剤から適宜選択することができ、例えばデンプン類、セルロース類、糖類、糖アルコール類などが挙げられる。デンプン類としては、部分アルファー化デンプン、トウモロコシデンプンなどが挙げられる。セルロース類としては、結晶セルロース、カルメロース、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロースなどが挙げられる。糖類としては、乳糖(乳糖水和物ともいう)、白糖などが挙げられる。糖アルコール類としては、D-ソルビトール、マンニトールなどが挙げられる。それらの中でも、部分アルファー化デンプンが特に好ましい。賦形剤は、一種でもよいし、二種以上を組み合わせてもよい。 The excipient to be mixed with the imidazole powder can be appropriately selected from the pharmaceutically acceptable powder excipients, and examples thereof include starches, celluloses, sugars and sugar alcohols. Examples of starches include partially pregelatinized starch and corn starch. Examples of celluloses include crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl cellulose calcium, and low-degree-of-substitution hydroxypropyl cellulose. Examples of sugars include lactose (also referred to as lactose hydrate) and sucrose. Examples of sugar alcohols include D-sorbitol and mannitol. Among them, partially pregelatinized starch is particularly preferable. The excipient may be one kind or a combination of two or more kinds.
本実施形態では、最終的な製剤である錠剤１錠当たりのイミダフェナシンの含量は、例えば0.025 mg以上２mg以下であり、好ましくは0.05 mg以上0.25 mg以下であり、より好ましくは0.1 mgである。このように製剤中のイミダフェナシンの含量は比較的微量であるので、本実施形態では、イミダフェナシンの粉末は、あらかじめ賦形剤と混合して調製されたイミダフェナシン倍散であってもよい。倍散を用いることにより、秤量誤差を低減できる。倍散の調製は、段階的に行ってもよい。例えば、イミダフェナシン原末と賦形剤とを混合して２〜30倍散(3.33〜50%イミダフェナシン散)を調製し、この倍散と賦形剤とをさらに混合して100〜200倍散(0.5〜１%イミダフェナシン散)を調製してもよい。倍散の調製工程は、２段階に限らず、３段階以上であってもよい。３段階の倍散の調製工程は、例えば、イミダフェナシン原末と賦形剤とを混合して２〜30倍散を調製し、得られた倍散と賦形剤とを混合して20〜100倍散を調製し、得られた倍散と賦形剤とを混合して100〜200倍散を調製する。倍散を調製するための賦形剤は、混合粉末を得る工程で用いる賦形剤と同じであってもよいし、異なっていてもよいが、好ましくは同じ賦形剤である In the present embodiment, the content of imidafenacin per tablet, which is the final preparation, is, for example, 0.025 mg or more and 2 mg or less, preferably 0.05 mg or more and 0.25 mg or less, and more preferably 0.1 mg. Since the content of imidafenacin in the preparation is relatively small as described above, in the present embodiment, the powder of imidafenacin may be imidafenacin double powder prepared by mixing with an excipient in advance. Weighing error can be reduced by using doubling. The preparation of the doubling may be carried out stepwise. For example, the raw powder of imidafenacin and the excipient are mixed to prepare 2 to 30 times powder (3.33 to 50% imidafenacin powder), and this double powder and the excipient are further mixed and 100 to 200 times powder (3.33 to 50% imidafenacin powder). 0.5-1% imidafenacin powder) may be prepared. The preparation step of doubling is not limited to two steps, and may be three or more steps. In the three-step doubling preparation step, for example, imidafenacin raw powder and an excipient are mixed to prepare a 2 to 30 fold powder, and the obtained doubling and the excipient are mixed to prepare 20 to 100 times. A doubling is prepared, and the obtained doubling and the excipient are mixed to prepare a 100-200 doubling. The excipient for preparing the double powder may be the same as or different from the excipient used in the step of obtaining the mixed powder, but is preferably the same excipient.
イミダフェナシンの粉末と賦形剤とを混合する方法は特に限定されず、例えば、２種以上の粉末を混合できる公知の混合機を用いればよい。そのような混合機としては、拡散式混合機、対流式混合機などが挙げられる。 The method for mixing the imidafenacin powder and the excipient is not particularly limited, and for example, a known mixer capable of mixing two or more kinds of powder may be used. Examples of such a mixer include a diffusion type mixer and a convection type mixer.
次いで、本実施形態の粒子の製造方法では、混合粉末と、結合剤を含む溶液又は懸濁液とを用いて、湿式造粒により、イミダフェナシンを含む粒子を得る。 Then, in the method for producing particles of the present embodiment, particles containing imidafenacin are obtained by wet granulation using a mixed powder and a solution or suspension containing a binder.
