JP2018177789A - Solid pharmaceutical composition containing solifenacin succinate - Google Patents
Solid pharmaceutical composition containing solifenacin succinate Download PDFInfo
- Publication number
- JP2018177789A JP2018177789A JP2018077321A JP2018077321A JP2018177789A JP 2018177789 A JP2018177789 A JP 2018177789A JP 2018077321 A JP2018077321 A JP 2018077321A JP 2018077321 A JP2018077321 A JP 2018077321A JP 2018177789 A JP2018177789 A JP 2018177789A
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- JP
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- Prior art keywords
- pharmaceutical composition
- solid pharmaceutical
- solifenacin succinate
- group
- content
- 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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- FBOUYBDGKBSUES-KEKNWZKVSA-N 1-azabicyclo[2.2.2]octan-3-yl (1s)-1-phenyl-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(OC2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-KEKNWZKVSA-N 0.000 title claims abstract description 107
- 229960001368 solifenacin succinate Drugs 0.000 title claims abstract description 107
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- FBOUYBDGKBSUES-VXKWHMMOSA-N solifenacin Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(O[C@@H]2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-VXKWHMMOSA-N 0.000 description 7
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は，コハク酸ソリフェナシンを含有する固形医薬組成物に関し，特に，非晶質体コハク酸ソリフェナシンを含有する固形医薬組成物に関する。 The present invention relates to a solid pharmaceutical composition containing solifenacin succinate, and more particularly to a solid pharmaceutical composition containing amorphous solifenacin succinate.
ソリフェナシンは，次式（１）で示される抗コリン作動薬であり，アセチルコリン受容体のうちムスカリン受容体，特にＭ３受容体に対する選択的な拮抗作用を有する。この作用に基づき，ソリフェナシンは，膀胱の平滑筋の緊張を低下させて膀胱に貯留される尿量を増加させることから，頻尿，尿意切迫感，尿失禁等の泌尿器疾患の治療及び予防に有用な成分として知られている。 Solifenacin is an anticholinergic agent represented by the following formula (1), and has selective antagonism of a muscarinic receptor, particularly an M 3 receptor, among acetylcholine receptors. Based on this action, solifenacin is useful for treatment and prevention of urological diseases such as frequent urination, urinary urgency and urinary incontinence since it reduces the smooth muscle tone of the bladder and increases the amount of urine stored in the bladder. Component is known as
上記用途の固形医薬組成物として，ソリフェナシンはコハク酸塩の形で使用されている。コハク酸ソリフェナシンには結晶体と非晶質体とが存在し，両形態は，同薬物自体の製造工程の諸条件やこれを主薬として含む固形医薬組成物の組成に依存して，単一の化合物中や組成物中に混在する結果となり易い。例えば，結晶体コハク酸ソリフェナシンを原料として製造された固形医薬組成物において，製造過程で非晶質体が高い割合で生成することが知られており，またこの非晶質体が固形医薬組成物におけるコハク酸ソリフェナシンの経時的分解の主たる原因であること，更に，製造過程でコハク酸ソリフェナシンの非晶質化が生じるのを抑制して，非晶質体の割合をコハク酸ソリフェナシン全体の一定レベル以下に収める方法も知られている（特許文献１）。 As a solid pharmaceutical composition for the above-mentioned applications, solifenacin is used in the form of succinate. Solifenacin succinate has a crystalline form and an amorphous form, and both forms are single depending on the conditions of the production process of the drug itself and the composition of the solid pharmaceutical composition containing it as a main drug. It tends to be mixed in the compound or in the composition. For example, in a solid pharmaceutical composition manufactured from crystalline solifenacin succinate as a raw material, it is known that a high proportion of an amorphous form is produced in the manufacturing process, and this amorphous form is a solid pharmaceutical composition. It is the main cause of the degradation of solifenacin succinate over time, and further suppresses the occurrence of amorphization of solifenacin succinate in the production process, and the ratio of the amorphous form to a certain level of solifenacin succinate overall There is also known a method to be described below (Patent Document 1).
他方，非晶質体のコハク酸ソリフェナシンを，固形医薬組成物中において安定化させるための試みも行われている。例えば，ソリフェナシン又はその塩の非晶質体に，クエン酸又はその塩，ピロ亜硫酸ナトリウム及びエチレンジアミン四酢酸塩から選択される１種又は２種以上を配合することにより，非晶質体の経時的な分解を抑制し得ること（特許文献２），安定化剤としてＰＥＧ，НРМС，МС，ＰＶＰ，ＰＶＰ−ＶＡ，ＰＶＡ，ポリメタクリレート，ソルビトール，マンニトール，マルチトール，オイドラギット Е，コリドン ＶＡ ６４，イソマルト等で被覆することにより結晶化を防止して非晶質体の状態を維持し得ること（特許文献３），ソリフェナシン又はその塩の非晶質体にリンゴ酸又はその塩及びメグルミン又はその塩から選択される少なくとも１種を配合することにより，非晶質体の状態を維持し得ること（特許文献４），ソリフェナシンに酒石酸，フマル酸及びコハク酸，マレイン酸から選ばれる１種以上を配合することにより非晶質体の形態を維持し得ること（特許文献５）が知られている。 On the other hand, attempts have also been made to stabilize the amorphous form of solifenacin succinate in solid pharmaceutical compositions. For example, by blending one or more selected from citric acid or its salt, sodium metabisulfite and ethylenediaminetetraacetic acid into the amorphous form of solifenacin or its salt, temporally the amorphous form Can suppress the decomposition (Patent Document 2), PEG as stabilizer, НРМС, МС, PVP, PVP-VA, PVA, polymethacrylate, sorbitol, mannitol, maltitol, Eudragit Е, Kollidon VA 64, isomalt etc. To prevent crystallization and maintain the amorphous state by coating with (see Patent Document 3), and select from malic acid or its salt and meglumine or its salt as the amorphous form of solifenacin or its salt It is possible to maintain the state of an amorphous form by blending at least one selected (Patent Document 4), solifenacin Tartaric, fumaric acid and succinic acid, it capable of maintaining the form of the amorphous substance (Patent Document 5) is known by blending one or more selected from maleic acid.
上記の背景において，本発明の一目的は，コハク酸ソリフェナシンを主薬として含んでなる固形医薬組成物であって，コハク酸ソリフェナシンが非晶質体であり，且つ，保存中に，コハク酸ソリフェナシンを非晶質体として維持でき（物理的安定化），その分解による不純物生成も抑制できる（化学的安定化）という特徴を備えた組成物を提供することにある。 In the above background, one object of the present invention is a solid pharmaceutical composition comprising solifenacin succinate as a main drug, wherein solifenacin succinate is amorphous and during storage, solifenacin succinate is It is an object of the present invention to provide a composition having the characteristics of being able to be maintained as an amorphous substance (physical stabilization) and capable of suppressing the formation of impurities due to its decomposition (chemical stabilization).