結合剤は、薬学的に許容されるものから適宜選択することができ、例えばセルロース類、ビニル系高分子、アクリル系高分子、デンプン類、ステアリルアルコール、ゼラチン、デキストリン、アラビアゴム、プルラン、マクロゴールなどが挙げられる。セルロース類としては、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース(ヒプロメロース)、結晶セルロース、ヒドロキシエチルメチルセルロース、エチルセルロース、メチルセルロースなどが挙げられる。ビニル系高分子としては、ポリビニルピロリドン(ポビドン)、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール完全けん化物、ポリビニルアルコール部分けん化物、カルボキシビニルポリマー、ポリ塩化ビニルなどが挙げられる。アクリル系高分子としては、アミノアルキルメタクリレートコポリマー(Ｅ又はRS)、メタクリル酸コポリマー(Ｌ、LD又はＳ)、アクリル酸エチル・メタクリル酸メチルコポリマー分散液などが挙げられる。デンプン類としては、デンプン(溶性)、デンプングリコール酸ナトリウムなどが挙げられる。それらの中でも、ヒドロキシプロピルセルロースが特に好ましい。結合剤は、一種でもよいし、二種以上を組み合わせてもよい。 The binder can be appropriately selected from pharmaceutically acceptable ones, for example, celluloses, vinyl polymers, acrylic polymers, starches, stearyl alcohol, gelatin, dextrin, gum arabic, pullulan, macrogol. And so on. Examples of celluloses include hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), crystalline cellulose, hydroxyethyl methyl cellulose, ethyl cellulose, methyl cellulose and the like. Examples of the vinyl polymer include polyvinylpyrrolidone (povidone), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol completely saponified product, polyvinyl alcohol partially saponified product, carboxyvinyl polymer, polyvinyl chloride and the like. Examples of the acrylic polymer include aminoalkyl methacrylate copolymer (E or RS), methacrylic acid copolymer (L, LD or S), ethyl acrylate / methyl methacrylate copolymer dispersion liquid and the like. Examples of starches include starch (soluble) and sodium starch glycolate. Among them, hydroxypropyl cellulose is particularly preferable. The binder may be one kind or a combination of two or more kinds.
本実施形態では、結合剤を薬学的に許容される溶媒中に溶解させた溶液、又は結合剤を該溶媒中に分散させた懸濁液(分散液ともいう)を、湿式造粒における造粒液として用いる。薬学的に許容される溶媒としては、例えば精製水、エタノール及びこれらの混液が挙げられる。好ましい溶媒は、精製水とエタノールとの混液である。 In the present embodiment, a solution in which the binder is dissolved in a pharmaceutically acceptable solvent, or a suspension in which the binder is dispersed in the solvent (also referred to as a dispersion) is granulated in wet granulation. Used as a liquid. Pharmaceutically acceptable solvents include, for example, purified water, ethanol and mixtures thereof. A preferred solvent is a mixture of purified water and ethanol.
本実施形態では、結合剤を含む溶液又は懸濁液は、さらに塩基性添加物を含んでもよい。塩基性添加物は、薬学的に許容されるものから適宜選択することができ、例えばメグルミン、水酸化マグネシウム、メタケイ酸アルミン酸マグネシウム、L-アルギニン、炭酸水素ナトリウム、炭酸ナトリウム、酸化マグネシウムなどが挙げられる。それらの中でも、メグルミン、水酸化マグネシウム、メタケイ酸アルミン酸マグネシウムが好ましい。塩基性添加物は、一種でもよいし、二種以上を組み合わせてもよい。 In this embodiment, the solution or suspension containing the binder may further contain a basic additive. The basic additive can be appropriately selected from pharmaceutically acceptable ones, and examples thereof include meglumin, magnesium hydroxide, magnesium aluminometasilicate, L-arginine, sodium hydrogencarbonate, sodium carbonate, magnesium oxide and the like. Be done. Among them, meglumine, magnesium hydroxide, and magnesium aluminate metasilicate are preferable. The basic additive may be one kind or a combination of two or more kinds.
本実施形態では、湿式造粒の手法に従って、結合剤を含む溶液又は懸濁液を混合粉末に添加することにより、イミダフェナシンを含む粒子を得ることができる。湿式造粒の種類は特に限定されないが、例えば撹拌造粒、流動層造粒、押し出し造粒、転動造粒、解砕造粒、噴霧造粒などから適宜選択できる。それらの中でも、撹拌造粒が特に好ましい。撹拌造粒は、公知の撹拌造粒機を用いて行うことができる。撹拌造粒機では、回転するブレードにより混合粉末を撹拌した状態で、結合剤を含む溶液又は懸濁液を滴下又は噴霧することで、混合粉末と、結合剤を含む溶液又は懸濁液とが混合及び分散されて、イミダフェナシンを含む粒子が生じる。 In this embodiment, particles containing imidafenacin can be obtained by adding a solution or suspension containing a binder to the mixed powder according to a wet granulation technique. The type of wet granulation is not particularly limited, and can be appropriately selected from, for example, stirring granulation, fluidized bed granulation, extrusion granulation, rolling granulation, crushing granulation, spray granulation, and the like. Among them, stirring granulation is particularly preferable. Stirring granulation can be performed using a known stirring granulator. In the stirring granulator, the mixed powder and the solution or suspension containing the binder are obtained by dropping or spraying the solution or suspension containing the binder while the mixed powder is stirred by a rotating blade. Mixing and dispersing yields imidaphenacin-containing particles.
本実施形態の粒子の製造方法では、湿式造粒により得られたイミダフェナシンを含む粒子を乾燥させる。乾燥手段は特に限定されないが、真空乾燥により粒子を乾燥させることが好ましい。真空乾燥は、公知の真空乾燥機を用いて行うことができる。造粒機に真空乾燥機能が付加されている場合は、その造粒機により乾燥させてもよい。本実施形態では、乾燥させた粒子を整粒して、所定の粒度分布となるようにすることが好ましい。 In the method for producing particles of the present embodiment, the particles containing imidafenacin obtained by wet granulation are dried. The drying means is not particularly limited, but it is preferable to dry the particles by vacuum drying. Vacuum drying can be performed using a known vacuum dryer. If the granulator has a vacuum drying function, it may be dried by the granulator. In the present embodiment, it is preferable to arrange the dried particles so that they have a predetermined particle size distribution.
本実施形態の粒子の製造方法によって得られたイミダフェナシンを含む粒子は、イミダフェナシンを有効成分とする錠剤を製造するための打錠用顆粒として用いることができる。後述の試験例１に示されるように、本実施形態の粒子の製造方法によって得られたイミダフェナシンを含む粒子から製造した錠剤(口腔内崩壊錠)は、イミダフェナシンを含む溶液を造粒液として用いる撹拌造粒によって得た粒子から製造した錠剤に比べて、温度(熱)に対する安定性が顕著に向上していた。よって、本発明のさらなる実施形態では、イミダフェナシンを有効成分とする錠剤の製造方法(以下、「錠剤の製造方法」ともいう)が提供される。 The particles containing imidafenacin obtained by the method for producing particles of the present embodiment can be used as tableting granules for producing tablets containing imidafenacin as an active ingredient. As shown in Test Example 1 described later, tablets (orally disintegrating tablets) produced from particles containing imidafenacin obtained by the method for producing particles of the present embodiment are stirred using a solution containing imidafenacin as a granulating solution. The stability against temperature (heat) was remarkably improved as compared with the tablet produced from the particles obtained by granulation. Therefore, in a further embodiment of the present invention, a method for producing a tablet containing imidafenacin as an active ingredient (hereinafter, also referred to as "method for producing a tablet") is provided.
本実施形態の錠剤の製造方法における、イミダフェナシンを含む粒子を得る工程、及び該粒子を乾燥させる工程の詳細は、本実施形態の粒子の製造方法について述べたことと同様である。本実施形態では、乾燥させたイミダフェナシンを含む粒子と、錠剤用添加物とを混合して、打錠用粉末を得る。そして、得られた打錠用粉末を圧縮成型して、イミダフェナシンを有効成分とする錠剤を得る。 The details of the step of obtaining the particles containing imidafenacin and the step of drying the particles in the method for producing tablets of the present embodiment are the same as those described for the method for producing particles of the present embodiment. In this embodiment, dried particles containing imidafenacin and a tablet additive are mixed to obtain a tableting powder. Then, the obtained tableting powder is compression-molded to obtain a tablet containing imidafenacin as an active ingredient.
錠剤用添加物は、錠剤の製造に通常用いられる添加物であり、薬学的に許容される賦形剤、崩壊剤、甘味剤、着色剤、滑沢剤などから適宜選択できる。賦形剤としては、結晶セルロースなどのセルロース類、乳糖などの糖類、D-マンニトールなどの糖アルコール類、トウモロコシデンプンなどのデンプン類などが挙げられる。崩壊剤としては、クロスポピドン、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロースなどが挙げられる。甘味剤としては、スクラロース、アセスルファムカリウム、アスパルテームなどが挙げられる。着色剤としては、三二酸化鉄、黄色三二酸化鉄などが挙げられる。滑沢剤としては、軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルクなどが挙げられる。 The tablet additive is an additive usually used in the production of tablets, and can be appropriately selected from pharmaceutically acceptable excipients, disintegrants, sweeteners, colorants, lubricants and the like. Examples of excipients include celluloses such as crystalline cellulose, sugars such as lactose, sugar alcohols such as D-mannitol, and starches such as corn starch. Examples of the disintegrant include crospopidone, croscarmellose sodium, low degree of substitution hydroxypropyl cellulose and the like. Examples of the sweetener include sucralose, acesulfame potassium, aspartame and the like. Examples of the colorant include iron sesquioxide and yellow iron sesquioxide. Examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, talc and the like.
打錠用粉末を得る工程及び錠剤を得る工程は、具体的には、次のようにして行われる。まず、乾燥させたイミダフェナシンを含む粒子と、滑沢剤を除く錠剤用添加物とを混合する。次いで、得られた混合物に滑沢剤を添加して混合し、打錠用粉末を得る。そして、得られた打錠用粉末を公知の打錠機で圧縮成型することにより、イミダフェナシンを有効成分とする錠剤を得ることができる。必要に応じて、得られた錠剤を、糖衣錠又はフィルムコーティング錠としてもよい。錠剤のコーティングは、パンコーティング法、流動コーティング法などの公知の方法により行うことができる。 Specifically, the step of obtaining the powder for tableting and the step of obtaining the tablet are carried out as follows. First, the dried particles containing imidafenacin and the tablet additive excluding the lubricant are mixed. Then, a lubricant is added to the obtained mixture and mixed to obtain a tableting powder. Then, by compression-molding the obtained tableting powder with a known tableting machine, a tablet containing imidafenacin as an active ingredient can be obtained. If necessary, the obtained tablets may be used as sugar-coated tablets or film-coated tablets. The tablet can be coated by a known method such as a pan coating method or a fluid coating method.
本実施形態では、打錠用粉末を得る工程の前に、乾燥させたイミダフェナシンを含む粒子をコーティングする工程を行ってもよい。粒子のコーティングは、流動コーティング法などの公知の方法により行うことができる。流動コーティング法では、例えば流動層造粒機を用いて、粒子を気流で流動化させた状態で、薬学的に許容されるコーティング剤の溶液又は懸濁液を噴霧することにより、粒子がコーティング剤で被覆される。コーティング剤は、薬学的に許容されるものから適宜選択することができ、例えばヒプロメロース、エチルセルロース、タルク、酸化チタンなどが挙げられる。コーティング剤は、一種でもよいし、二種以上を組み合わせてもよい。 In the present embodiment, the step of coating the dried particles containing imidafenacin may be performed before the step of obtaining the tableting powder. The particles can be coated by a known method such as a flow coating method. In the fluidized coating method, for example, a fluidized bed granulator is used to spray a solution or suspension of a pharmaceutically acceptable coating agent in a state where the particles are fluidized by an air flow, so that the particles are coated with a coating agent. Covered with. The coating agent can be appropriately selected from pharmaceutically acceptable ones, and examples thereof include hypromellose, ethyl cellulose, talc, and titanium oxide. The coating agent may be one kind or a combination of two or more kinds.