上記の目的のために検討の結果，本発明者は，非晶質体コハク酸ソリフェナシンを主薬とする固形製剤の処方化において，特定の化合物を配合することで，固形製剤製造時における結晶化を防止して，コハク酸ソリフェナシンを非晶質体として含む固形製剤を製造することができ，且つ保存中における結晶生成も十分に防止して非晶質体の形態を維持できること，及び別の特定の化合物を更に配合することで，非晶質体コハク酸ソリフェナシンを化学的に安定化させて分解による類縁物質の生成を抑制できることを見出し，これらの発見に基づき検討を重ねて本発明を完成させた。即ち，本発明は以下を提供する。 As a result of examination for the above-mentioned purpose, the present inventor, in formulating a solid preparation containing amorphous solifenate succinate as the main drug, the crystallization during the preparation of the solid preparation by blending a specific compound To prevent the formation of a solid preparation containing solifenacin succinate as an amorphous form, and to sufficiently prevent the formation of crystals during storage to maintain the form of the amorphous form, and other specific By further blending the compound, it has been found that the amorphous form of solifenacin succinate can be chemically stabilized to suppress the formation of a related substance by decomposition, and the present invention has been completed by repeating studies based on these findings. . That is, the present invention provides the following.
１．コハク酸ソリフェナシンを含んでなる固形医薬組成物であって，コハク酸ソリフェナシンが非晶質体であり，且つ安息香酸ナトリウム，亜硫酸ナトリウム，リン酸水素カルシウム，ソルビン酸，及びＬ−システイン塩酸塩からなる第１群より選ばれる１又は２以上の化合物を含むものである，固形医薬組成物。
２．親油性抗酸化剤を更に含むものである，上記１の固形医薬組成物。
３．該親油性抗酸化剤が，ジブチルヒドロキシトルエン，ジブチルヒドロキシアニソール，アスコルビン酸ステアリン酸エステル及びトコフェロールからなる群より選ばれるものである，上記２の固形医薬組成物。
４．該第１群より選ばれる化合物が，安息香酸ナトリウムである，上記１〜３の何れかの固形医薬組成物。
５．賦形剤及び結合剤を更に含むものである，上記１〜４の何れかの固形医薬組成物。
６．該組成物におけるコハク酸ソリフェナシン含量が１．４〜４重量％である，上記１〜５の何れかの固形医薬組成物。
７．該組成物における該第１群の化合物の含量が１〜１０重量％である，上記１〜６の何れかの固形医薬組成物。
８．該組成物における親油性抗酸化剤の含量が０．０１〜３．３重量％である，上記１〜７の何れかの固形医薬組成物。
９．該組成物における該１群の化合物の含量が，コハク酸ソリフェナシンの含量に対し，重量比で０．３〜６倍である，上記１〜７の何れかの固形医薬組成物。
１０．該組成物における親油性抗酸化剤の含量が，コハク酸ソリフェナシンの含量に対し，重量比で０．００３〜２倍である，上記１〜９の何れかの固形医薬組成物。
１１．該賦形剤が，単糖類，二糖類等，糖アルコール，デンプン類，結晶セルロース，セルロース誘導体，デキストラン，及びデキストリンからなる群より選ばれる１種又は２種以上である，上記１〜１０の何れかの固形医薬組成物。
１２．該結合剤が，ヒドロキシプロピルメチルセルロース，ヒドロキシプロピルセルロース，メチルセルロース，及びポリビニルピロリドンからなる群より選ばれるものである，上記１〜１１の何れかの固形医薬組成物。
１３．錠剤，散剤，顆粒剤，カプセル剤又は丸剤の形態である，上記１〜１２の何れかの固形医薬組成物。
１４．非晶質体コハク酸ソリフェナシンを薬効成分として含んでなる，錠剤の形態の固形医薬組成物の製造方法であって，賦形剤の粉末を，コハク酸ソリフェナシンと，少なくとも１種の結合剤と，安息香酸ナトリウム，亜硫酸ナトリウム，リン酸水素カルシウム，ソルビン酸，及びＬ−システイン塩酸塩からなる第１群より選ばれる１又は２以上の化合物とを含んでなる溶液で造粒することを含む顆粒製造工程を含み，得られた顆粒に滑沢剤を含んでなる添加剤を添加，混合して打錠することを含むものである，製造方法。
１５．該顆粒製造工程が，該造粒後に造粒物に親油性抗酸化剤を添加することを含んでなるものである，上記１４の製造方法。
１６．該親油性抗酸化剤が，ジブチルヒドロキシトルエン，ジブチルヒドロキシアニソール，アスコルビン酸ステアリン酸エステル及びトコフェロールからなる群より選ばれるものである，上記１５の製造方法。
１７．該親油性抗酸化剤の添加が，該親油性抗酸化剤の溶液を該造粒物に噴霧し乾燥させることにより行われるものである，上記１５又は１６の製造方法。
１８．該第１群より選ばれる化合物が，安息香酸ナトリウムである，上記１４〜１７の何れかの製造方法。
１９．該組成物におけるコハク酸ソリフェナシンの含量が１．４〜４重量％である，上記１３〜１８の何れかの製造方法。
２０．該組成物における該第１群より選ばれる化合物の含量が１〜１０重量％である，上記１４〜１９の何れかの製造方法。
２１．該組成物における該親油性抗酸化剤の含量が０．０１〜３．３重量％である，上記１４〜２０の何れかの製造方法。
２２．該組成物における該１群より選ばれる化合物の含量が，コハク酸ソリフェナシンの含量に対し，重量比で０．３〜６倍である，上記１４〜２１の何れかの製造方法。
２３．該組成物における該親油性抗酸化剤の含量が，コハク酸ソリフェナシンの含量に対し，重量比で０．００３〜２倍である，上記１４〜２２の何れかの製造方法。
２４．該賦形剤が，単糖類，二糖類等，糖アルコール，デンプン類，結晶セルロース，デキストラン，及びデキストリンからなる群より選ばれる１種又は２種以上である，上記１４〜２３の何れかの製造方法。
２５．該結合剤が，ヒドロキシプロピルメチルセルロース，他のヒドロキシプロピルセルロース，ポリビニルピロリドン及びメチルセルロースからなる群より選ばれるものである，上記１４〜２４の何れかの製造方法。
２６．得られた錠剤にコーティングを施すステップを更に含む，上記１４〜２５の何れかの製造方法。
1. A solid pharmaceutical composition comprising solifenacin succinate, wherein solifenacin succinate is amorphous and consists of sodium benzoate, sodium sulfite, calcium hydrogen phosphate, sorbic acid, and L-cysteine hydrochloride. A solid pharmaceutical composition comprising one or more compounds selected from the first group.
2. The solid pharmaceutical composition according to the above 1, further comprising a lipophilic antioxidant.
3. 3. The solid pharmaceutical composition according to 2 above, wherein said lipophilic antioxidant is selected from the group consisting of dibutyl hydroxytoluene, dibutyl hydroxyanisole, ascorbic acid stearate and tocopherol.
4. The solid pharmaceutical composition according to any one of the above 1 to 3, wherein the compound selected from the first group is sodium benzoate.
5. The solid pharmaceutical composition according to any one of the above 1 to 4, further comprising an excipient and a binder.
6. The solid pharmaceutical composition according to any one of the above 1 to 5, wherein the content of solifenacin succinate in the composition is 1.4 to 4% by weight.
7. The solid pharmaceutical composition according to any one of the above 1 to 6, wherein the content of the compound of the first group in the composition is 1 to 10% by weight.
8. The solid pharmaceutical composition according to any one of the above 1 to 7, wherein the content of the lipophilic antioxidant in the composition is 0.01 to 3.3% by weight.
9. The solid pharmaceutical composition according to any one of the above 1 to 7, wherein the content of the group 1 compound in the composition is 0.3 to 6 times by weight the content of solifenacin succinate.
10. The solid pharmaceutical composition according to any one of the above 1 to 9, wherein the content of the lipophilic antioxidant in the composition is 0.003 to 2 times by weight the content of solifenacin succinate.
11. Any of the above 1 to 10, wherein the excipient is one or more selected from the group consisting of monosaccharides, disaccharides, etc., sugar alcohols, starches, crystalline cellulose, cellulose derivatives, dextrans, and dextrins. Solid pharmaceutical composition.
12. 12. The solid pharmaceutical composition according to any one of the above 1 to 11, wherein the binder is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and polyvinyl pyrrolidone.
13. The solid pharmaceutical composition according to any one of the above 1 to 12, which is in the form of a tablet, a powder, a granule, a capsule or a pill.
14. A method for producing a solid pharmaceutical composition in the form of a tablet, comprising amorphous amorphous solifenacin succinate as a medicinal ingredient, which is a powder of an excipient, solifenacin succinate and at least one binder, Granule production including granulation with a solution comprising one or more compounds selected from the first group consisting of sodium benzoate, sodium sulfite, calcium hydrogen phosphate, sorbic acid, and L-cysteine hydrochloride Including the steps of: adding an additive comprising a lubricant to the obtained granules, mixing and tableting.
15. 15. The method according to 14 above, wherein the granule production step comprises adding a lipophilic antioxidant to the granule after the granulation.
16. The method according to above 15, wherein the lipophilic antioxidant is selected from the group consisting of dibutylhydroxytoluene, dibutylhydroxyanisole, ascorbic acid stearate and tocopherol.
17. The method according to the above 15 or 16, wherein the addition of the lipophilic antioxidant is carried out by spraying a solution of the lipophilic antioxidant onto the granules and drying.
18. The method according to any one of 14 to 17, wherein the compound selected from the first group is sodium benzoate.
19. The method according to any of the above 13 to 18, wherein the content of solifenacin succinate in the composition is 1.4 to 4% by weight.
20. The method according to any one of 14 to 19, wherein the content of the compound selected from the first group in the composition is 1 to 10% by weight.
21. The method according to any of 14 to 20, wherein the content of the lipophilic antioxidant in the composition is 0.01 to 3.3% by weight.
22. 15. The method according to any one of 14 to 21 above, wherein the content of the compound selected from the first group in the composition is 0.3 to 6 times by weight the content of solifenacin succinate.
23. The method according to any of the above 14 to 22, wherein the content of the lipophilic antioxidant in the composition is 0.003 to 2 times by weight the content of solifenacin succinate.
24. The preparation according to any of the above 14 to 23, wherein the excipient is one or more selected from the group consisting of monosaccharides, disaccharides, etc., sugar alcohols, starches, crystalline cellulose, dextran, and dextrin. Method.
25. The method according to any of 14 to 24, wherein the binder is selected from the group consisting of hydroxypropyl methylcellulose, other hydroxypropyl cellulose, polyvinyl pyrrolidone and methyl cellulose.
26. The method according to any of the above 14 to 25, further comprising the step of applying a coating to the obtained tablet.
上記構成になる本発明によれば，製造工程やその後の保存中におけるコハク酸ソリフェナシンの結晶化を十分に防止（物理的安定化）して，非晶質体であるコハク酸ソリフェナシン含む固形医薬組成物を提供することができる。また，本発明によれば，結晶に比べて化学的安定性が低下し分解物を生じやすい性質を持つ非晶質体コハク酸ソリフェナシンであるにも関わらず，その安定性を高め（化学的安定化），製造工程並びにその後の保存時における分解を抑制することができる。 According to the present invention configured as described above, a solid pharmaceutical composition containing solifenacin succinate, which is an amorphous substance, with sufficient prevention (physical stabilization) of crystallization of solifenacin succinate during the manufacturing process and subsequent storage Can provide the goods. Moreover, according to the present invention, although it is an amorphous form of solifenacin succinate which has a property that chemical stability is lower than that of crystals and it is easy to generate a degradation product, its stability is enhanced (chemical stability (chemical stability Decomposition) during the production process and subsequent storage.
本発明において，「固形医薬組成物」の語は，固形の医薬組成物を特に限定なく包含し，錠剤，散剤，顆粒剤，カプセル剤，丸剤を含む。これらのうち，製造，取扱い及び服用の便利さにおいて，錠剤が特に好ましい。錠剤の例としては，裸錠，糖衣錠，フィルムコーティング錠，徐放性錠，腸溶錠，舌下錠，口内崩壊錠（ＯＤ錠）等が挙げられるが，これらに限定されない。 In the present invention, the term "solid pharmaceutical composition" includes, without limitation, solid pharmaceutical compositions, and includes tablets, powders, granules, capsules and pills. Of these, tablets are particularly preferred for their convenience of manufacture, handling and dosing. Examples of tablets include, but are not limited to, plain tablets, sugar-coated tablets, film-coated tablets, sustained release tablets, enteric-coated tablets, sublingual tablets, orally disintegrating tablets (OD tablets) and the like.
本発明において，試料中のコハク酸ソリフェナシンが非晶質体であるというときは，当該試料の粉末Ｘ線回折（ＸＲＤ）像において，コハク酸ソリフェナシンが結晶体の場合に見られるべきピークが，僅かしか又は実質的に認められないことをいい，より具体的には，結晶体の場合に認められる複数のピークに対して，同位置にピークが認められる場合でもそれらのピークの総面積が，全てが結晶体である場合のピークの総面積に比べて好ましくは２０％以下，より好ましくは１５％以下，更に好ましくは１０％以下，尚も好ましくは５％以下，特に好ましくは１％以下であることをいう。 In the present invention, when solifenacin succinate in a sample is in an amorphous form, the peak to be observed when solifenacin succinate is a crystalline form in the powder X-ray diffraction (XRD) image of the sample is slightly It can be said that it is not recognized or is substantially recognized. More specifically, with respect to a plurality of peaks observed in the case of a crystal, the total area of all the peaks is recognized even if the peaks are observed at the same position. Is preferably 20% or less, more preferably 15% or less, still more preferably 10% or less, still more preferably 5% or less, particularly preferably 1% or less, as compared to the total area of the peaks when crystalline It means that.