好ましい実施形態では、コーティングする工程では、乾燥させたイミダフェナシンを含む粒子を中間層で被覆する第１コーティング工程と、該中間層をコーティングする第２コーティング工程とを行う。有効成分であるイミダフェナシンとコーティング剤との間の何らかの相互作用により、有効成分が分解する場合又はそのおそれがある場合、該コーティング剤を最外層に用い、粒子と最外層との間に中間層を形成することにより、有効成分の分解を抑制又は低減できる。 In a preferred embodiment, the coating step involves a first coating step of coating the dried particles containing imidafenacin with an intermediate layer and a second coating step of coating the intermediate layer. If the active ingredient decomposes or is likely to decompose due to some interaction between the active ingredient imidafenacin and the coating agent, the coating agent is used as the outermost layer and an intermediate layer is provided between the particles and the outermost layer. By forming, the decomposition of the active ingredient can be suppressed or reduced.
中間層に用いられるコーティング剤としては、薬学的に許容される水溶性高分子が好ましく、例えばヒプロメロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ポリビニルアルコールなどが挙げられる。水溶性高分子は、一種でもよいし、二種以上を組み合わせてもよい。中間層は、必要に応じて、薬学的に許容される非高分子のコーティング剤をさらに含んでもよい。そのようなコーティング剤としては、例えばタルク、酸化チタン、珪酸などが挙げられる。 The coating agent used for the intermediate layer is preferably a pharmaceutically acceptable water-soluble polymer, and examples thereof include hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol. The water-soluble polymer may be one kind or a combination of two or more kinds. The intermediate layer may further contain a pharmaceutically acceptable non-polymeric coating, if desired. Examples of such a coating agent include talc, titanium oxide, silicic acid and the like.
最外層に用いられるコーティング剤としては、例えば水不溶性高分子、胃溶性高分子及び腸溶性高分子が挙げられる。水不溶性高分子としては、例えばエチルセルロース、メタクリル酸共重合体、メタクリル酸メチルとメタクリル酸ブチル、メタクリル酸ジメチルアミノエチルの共重合体などが挙げられる。胃溶性高分子としては、例えばアミノアルキルメタクリレートコポリマー、ポリビニルアルコールジエチルアミノアセテートなどが挙げられる。腸溶性高分子としては、例えばメタクリル酸共重合体、セルロースアセテートフタレート、ヒプロメロースフタレート、ポリビニルアルコールアセテートフタレートなどが挙げられる。水不溶性高分子、胃溶性高分子及び腸溶性高分子はそれぞれ、一種でもよいし、二種以上を組み合わせてもよい。 Examples of the coating agent used for the outermost layer include water-insoluble polymers, gastric-soluble polymers and enteric-soluble polymers. Examples of the water-insoluble polymer include ethyl cellulose, a methacrylic acid copolymer, a copolymer of methyl methacrylate and butyl methacrylate, and a copolymer of dimethylaminoethyl methacrylate. Examples of the gastric soluble polymer include aminoalkyl methacrylate copolymer and polyvinyl alcohol diethylaminoacetate. Examples of the enteric polymer include methacrylic acid copolymer, cellulose acetate phthalate, hypromerose phthalate, polyvinyl alcohol acetate phthalate and the like. The water-insoluble polymer, the gastric-soluble polymer, and the enteric-soluble polymer may be used alone or in combination of two or more.
最外層は、必要に応じて、薬学的に許容される添加物をさらに含んでもよい。そのような添加物としては、例えば着色剤、非高分子のコーティング剤などが挙げられる。着色剤としては、例えば三二酸化鉄、黄色三二酸化鉄、黄色４号アルミニウムレーキ、黄色５号アルミニウムレーキなどが挙げられる。非高分子のコーティング剤としては、例えばタルク、酸化チタン、珪酸などが挙げられる。 The outermost layer may further contain pharmaceutically acceptable additives, if desired. Examples of such additives include colorants, non-polymeric coating agents and the like. Examples of the colorant include iron sesquioxide, yellow iron sesquioxide, yellow No. 4 aluminum lake, and yellow No. 5 aluminum lake. Examples of the non-polymer coating agent include talc, titanium oxide, silicic acid and the like.
本実施形態では、錠剤は口腔内崩壊錠であってもよい。よって、本発明のさらなる実施形態では、イミダフェナシンを有効成分とする口腔内崩壊錠の製造方法(以下、「OD錠の製造方法」ともいう)が提供される。 In this embodiment, the tablet may be an orally disintegrating tablet. Therefore, in a further embodiment of the present invention, a method for producing an orally disintegrating tablet containing imidafenacin as an active ingredient (hereinafter, also referred to as "method for producing an OD tablet") is provided.
本実施形態のOD錠の製造方法における、イミダフェナシンを含む粒子を得る工程、及び該粒子を乾燥させる工程の詳細は、本実施形態の粒子の製造方法について述べたことと同様である。本実施形態のOD錠の製造方法では、水の存在下で急速に崩壊するという性質を錠剤に付与するため、崩壊性粒子を用いる。崩壊性粒子自体は当該技術分野で公知であり、例えば国際公開第2017/217494号に記載されている(当該文献は、参照により本明細書に組み込まれる)。 The details of the step of obtaining particles containing imidafenacin and the step of drying the particles in the method for producing OD tablets of the present embodiment are the same as those described for the method for producing particles of the present embodiment. In the method for producing an OD tablet of the present embodiment, disintegrating particles are used in order to impart the property of rapidly disintegrating in the presence of water to the tablet. The disintegrating particles themselves are known in the art and are described, for example, in WO 2017/217494 (the document is incorporated herein by reference).
崩壊性粒子は、薬学的に許容される、デンプン由来の崩壊剤を含むことが好ましい。デンプン由来の崩壊剤としては、例えばトウロモロコシデンプン、部分アルファー化デンプン、バレイショデンプン、ヒドロキシプロピルスターチなどが挙げられる。これらの中でも、トウロモロコシデンプン及び部分アルファー化デンプンが特に好ましい。デンプン由来の崩壊剤は、一種でもよいし、二種以上を組み合わせてもよい。 The disintegrating particles preferably contain a pharmaceutically acceptable starch-derived disintegrant. Examples of starch-derived disintegrants include touro sorghum starch, partially pregelatinized starch, potato starch, hydroxypropyl starch and the like. Of these, touro sorghum starch and partially pregelatinized starch are particularly preferred. The starch-derived disintegrant may be one type or a combination of two or more types.
崩壊性粒子は、薬学的に許容される添加物(賦形剤、上記以外の崩壊剤、結合剤、流動化剤、着色剤など)をさらに含むことが好ましい。賦形剤としては、乳糖、結晶セルロース、D-マンニトールなどが挙げられる。これらの中でも、乳糖が特に好ましい。デンプン由来以外の崩壊剤としては、クロスポビドン、クロスカルメロースナトリウムなどが挙げられる。結合剤としてはエチルセルロースなどが挙げられる。流動化剤としては、軽質無水ケイ酸、合成ケイ酸アルミニウム、含水二酸化ケイ素などが挙げられる。着色剤としては、三二酸化鉄、黄色三二酸化鉄などが挙げられる。これらの添加物はそれぞれ、一種でもよいし、二種以上を組み合わせてもよい。 The disintegrating particles preferably further contain pharmaceutically acceptable additives (excipients, disintegrants other than those mentioned above, binders, fluidizers, colorants, etc.). Excipients include lactose, crystalline cellulose, D-mannitol and the like. Of these, lactose is particularly preferred. Examples of disintegrants other than those derived from starch include crospovidone and croscarmellose sodium. Examples of the binder include ethyl cellulose and the like. Examples of the fluidizing agent include light anhydrous silicic acid, synthetic aluminum silicate, and hydrous silicon dioxide. Examples of the colorant include iron sesquioxide and yellow iron sesquioxide. Each of these additives may be one kind, or two or more kinds may be combined.
崩壊性粒子は、例えば、次のようにして得ることができる。まず、賦形剤、結合剤、及び流動化剤を含む粉末に、デンプン由来の崩壊剤を含む溶液又は懸濁液を添加して、湿式造粒により顆粒を得る。例えば、流動層造粒の場合では、結合剤、及び流動化剤を含む粉末を気流で流動化させて混和し、この状態で、デンプン由来の崩壊剤を含む溶液又は懸濁液を噴霧することにより、顆粒を得る。そして、得られた顆粒を乾燥及び整粒して、崩壊性粒子を得る。 Disintegrating particles can be obtained, for example, as follows. First, a solution or suspension containing a starch-derived disintegrant is added to a powder containing an excipient, a binder, and a fluidizing agent, and granules are obtained by wet granulation. For example, in the case of fluidized bed granulation, a powder containing a binder and a fluidizing agent is fluidized by an air flow to be mixed, and in this state, a solution or suspension containing a starch-derived disintegrant is sprayed. To obtain granules. Then, the obtained granules are dried and sized to obtain disintegrating particles.
本実施形態のOD錠の製造方法では、乾燥させたイミダフェナシンを含む粒子と、崩壊性粒子と、錠剤用添加物とを混合して、打錠用粉末を得る。錠剤用添加物の詳細は、本実施形態の錠剤の製造方法について述べたことと同様である。そして、得られた打錠用粉末を公知の打錠機で圧縮成型することにより、イミダフェナシンを有効成分とする口腔内崩壊錠を得ることができる。 In the method for producing an OD tablet of the present embodiment, dried particles containing imidafenacin, disintegrating particles, and a tablet additive are mixed to obtain a tableting powder. The details of the tablet additive are the same as those described for the method for producing a tablet of the present embodiment. Then, by compression-molding the obtained tableting powder with a known tableting machine, an orally disintegrating tablet containing imidafenacin as an active ingredient can be obtained.
本実施形態では、打錠用粉末を得る工程の前に、乾燥させたイミダフェナシンを含む粒子をコーティングする工程を行ってもよい。該粒子のコーティング工程の詳細は、本実施形態の錠剤の製造方法について述べたことと同様である。 In the present embodiment, the step of coating the dried particles containing imidafenacin may be performed before the step of obtaining the tableting powder. The details of the coating process of the particles are the same as those described for the method for producing tablets of the present embodiment.