本発明の固形医薬組成物において，安息香酸ナトリウム，亜硫酸ナトリウム，リン酸水素カルシウム，ソルビン酸，及びＬ−システイン塩酸塩からなる第１群の化合物は，コハク酸ソリフェナシンの結晶化を防止して非晶質体として安定化させる安定化剤（第１群の安定化剤）として機能し，これらから選ばれる１種又は２種以上を用いることができる。これらのうち安息香酸ナトリウムが特に好ましい。 In the solid pharmaceutical composition of the present invention, the first group of compounds consisting of sodium benzoate, sodium sulfite, calcium hydrogen phosphate, sorbic acid and L-cysteine hydrochloride prevents crystallization of solifenacin succinate and prevents It functions as a stabilizer that stabilizes as a crystalline substance (stabilizer of the first group), and one or more selected from these can be used. Of these, sodium benzoate is particularly preferred.
また本発明の固形医薬組成物において，上記第１群の安定化剤に加えて，組成物中において非晶質体の状態で維持されるコハク酸ソリフェナシンの分解を抑制するために，化学的安定化剤として親油性抗酸化剤を配合することがより好ましい。特に好ましい親油性抗酸化剤の例としては，ジブチルヒドロキシトルエン，並びにこれと同様に化学構造中にフェノール性水酸基を１個有する抗酸化剤であるジブチルヒドロキシアニソール及びトコフェロールや，アスコルビン酸ステアリン酸エステルが挙げられる。 Further, in the solid pharmaceutical composition of the present invention, in addition to the above-mentioned stabilizer of the first group, the compound is chemically stable in order to suppress the decomposition of solifenacin succinate which is maintained in the amorphous state in the composition. It is more preferable to incorporate a lipophilic antioxidant as an agent. Examples of particularly preferred lipophilic antioxidants include dibutyl hydroxytoluene and dibutyl hydroxyanisole and tocopherol which are antioxidants having one phenolic hydroxyl group in the chemical structure as well as this, and ascorbic acid stearic acid ester. It can be mentioned.
本発明の固形医薬組成物におけるコハク酸ソリフェナシンの含量は，１．４〜４重量％であることが好ましい。なお，本発明の固形医薬組成物の重量に対する各成分の含量を重量％で表示するに際し，当該固形医薬組成物がコーティング錠の形態である場合には，組成物の重量としてコーティング直前の錠剤（素錠）の重量を用いる。コーティング層は素錠の表面を覆うに止まり，主薬であるコハク酸ソリフェナシンと安定化剤，賦形剤等の添加剤が接触するのは，素錠中においてだからである。 The content of solifenacin succinate in the solid pharmaceutical composition of the present invention is preferably 1.4 to 4% by weight. In addition, when displaying the content of each component with respect to the weight of the solid pharmaceutical composition of the present invention in weight%, when the solid pharmaceutical composition is in the form of a coated tablet, the tablet just before coating is used as the weight of the composition ( Use the weight of the uncoated tablet). The coating layer only covers the surface of the uncoated tablet, and the main agent solifenacin succinate is in contact with additives such as stabilizers and excipients because it is in the uncoated tablet.
本発明の固形医薬組成物中において，第１群より選ばれる化合物に安定化の効果を発揮させる上で非晶質体コハク酸ソリフェナシンの量（重量）に対し配合する当該化合物の量（重量比）（複数種を配合するときはそれらの合計）に特に明確な上限，下限はないが，０．３〜６倍であることが一般に好ましく，０．４〜４倍であることがより好ましく，０．５〜３倍であることが更に好ましい。 In the solid pharmaceutical composition of the present invention, the amount (weight ratio) of the compound to be blended with the amount (weight) of the amorphous form solifenacin succinate in order to exert the stabilizing effect on the compound selected from the first group ) (There are no distinct upper and lower limits to the combination of two or more types, but it is generally preferred to be 0.3 to 6 times, more preferably 0.4 to 4 times, More preferably, it is 0.5 to 3 times.
また，非晶質体コハク酸ソリフェナシンの量（重量）に対するジブチルヒドロキシトルエン等の親油性抗酸化剤の配合量（重量比）にも，特に明確な上限，下限はないが，０．００３〜２倍の範囲で適宜設定することができる。従って例えば，０．００３倍，０．００６倍，０．０１５倍，０．０２倍，０．０５倍，０．１倍，０．３倍，０．５倍，１倍，２倍等から適宜選ばれる２つの値を両端とする範囲として設定できる。 Also, the blending amount (weight ratio) of a lipophilic antioxidant such as dibutyl hydroxytoluene to the amount (weight) of amorphous amorphous solifenacin succinate is not particularly upper and lower limits, though it is 0.003 to 2 It can be set appropriately in the range of double. Therefore, for example, from 0.003 times, 0.006 times, 0.015 times, 0.02 times, 0.02 times, 0.05 times, 0.1 times, 0.3 times, 0.5 times, 1 times, 2 times etc. It can set as a range which makes two values chosen suitably an end.
また，本発明の固形医薬組成物における第１群より選ばれる化合物の含量は，好ましくは１〜１０重量％，より好ましくは，１．３〜６．７重量％，更に好ましくは２〜５重量％，特に好ましくは３〜４重量％である。 The content of the compound selected from Group 1 in the solid pharmaceutical composition of the present invention is preferably 1 to 10% by weight, more preferably 1.3 to 6.7% by weight, still more preferably 2 to 5%. %, Particularly preferably 3 to 4% by weight.
また，本発明の固形医薬組成物におけるジブチルヒドロキシトルエン等の親油性抗酸化剤の含量に明確な上限，下限はないが，例えば０．０１重量％〜３．３重量％の範囲で適宜設定することができる。従って例えば，０．０１重量％，０．０２重量％，０．０３重量％，０．０５重量％，０．１重量％，０．３重量％，０．７重量％，１．５重量％，２重量％，２．７重量％，及び３．３重量％から適宜選ばれる２つの値を両端とする範囲として設定できる。 In addition, the content of lipophilic antioxidant such as dibutyl hydroxytoluene in the solid pharmaceutical composition of the present invention does not have a clear upper limit or lower limit, but is appropriately set, for example, in the range of 0.01 wt% to 3.3 wt% be able to. Thus, for example, 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.05 wt%, 0.1 wt%, 0.3 wt%, 0.7 wt%, 1.5 wt% , 2 wt%, 2.7 wt%, and 3.3 wt% can be set as a range having two values selected as appropriate.