本実施形態の製造方法により得られる錠剤(口腔内崩壊錠)は、特許文献１に記載されるようなイミダフェナシンの溶液を用いる製造方法で得られる錠剤に比べて、温度(熱)に対する安定性がより優れている。なお、温度(熱)に対する安定性は、当業者であれば、当該技術分野において公知の方法(安定性試験など)により評価できる。そのような方法としては、後述の試験例１に示されるような苛酷試験などが挙げられる。具体的には、イミダフェナシンを含む錠剤を容器に入れて高温(例えば70℃)の温度条件下で数日(例えば９日間)貯蔵し、適切な溶媒で有効成分及びその類縁物質を抽出した後、液体クロマトグラフィーにより類縁物質の量を分析することが挙げられる。類縁物質とは、有効成分の分解生成物の総称である。 The tablets (orally disintegrating tablets) obtained by the production method of the present embodiment are more stable to temperature (heat) than the tablets obtained by the production method using a solution of imidafenacin as described in Patent Document 1. Better. A person skilled in the art can evaluate the stability with respect to temperature (heat) by a method known in the art (stability test or the like). Examples of such a method include a severe test as shown in Test Example 1 described later. Specifically, tablets containing imidafenacin are placed in a container and stored under high temperature conditions (for example, 70 ° C.) for several days (for example, 9 days), and after extracting the active ingredient and its related substances with an appropriate solvent, the active ingredient and its related substances are extracted. Analysis of the amount of related substances by liquid chromatography can be mentioned. A related substance is a general term for decomposition products of active ingredients.
別の実施形態は、イミダフェナシンの粉末と賦形剤との混合粉末と、結合剤を含む溶液又は懸濁液とを用いて、湿式造粒によりイミダフェナシンを含む粒子を得て、得られた粒子を用いてイミダフェナシンを有効成分として含む錠剤を製造することにより、該錠剤の製造過程及び／又は該錠剤の保存期間における類縁物質の発生を抑制する方法である。ここで、「錠剤の製造過程」との用語は、本実施形態の錠剤の製造方法及びOD錠の製造方法における所定の一工程及び一連の工程の両方を包含する。「保存期間」との用語は、錠剤の製造後から錠剤が使用(服用)されるまでの期間をいう。後述の試験例１に示されるように、本実施形態の製造方法により得られる錠剤(口腔内崩壊錠)では、製造直後、類縁物質は実質的に検出されないか又は極めて微量(例えば検出限界以下)となる。また、本実施形態の製造方法により得られる錠剤は、特許文献１に記載されるようなイミダフェナシンの溶液を用いる製造方法で得られる錠剤に比べて、保存期間中の類縁物質の発生量が顕著に低減する。 In another embodiment, a mixed powder of imidazole powder and an excipient is used, and a solution or suspension containing a binder is used to obtain particles containing imidazole by wet granulation, and the obtained particles are obtained. It is a method of suppressing the generation of related substances during the manufacturing process of the tablet and / or the storage period of the tablet by producing a tablet containing imidaphenacin as an active ingredient. Here, the term "tablet manufacturing process" includes both a predetermined one step and a series of steps in the tablet manufacturing method and the OD tablet manufacturing method of the present embodiment. The term "storage period" refers to the period from the time a tablet is manufactured until the tablet is used (taken). As shown in Test Example 1 described later, in the tablets (orally disintegrating tablets) obtained by the production method of the present embodiment, substantially no related substances are detected immediately after production, or extremely trace amounts (for example, below the detection limit). It becomes. Further, the tablets obtained by the production method of the present embodiment generate a remarkable amount of related substances during the storage period as compared with the tablets obtained by the production method using a solution of imidafenacin as described in Patent Document 1. Reduce.
以下に、本発明を実施例により詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited to these Examples.
[試験例１]
試験例１では、イミダフェナシン及び結合剤を含む溶液と、賦形剤とを用いる湿式造粒により得られた粒子から製造した製剤(比較例)、及び、イミダフェナシンの粉末及び賦形剤の混合粉末と、結合剤を含む造粒液とを用いる湿式造粒により得られた粒子から製造した製剤(実施例１)の温度に対する安定性を比較した。
[Test Example 1]
In Test Example 1, a preparation (comparative example) produced from particles obtained by wet granulation using a solution containing imidazole and a binder and an excipient, and a mixed powder of imidazole powder and an excipient are used. , The stability of the preparation (Example 1) produced from the particles obtained by wet granulation using a granulation solution containing a binder with respect to temperature was compared.
１．口腔内崩壊錠の製造
(1.1) 崩壊性粒子
乳糖水和物、エチルセルロース及び軽質無水ケイ酸を流動層造粒機へ投入し、トウモロコシデンプン、部分アルファー化デンプン及び三二酸化鉄を精製水に分散させた分散液をスプレーした。得られた粒子を乾燥及び整粒して、崩壊性粒子を得た。
1. 1. Manufacture of orally disintegrating tablets
(1.1) Disintegrating particles Lactose hydrate, ethyl cellulose and light anhydrous silicic acid were put into a fluidized bed granulator, and a dispersion liquid in which corn starch, partially pregelatinized starch and iron sesquioxide were dispersed in purified water was sprayed. .. The obtained particles were dried and sized to obtain disintegrating particles.
(1.2) 実施例１の口腔内崩壊錠の製造
表１に、実施例１の口腔内崩壊錠の処方(１錠当たりの成分量)を示す。この錠剤を、次のようにして製造した。イミダフェナシン原薬粉末と部分アルファー化デンプンとを拡散式混合機を用いて混合して、混合粉末を得た。メグルミン及びヒドロキシプロピルセルロースを、精製水とエタノールとの混液に溶解して、造粒液を得た。イミダフェナシンを含む混合粉末を撹拌造粒機に投入し、造粒液をスプレーして造粒した。得られた粒子を解砕し、真空定温乾燥機を用いて乾燥した後、整粒して、イミダフェナシンを含む粒子を得た。得られた粒子を流動層造粒機に投入し、ヒプロメロースを精製水に溶解したコーティング液Ｉをスプレーした後、乾燥及び整粒して、コーティング粒子Ｉを得た。エチルセルロース、酸化チタン、三二酸化鉄及びタルクを、精製水とエタノールとの混液中に分散させて、分散液を得た。得られたコーティング粒子Ｉを流動層造粒機に投入し、分散液をスプレーした後、乾燥及び整粒して、イミダフェナシンを含むコーティング粒子IIを得た。得られたコーティング粒子II、上記(1.1)で得た崩壊性粒子、エチルセルロース、クロスポピドン、軽質無水ケイ酸及びスクラロースを拡散式混合機に投入し、混合した。さらにステアリン酸マグネシウムを投入して混合し、打錠用粉末を得た。得られた打錠用粉末を、ロータリー式打錠機を用いて打錠し、実施例１の口腔内崩壊錠を得た。
(1.2) Production of Orally Disintegrating Tablets of Example 1 Table 1 shows the formulation (ingredient amount per tablet) of the orally disintegrating tablets of Example 1. This tablet was produced as follows. The imidafenacin drug substance powder and partially pregelatinized starch were mixed using a diffusion mixer to obtain a mixed powder. Meglumine and hydroxypropyl cellulose were dissolved in a mixed solution of purified water and ethanol to obtain a granulated solution. The mixed powder containing imidafenacin was put into a stirring granulator and sprayed with a granulating solution to granulate. The obtained particles were crushed, dried using a vacuum constant temperature dryer, and then sized to obtain particles containing imidafenacin. The obtained particles were put into a fluidized bed granulator, sprayed with a coating liquid I in which hypromellose was dissolved in purified water, and then dried and sized to obtain coated particles I. Ethyl cellulose, titanium oxide, iron sesquioxide and talc were dispersed in a mixed solution of purified water and ethanol to obtain a dispersion. The obtained coating particles I were put into a fluidized bed granulator, sprayed with a dispersion liquid, dried and sized to obtain coating particles II containing imidafenacin. The obtained coating particles II, the disintegrating particles obtained in (1.1) above, ethyl cellulose, crospopidone, light silicic anhydride and sucralose were put into a diffusion mixer and mixed. Further, magnesium stearate was added and mixed to obtain a powder for tableting. The obtained tableting powder was locked using a rotary locking machine to obtain an orally disintegrating tablet of Example 1.
(1.3) 比較例の口腔内崩壊錠の製造
表１に示されるように、比較例の口腔内崩壊錠の処方は、実施例１と同じである。比較例の口腔内崩壊錠を、次のようにして製造した。イミダフェナシン原薬粉末、メグルミン及びヒドロキシプロピルセルロースを、精製水とエタノールとの混液に溶解して、造粒液を得た。部分アルファー化デンプンを撹拌造粒機に投入し、造粒液をスプレーして造粒した。得られた粒子を解砕し、真空定温乾燥機を用いて乾燥した後、整粒して、イミダフェナシンを含む粒子を得た。得られた粒子を解砕し、真空定温乾燥機を用いて乾燥した後、整粒して、イミダフェナシンを含む粒子を得た。以降の工程は実施例１と同様にして、イミダフェナシンを含む粒子から、比較例の口腔内崩壊錠を得た。
(1.3) Production of Orally Disintegrating Tablets of Comparative Example As shown in Table 1, the formulation of the orally disintegrating tablet of Comparative Example is the same as that of Example 1. An orally disintegrating tablet of a comparative example was produced as follows. Imidafenacin drug substance powder, meglumine and hydroxypropyl cellulose were dissolved in a mixed solution of purified water and ethanol to obtain a granulated solution. The partially pregelatinized starch was put into a stirring granulator and sprayed with a granulating liquid to granulate. The obtained particles were crushed, dried using a vacuum constant temperature dryer, and then sized to obtain particles containing imidafenacin. The obtained particles were crushed, dried using a vacuum constant temperature dryer, and then sized to obtain particles containing imidafenacin. Subsequent steps were carried out in the same manner as in Example 1 to obtain an orally disintegrating tablet of Comparative Example from particles containing imidafenacin.
２．安定性試験
実施例１及び比較例の錠剤をそれぞれポリエチレン製の密閉容器に入れ、温度70℃の環境下で９日間貯蔵した。製造直後及び９日後の類縁物質の量を、次のように測定した。まず、錠剤を一定量の0.1 mol/L塩酸試液にて抽出し、メタノールを加えた後，メンブランフィルターでろ過して試料溶液を得た。各試料溶液を、下記の条件で液体クロマトグラフィーにより分析した。試料溶液の各々のピーク面積を自動積分法により測定し、面積百分率法によりそれらの量を求めた。
2. Stability test The tablets of Example 1 and Comparative Example were placed in a closed polyethylene container, respectively, and stored in an environment at a temperature of 70 ° C. for 9 days. The amount of related substances immediately after production and after 9 days was measured as follows. First, tablets were extracted with a constant amount of 0.1 mol / L hydrochloric acid TS, methanol was added, and the tablets were filtered through a membrane filter to obtain a sample solution. Each sample solution was analyzed by liquid chromatography under the following conditions. The peak area of each of the sample solutions was measured by the automatic integration method, and their amounts were determined by the area percentage method.