本発明の目的に反しない限り，本発明の固形医薬組成物には，その個々の具体的な製剤形態に応じて，賦形剤，結合剤，崩壊剤，滑沢剤，コーティング剤，発泡剤，その他，固形医薬組成物の製造に使用される慣用の添加剤を１種又は２種以上を適宜選択して配合することができる。 The solid pharmaceutical composition of the present invention may, depending on its specific formulation form, an excipient, a binder, a disintegrant, a lubricant, a coating agent, a foaming agent, unless it is against the object of the present invention. In addition, one or two or more conventional additives used for producing a solid pharmaceutical composition can be appropriately selected and blended.
賦形剤としては，ブドウ糖，粉糖，乳糖のような単糖類，二糖類等，マンニトール等の糖アルコール，トウモロコシデンプンなどのようなデンプン類，結晶セルロース，ヒドロキシプロピルメチルセルロース，ヒドロキシプロピルセルロース，低置換度ヒドロキシプロピルセルロース等のセルロース誘導体，デキストラン，デキストリン等が挙げられるが，これらに限定されない。 Excipients include glucose, powdered sugar, monosaccharides such as lactose, disaccharides, sugar alcohols such as mannitol, starches such as corn starch, crystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, low substitution And cellulose derivatives such as hydroxypropyl cellulose, dextran, dextrin and the like, but not limited thereto.
結合剤の例としては，ヒドロキシプロピルメチルセルロース，ヒドロキシプロピルセルロース，メチルセルロース，エチルセルロース等のセルロース誘導体，部分アルファー化デンプン，ポリビニルピロリドン，ポリビニルアルコール，ポリエチレングリコール等が挙げられるが，これらに限定されない。 Examples of the binder include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose derivatives such as methyl cellulose and ethyl cellulose, partially pregelatinized starch, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and the like.
崩壊剤の例としては，トウモロコシデンプン，馬鈴薯デンプン等のデンプン類，部分アルファー化デンプン，カルメロース，カルメロースカルシウム，クロスカルメロースナトリウム，クロスポビドン，低置換度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等が挙げられるが，これらに限定されない。 Examples of disintegrants include corn starch, starches such as potato starch, partially pregelatinized starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose and the like. However, it is not limited to these.
滑沢剤の例としては，ステアリン酸，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，硬化油，フマル酸ステアリルナトリウム，ショ糖脂肪酸エステル等が挙げられるが，これらに限定されない。 Examples of lubricants include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated oil, sodium stearyl fumarate, sucrose fatty acid ester and the like.
コーティング剤の例としては，ヒドロキシプロピルメチルセルロース，タルク，酸化チタン，黄色三二酸化鉄，及び乳糖等が挙げられるが，これらに限定されない。 Examples of coating agents include, but are not limited to, hydroxypropyl methylcellulose, talc, titanium oxide, yellow ferric oxide, and lactose.
発泡剤の例としては，炭酸水素ナトリウム等が挙げられる。 Examples of the blowing agent include sodium hydrogen carbonate and the like.
本発明の固形医薬組成物の製造方法は特定の方法に限定されず，当業者は適宜所望により設計することできる。例えば，
（ａ）結晶体コハク酸ソリフェナシンと，結合剤と，第１群の安定化剤のうち少なくとも１種とを含む溶液（例えば，アルコール水混液による溶液）を準備し，賦形剤粉末を含む流動層にこれを噴霧して造粒し，必要に応じてジブチルヒドロキシトルエン等の親油性抗酸化剤も溶液（例えば，アルコール水混液による溶液）の形で，（例えば噴霧する等により）更に加え，必要に応じて乾燥させ，得られた顆粒と，滑沢剤を含む添加剤とを混合して打錠するか；
（ｂ）賦形剤粉末と第１群の安定化剤のうち少なくとも１種の粉末とを含む流動層に，結晶体コハク酸ソリフェナシンと，結合剤とを含む溶液（例えば，水溶液）を噴霧して造粒し，必要に応じてジブチルヒドロキシトルエン等の親油性抗酸化剤も溶液（例えば，アルコール水混液による溶液）の形で，（例えば噴霧する等により）更に加え，必要に応じて乾燥させ，得られた顆粒と，滑沢剤を含む添加剤とを混合して打錠するか；又は
（ｃ）結晶体コハク酸ソリフェナシンと，結合剤と，第１群の安定化剤の少なくとも１種とを含む溶液，ジブチルヒドロキシトルエン等の親油性抗酸化剤を含む溶液（例えば，アルコール溶液），及び賦形剤を含む粉末を，混合して練合し，乾燥，粉砕，整粒して，これに滑沢剤を含む添加剤を混合して打錠する方法
が挙げられるが，これらに限定されず，錠剤の製造における慣用の方法を用いて製造することができる。
The method for producing the solid pharmaceutical composition of the present invention is not limited to a specific method, and can be designed as desired by those skilled in the art. For example,
(A) Prepare a solution (for example, a solution of a mixture of alcohol and water) containing crystalline solifenacin succinate, a binder, and at least one of the first group of stabilizers, and include an excipient powder The layer is sprayed and granulated, and if necessary, a lipophilic antioxidant such as dibutyl hydroxytoluene is also added (eg, by spraying) in the form of a solution (eg, a solution of an alcohol water mixture), If necessary, dry and mix the obtained granules with an additive containing a lubricant and compress into tablets;
(B) Spray a solution (for example, an aqueous solution) containing crystalline solifenacin succinate and a binder in a fluid bed containing an excipient powder and at least one powder of the first group of stabilizers Granulate, and if necessary, add a lipophilic antioxidant such as dibutyl hydroxytoluene in the form of a solution (for example, a solution of an alcohol water mixture) (for example, by spraying) and dry it if necessary. (C) crystalline solifenacin succinate, a binder, and at least one of a first group of stabilizers, and tableted by mixing the obtained granules with an additive containing a lubricant; And a solution containing a lipophilic antioxidant such as dibutyl hydroxytoluene (for example, an alcohol solution), and a powder containing an excipient are mixed, kneaded, dried, crushed, and sized, Add additives including lubricant to this and Methods of locking include, but are not limited to, methods which can be manufactured using conventional methods in the manufacture of tablets.
本発明において，錠剤をコーティング錠の形態で提供する場合，コーティングは，糖衣やフィルムコーティング等，錠剤のコーティングにおいて慣用されている種々の方法から，目的に応じ任意に選んで用いることができる。例えば，フィルムコーティング錠は，ヒドロキシプロピルメチルセルロース，ヒドロキシプロピルセルロース，タルク，酸化チタン，着色剤等の慣用の材料を適宜用いて調製した水分散液を素錠に噴霧し乾燥させることで製造することができる。 In the present invention, when the tablet is provided in the form of a coated tablet, the coating can be optionally selected from various methods commonly used in tablet coating, such as sugar coating and film coating, according to the purpose. For example, film-coated tablets can be produced by spraying and drying an aqueous dispersion prepared using conventional materials such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, talc, titanium oxide, coloring agents and the like, as appropriate. it can.
なお，コハク酸ソリフェナシンは，経時的に分解が起こった場合，主たる類縁物質としてＮ−オキシド体を生成することが知られている。保存中における本発明の固形医薬組成物中のコハク酸ソリフェナシンの化学的安定性は，コハク酸ソリフェナシンそれ自体の残存量を測定することにより判断できるが，分解前には存在しないＮ−オキシド体の生成を検出し定量することにより，僅かな分解でも確実に捉えることができるため，長期保存下の安定性の予測を行うための便利な指標として，利用することができる。 In addition, it is known that solifenacin succinate produces N-oxide as a main analogue when degradation occurs with time. Although the chemical stability of solifenacin succinate in the solid pharmaceutical composition of the present invention during storage can be judged by measuring the residual amount of solifenacin succinate itself, it is not present before decomposition of N-oxide By detecting and quantifying the formation, even a slight decomposition can be reliably captured, and therefore, it can be used as a convenient index for predicting the stability under long-term storage.
以下，実施例を参照して本発明を更に詳細に説明するが，本発明がそれらの実施例に限定されることは意図しない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not intended to be limited to these examples.
１．固形医薬組成物でのコハク酸ソリフェナシン安定性検討（安定剤不含）
（１）錠剤の製造
コハク酸ソリフェナシン（結晶体原薬）を用いて，従来処方である特許文献１の実施例１に準じ（但し，フィルムコーティング工程は省く），表１に示す組成で結晶体コハク酸ソリフェナシンを含有する錠剤１を下記手順により製造すると共に，同じ組成で，但し結晶体コハク酸ソリフェナシンの溶解工程を含む手順により，非晶質体コハク酸ソリフェナシンを含んでなる錠剤２を製造した。
1. Solifenacin succinate stability study in solid pharmaceutical composition (stabilizer free)
(1) Production of tablet Based on solifenacin succinate (crystalline drug substance), according to Example 1 of Patent Document 1 which is a conventional formulation (however, the film coating step is omitted), crystalline substance having the composition shown in Table 1 A tablet 1 containing solifenacin succinate was prepared according to the following procedure and a tablet 2 comprising amorphous solifenacin succinate was prepared according to the procedure but including the dissolution step of crystalline solifenacin succinate with the same composition .
（ａ）製法１−結晶体コハク酸ソリフェナシン含有錠（錠剤１）
乳糖水和物，トウモロコシデンプン，及びコハク酸ソリフェナシン（結晶体）を流動層造粒装置に投入し，これにヒドロキシプロピルメチルセルロースの水溶液を噴霧して造粒し，乾燥，整粒した後，ステアリン酸マグネシウムを添加，混合して打錠し，錠剤１として素錠を得た。ここに，錠剤中のコハク酸ソリフェナシンは，結晶体をそのまま造粒に用いていることから，大半の部分は結晶体である。
(A) Preparation method 1-crystalline form solifenacin succinate containing tablet (tablet 1)
A lactose hydrate, corn starch, and solifenacin succinate (crystal) are charged into a fluid bed granulator, which is granulated by spraying an aqueous solution of hydroxypropyl methylcellulose, dried, sized, and stearic acid. Magnesium was added, mixed and compressed into tablets to obtain uncoated tablets. Here, since solifenacin succinate in the tablet is used as it is for crystallization, most of the portion is crystalline.
（ｂ）製法２−非晶質体コハク酸ソリフェナシン含有錠（錠剤２）
乳糖水和物，及びトウモロコシデンプンを流動層造粒装置に投入し，これにコハク酸ソリフェナシンとヒドロキシプロピルメチルセルロースの水溶液を噴霧して造粒し，乾燥，整粒した後，ステアリン酸マグネシウムを添加，混合して打錠し，錠剤２として素錠を得た。ここに，錠剤中のコハク酸ソリフェナシンは，一旦溶解させて賦形剤に噴霧しそのまま乾燥させたものであることから，非晶質の状態である。
(B) Preparation method 2-amorphous form solifenacin succinate containing tablet (tablet 2)
Lactose hydrate and corn starch are placed in a fluid bed granulator, granulated with an aqueous solution of solifenacin succinate and hydroxypropyl methylcellulose sprayed and granulated, dried and sized, and then magnesium stearate is added, The mixture was mixed and compressed into tablets and tablets were obtained. Here, solifenacin succinate in the tablet is in an amorphous state since it is dissolved once, sprayed on an excipient and dried as it is.
（２）安定性の検討
上記で得られた錠剤１（結晶体）及び錠剤２（非晶質体）につき，コハク酸ソリフェナシンのＮ−オキシド体の量を測定し，初期値とした。次いで，錠剤１，錠剤２，及び結晶体原薬を，それぞれポリエチレン瓶に入れ，７０℃で９日間，６０℃で３週，２５℃７５％ＲＨ（開放）で１及び３か月，４０℃７５％ＲＨ（開放）で１及び３か月，並びに４０℃７５％ＲＨ（密閉）で１及び３か月保存し，次の方法により，Ｎ−オキシド体の量を測定した。
(2) Examination of stability About the tablet 1 (crystal body) and tablet 2 (amorphous body) which were obtained above, the quantity of the N-oxide body of solifenacin succinate was measured, and it was set as the initial value. Then, put tablet 1, tablet 2 and crystalline drug substance into polyethylene bottles, respectively, at 70 ° C. for 9 days, 3 weeks at 60 ° C., 1 and 3 months at 25 ° C. 75% RH (open), 40 ° C. It was stored at 75% RH (open) for 1 and 3 months, and at 40 ° C. 75% RH (closed) for 1 and 3 months, and the amount of N-oxide was measured by the following method.
（ａ）Ｎ−オキシド体の測定方法
コハク酸ソリフェナシンの類縁物質であるＮ−オキシド体の生成量を，ＨＰＬＣ分析法により測定した。Ｎ−オキシド体の生成量は，コハク酸ソリフェナシンに由来するＨＰＬＣの全ピーク面積中のＮ−オキシド体のピーク面積の割合（％）として表した。本測定に使用した試料溶液，および，ＨＰＬＣの測定条件は以下の通りである。
〔試料溶液〕：
コハク酸ソリフェナシン２０ｇに相当する量をとり，８０％メタノールを加えて正確に５０ｍＬとし，メンブランフィルターでろ過する。試料溶液２０μＬ正確にとり，次の条件で測定する。
〔ＨＰＬＣ測定条件〕：
・検出器：紫外可視吸光光度計（測定波長：２２０ｍｍ）
・カラム：内径４．６ｍｍ，長さ１０ｃｍのステンレス管に３μｍの液体クロマトグラフィー用オクタデシルシリカゲルを充填する。
・カラム温度：４０℃
・移動相Ａ：水１０００ｍＬにトリエチルアミン５ｍＬを加え，リン酸を４ｍＬ加えたもの。
・移動相Ｂ：アセトニトリル９００ｍＬに水１００ｍＬを加え，トリエチルアミン５ｍＬを加え，リン酸を４ｍＬ加えたもの。
・移動相の送液：移動相Ａ及び移動相Ｂの混合比を次のように変えて濃度勾配制御する。
・移動相の流速：１ｍＬ／分
・Ｎ−オキシド体の保持時間：２７分
(A) Measurement Method of N-Oxide Form The amount of N-oxide form, which is a related substance of solifenacin succinate, was measured by HPLC analysis. The amount of N-oxide formed was expressed as a percentage (%) of the peak area of N-oxide in the total peak area of HPLC derived from solifenacin succinate. The sample solution used for this measurement and the measurement conditions of HPLC are as follows.