＜試験条件＞
検出器：紫外吸光光度計(測定波長：230 nm)
カラム： ACQUITY UPLC BEH C18 2.1 mm×15 cm，1.7μm
カラム温度：40℃付近の一定温度
移動相Ａ：リン酸水素二アンモニウム1.32 gを水1000 mLに溶かし、アンモニア水(28)を加えてpH 9.5に調整する。
移動相Ｂ：アセトニトリル
移動相の送液：移動相Ａ及び移動相Ｂの混合比を変えて濃度勾配制御した。
<Test conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength: 230 nm)
Column: ACQUITY UPLC BEH C18 2.1 mm x 15 cm, 1.7 μm
Column temperature: Constant temperature around 40 ° C Mobile phase A: Dissolve 1.32 g of diammonium hydrogen phosphate in 1000 mL of water and add aqueous ammonia (28) to adjust the pH to 9.5.
Mobile phase B: Acetonitrile Mobile phase liquid feed: The concentration gradient was controlled by changing the mixing ratio of the mobile phase A and the mobile phase B.
３．結果
表２に、各錠剤についての総類縁の量(%)を示す。総類縁とは、検出された全て類縁物質の合計である。
3. 3. Results Table 2 shows the total relative amount (%) for each tablet. The total association is the total of all related substances detected.
表２に示されるように、比較例の錠剤では、製造直後の時点で既に類縁物質が多く生じていた。これに対して、実施例１の錠剤では、製造直後において類縁物質は検出されなかった。この結果から、イミダフェナシンの粉末及び造粒液を用いて湿式造粒により粒子を得て、その粒子を用いて錠剤を製造することにより、錠剤の製造過程におけるイミダフェナシンの分解を抑制できることが示唆された。また、70℃で９日間の貯蔵後の類縁物質の生成量は、実施例１の錠剤では、比較例の錠剤に比べて顕著に抑制された。このことから、イミダフェナシンの粉末及び造粒液を用いて湿式造粒により粒子を得て、その粒子を用いて錠剤を製造することにより、保存期間中、温度(熱)に対して安定なイミダフェナシン含有製剤が得られることが示唆された。 As shown in Table 2, in the tablets of the comparative example, a large amount of related substances were already generated immediately after the production. On the other hand, in the tablet of Example 1, no related substance was detected immediately after production. From this result, it was suggested that the decomposition of imidafenacin in the tablet manufacturing process can be suppressed by obtaining particles by wet granulation using the imidafenacin powder and the granulating solution and manufacturing the tablets using the particles. .. In addition, the amount of related substances produced after storage at 70 ° C. for 9 days was significantly suppressed in the tablets of Example 1 as compared with the tablets of Comparative Examples. From this, particles are obtained by wet granulation using imidafenacin powder and granulation solution, and tablets are produced using the particles, whereby imidafenacin is contained stably with respect to temperature (heat) during the storage period. It was suggested that a formulation could be obtained.
Claims (12)
前記混合粉末と、結合剤を含む溶液又は懸濁液とを用いて、湿式造粒により、イミダフェナシンを含む粒子を得る工程と、
前記粒子を乾燥させる工程と
を含む、イミダフェナシンを含む粒子の製造方法。 A step of mixing an imidafenacin powder and an excipient to obtain a mixed powder,
A step of obtaining particles containing imidafenacin by wet granulation using the mixed powder and a solution or suspension containing a binder.
A method for producing particles containing imidafenacin, which comprises a step of drying the particles.
前記混合粉末と、結合剤を含む溶液又は懸濁液とを用いて、湿式造粒により、イミダフェナシンを含む粒子を得る工程と、
前記粒子を乾燥させる工程と、
乾燥させた前記粒子と、錠剤用添加物とを混合して、打錠用粉末を得る工程と、
前記打錠用粉末を圧縮成型して錠剤を得る工程と
を含む、イミダフェナシンを有効成分とする錠剤の製造方法。 The process of mixing imidafenacin powder and excipients to obtain a mixed powder,
A step of obtaining particles containing imidafenacin by wet granulation using the mixed powder and a solution or suspension containing a binder.
The step of drying the particles and
A step of mixing the dried particles with a tablet additive to obtain a tableting powder.
A method for producing a tablet containing imidafenacin as an active ingredient, which comprises a step of compression-molding the tableting powder to obtain a tablet.
前記混合粉末と、結合剤を含む溶液又は懸濁液とを用いて、湿式造粒により、イミダフェナシンを含む粒子を得る工程と、
前記粒子を乾燥させる工程と、
乾燥させた前記粒子と、崩壊性粒子と、錠剤用添加物とを混合して、打錠用粉末を得る工程と、
前記打錠用粉末を圧縮成型して口腔内崩壊錠を得る工程と
を含む、イミダフェナシンを有効成分とする口腔内崩壊錠の製造方法。 A step of mixing an imidafenacin powder and an excipient to obtain a mixed powder,
A step of obtaining particles containing imidafenacin by wet granulation using the mixed powder and a solution or suspension containing a binder.
The step of drying the particles and
A step of mixing the dried particles, disintegrating particles, and a tablet additive to obtain a tableting powder.
A method for producing an orally disintegrating tablet containing imidafenacin as an active ingredient, which comprises a step of compression-molding the tableting powder to obtain an orally disintegrating tablet.
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