[Sample solution]:
Take an amount corresponding to 20 g of solifenacin succinate, add 80% methanol to make exactly 50 mL, and filter with a membrane filter. Take exactly 20 μL of the sample solution and measure under the following conditions.
[HPLC measurement conditions]:
・ Detector: UV-visible absorptiometer (measurement wavelength: 220 mm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 10 cm is packed with 3 μm octadecyl silica gel for liquid chromatography.
・ Column temperature: 40 ° C
Mobile phase A: To 1000 mL of water was added 5 mL of triethylamine and 4 mL of phosphoric acid.
Mobile phase B: 100 mL of water is added to 900 mL of acetonitrile, 5 mL of triethylamine is added, and 4 mL of phosphoric acid is added.
Transfer of mobile phase: The concentration ratio is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.
・ Flow rate of mobile phase: 1 mL / min ・ Holding time of N-oxide: 27 minutes
結果を表３に示す。 The results are shown in Table 3.
表３に見られるように，非晶質体コハク酸ソリフェナシン含有錠（錠剤２）は，結晶体コハク酸ソリフェナシン含有錠（錠剤１）に比べて，いずれの条件においても，Ｎ−オキシド体が増加しており，非晶質体とすることにより化学的安定性の低下が認められた。 As seen in Table 3, the amorphous solifenacin succinate containing tablet (Tablet 2) showed an increase in the N-oxide form under any condition as compared with the crystalline solifenacin succinate containing tablet (Tablet 1). In the amorphous state, a decrease in chemical stability was observed.
２．安定化剤の探索
コハク酸ソリフェナシンの安定性の改善のため，安定化剤の探索を以下の通りに行った。
（１）検体の調製
１００ｍｇのコハク酸ソリフェナシン原薬（結晶体），１００ｍｇのヒドロキシプロピルメチルセルロース，及び下記の安定化剤候補化合物の何れかの１００ｍｇを精製水に溶解又は分散させ，これを凍結乾燥して，非晶質体コハク酸ソリフェナシンを含む試験検体とした。また，安定化剤候補化合物を加えないこと以外は上記と同様にして製造した凍結乾燥物を対照検体とした。
・安定化剤候補化合物：安息香酸ナトリウム，アスコルビン酸，トコフェロール，Ｌ−システイン塩酸塩（一水和物として），亜硫酸水素ナトリウム，亜硫酸ナトリウム，ジブチルヒドロキシトルエン，リン酸二水素ナトリウム，リン酸水素カルシウム（無水物として），ソルビン酸，クエン酸トリエチル。
2. Search for a Stabilizer In order to improve the stability of solifenacin succinate, a search for a stabilizer was conducted as follows.
(1) Preparation of sample 100 mg of solifenacin succinate drug substance (crystal), 100 mg of hydroxypropyl methylcellulose, and 100 mg of any of the following stabilizer candidate compounds are dissolved or dispersed in purified water and lyophilized. The test sample contained amorphous sophinate succinate. In addition, a lyophilizate produced in the same manner as described above except that no stabilizer candidate compound was added was used as a control sample.
-Stabilizer candidate compounds: sodium benzoate, ascorbic acid, tocopherol, L-cysteine hydrochloride (as monohydrate), sodium bisulfite, sodium sulfite, dibutylhydroxytoluene, sodium dihydrogenphosphate, calcium hydrogenphosphate (As anhydride), sorbic acid, triethyl citrate.
（２）安定性試験１：Ｎ−オキシド体の生成抑制効果の検討
上記の各試験検体及び対照検体をそれぞれポリエチレン瓶に入れ，７０℃で９日間（密閉）保存し，Ｎ−オキシド体の生成量を測定した。なおＮ−オキシド体の生成量が０．５％未満であるものを良好と判断した。
(2) Stability test 1: Examination of the formation inhibitory effect of N-oxide form Each of the above-mentioned test specimen and control specimen are put in a polyethylene bottle and stored at 70 ° C. for 9 days (sealed) to produce N-oxide The amount was measured. In addition, it was judged that the thing whose production amount of N-oxide body is less than 0.5% was favorable.
その結果，対照検体のＮ−オキシド体含量は３％であり，これに対し，安息香酸ナトリウム，Ｌ−システイン塩酸塩，ジブチルヒドロキシトルエン，リン酸二水素ナトリウム，又はクエン酸トリエチルを含む試験検体のＮ−オキシド体含量は０．５％を大きく下回り，優れた安定化効果を示した。 As a result, the N-oxide content of the control sample is 3%, while that of the test sample containing sodium benzoate, L-cysteine hydrochloride, dibutylhydroxytoluene, sodium dihydrogen phosphate or triethyl citrate. The N-oxide content was well below 0.5%, showing an excellent stabilization effect.
（３）安定性試験２：結晶化の抑制効果の検討
上記の各試験検体及び対照検体をそれぞれポリエチレン瓶に入れ，密閉状態で７０℃にて９日間，開放状態で２５℃７５％ＲＨにて１週間，及び密閉状態で４０℃７５％ＲＨにて１か月の各条件でそれぞれ保存した。対照検体及び各試験検体の外観を観察して記録し，コハク酸ソリフェナシンに関し相互に等量となるように各検体から一部を採取し，それぞれ粉末Ｘ線回折の測定を行って，コハク酸ソリフェナシン原体における結晶由来のピークが認められるか否かを比較した。結晶化の有無の確認は，D8 ADVANCE（Bruker製）を用いてＸＲＤ法により行い，２θ＝１４℃及び１８℃付近に特異的なピークがなければ，非晶質体であると判定した。
(3) Stability test 2: Examination of the inhibitory effect on crystallization The test samples and the control sample described above are placed in polyethylene bottles, respectively, and sealed at 70 ° C. for 9 days, open at 25 ° C. 75% RH They were stored for 1 week and under sealed conditions at 40 ° C. and 75% RH for 1 month. The appearance of the control sample and each test sample is observed and recorded, a part is taken from each sample so as to be mutually equal with respect to solifenacin succinate, and powder X-ray diffraction measurement is performed, respectively, solifenacin succinate Whether or not a crystal-derived peak in the drug substance was observed was compared. The confirmation of the presence or absence of crystallization was performed by XRD method using D8 ADVANCE (manufactured by Bruker), and if there were no specific peaks in the vicinity of 2θ = 14 ° C. and 18 ° C., it was determined to be an amorphous form.
その結果，対照検体では，コハク酸ソリフェナシンの結晶化が認められた。これに対し，安定化剤候補化合物のうち安息香酸ナトリウム，亜硫酸ナトリウム，リン酸水素カルシウム，ソルビン酸，又はＬ−システイン塩酸塩を含む試験検体では，何れの保存条件でも結晶化は認められず，これらの化合物が，コハク酸ソリフェナシンの結晶化に対する防止効果を有することが判明した。また，ジブチルヒドロキシトルエンを含む試験検体では，他の条件で結晶化は認められなかったものの過酷条件（７０℃）においては，結晶化の促進が認められた。これらの結果から，安息香酸ナトリウム，亜硫酸ナトリウム，リン酸水素カルシウム，ソルビン酸，及びＬ−システイン塩酸塩が，製剤中の非晶質体コハク酸ソリフェナシンの結晶化防止に特に有効な安定化剤として配合できるものと判断された。具体的な製剤の構成に際してそれらの中から安息香酸ナトリウムを選び，これを含む非晶質体コハク酸ソリフェナシン含有錠を次の通りに製造して，製剤形態での安定性を評価した。 As a result, crystallization of solifenacin succinate was observed in the control sample. On the other hand, in the test sample containing sodium benzoate, sodium sulfite, calcium hydrogen phosphate, sorbic acid or L-cysteine hydrochloride among the stabilizer candidate compounds, no crystallization is observed under any storage conditions, It has been found that these compounds have an inhibitory effect on the crystallization of solifenacin succinate. In addition, in the test sample containing dibutylhydroxytoluene, although crystallization was not observed under other conditions, acceleration of crystallization was observed under severe conditions (70 ° C.). From these results, sodium benzoate, sodium sulfite, calcium hydrogen phosphate, sorbic acid, and L-cysteine hydrochloride are particularly effective stabilizers for preventing crystallization of amorphous solifenacin succinate in the preparation. It was judged that it could be blended. Among them, sodium benzoate was selected from the compositions, and an amorphous solifenacin succinate containing tablet was prepared as follows to evaluate its stability in the form of formulation.
３．安息香酸ナトリウム配合非晶質体コハク酸ソリフェナシン含有錠の製造及び評価
（１）錠剤の製造
表４に従い３通りの量で安息香酸ナトリウムを配合した非晶質体コハク酸ソリフェナシン含有錠を，下記の方法により製造した。
3. Preparation and evaluation of sodium benzoate-containing amorphous form solifenacin succinate containing tablet (1) Preparation of tablet An amorphous form solifenacin succinate containing tablet containing sodium benzoate in three amounts according to Table 4 is as follows: Manufactured by the method.
Ｄ−マンニトールと結晶セルロースを流動層造粒装置に投入し，これに水エタノール混液中のコハク酸ソリフェナシン，ヒドロキシプロピルメチルセルロース，安息香酸ナトリウムの溶液を噴霧して造粒し，乾燥，整粒して顆粒を得た。この顆粒とステアリン酸マグネシウムとを混合して打錠することにより，非晶質体コハク酸ソリフェナシン含有の素錠を得た。 Charge D-mannitol and crystalline cellulose into a fluid bed granulator, spray a solution of solifenacin succinate, hydroxypropyl methylcellulose and sodium benzoate in a mixture of water and ethanol, granulate, dry and size Granules were obtained. The granules and magnesium stearate were mixed and tableted to obtain an amorphous tablet containing amorphous solifenacin succinate.
（２）錠剤の安定性試験
（ａ）Ｎ−オキシド体の生成による評価
上記の錠剤をポリエチレン瓶に入れ，各種の条件で保存した後，Ｎ−オキシド体の生成量を測定した。保存条件及び測定結果を併せて，表５に示す。
(2) Stability Test of Tablet (a) Evaluation by Formation of N-Oxide Body The above tablet was placed in a polyethylene bottle and stored under various conditions, and then the amount of N-oxide body formed was measured. The storage conditions and the measurement results are shown in Table 5.
表５からは，全体として，安息香酸ナトリウムの配合量が多い程，Ｎ−オキシド体の量が少ないという傾向が見られる。 It can be seen from Table 5 that as the blending amount of sodium benzoate is larger, the amount of N-oxide is smaller as a whole.
（ｂ）結晶化の有無に基づく評価
他方，錠剤３〜５について，コハク酸ソリフェナシンの結晶化が起こるか否かの点からの安定性を検討した。即ち，結晶体原薬及び製造直後の錠剤３〜５のそれぞれにつき，粉末Ｘ線回折により結晶化の有無を調べ，またそれらの錠剤をポリエチレン瓶に入れて４０℃７５％ＲＨ（密閉）で３か月及び４０℃７５％ＲＨ（開放）で３か月の条件で保存したものについて同様に結晶化の有無を調べた。その結果，製造直後の各錠剤，保存後の各錠剤の何れにも結晶化は認められず，コハク酸ソリフェナシンの実質的に全量が非晶質体の状態にあることが確認された。結晶体原薬，製造直後並びに４０℃７５％ＲＨ（密閉及び開放）で３か月保存後の錠剤４の粉末Ｘ線回折チャートを，例として図１に並べて示す。
(B) Evaluation based on the presence or absence of crystallization On the other hand, for the tablets 3 to 5, the stability was examined in terms of whether crystallization of solifenacin succinate occurred or not. That is, each of the crystalline drug substance and tablets 3 to 5 immediately after production is examined for the presence or absence of crystallization by powder X-ray diffraction, and the tablets are put in polyethylene bottles and 3 at 40 ° C. 75% RH (sealed). It was similarly examined for the presence or absence of crystallization about what was stored on condition of three months at 40 degreeC 75% RH (open | release) and months. As a result, no crystallization was observed in any of the tablets immediately after production and the tablets after storage, and it was confirmed that substantially all of the solifenacin succinate was in an amorphous state. The powder X-ray diffraction charts of the crystalline drug substance, the tablet 4 immediately after production and after storage for 3 months at 40 ° C. and 75% RH (sealed and opened) are shown as an example in FIG.
４．錠剤中のコハク酸ソリフェナシンの分解抑制手段の検討
結晶化が保存中でも防止できることが上記で確認された安息香酸ナトリウム配合非晶質体コハク酸ソリフェナシン含有錠について，更に，Ｎ−オキシド体の生成抑制手段の検討を行った。即ち，前述の安定化剤の探索の部においてＮ−オキシド体の生成を強力に抑制することが見出されている親油性抗酸化剤としてジブチルヒドロキシトルエンを，安息香酸ナトリウム含む上記非晶質体コハク酸ソリフェナシン含有錠に追加の安定化剤として配合することによる安定化効果を，以下の通りに検討した。
4. Examination of means for suppressing the decomposition of solifenacin succinate in tablets For sodium benzoate containing amorphous form solifenacin succinate containing tablets confirmed above that crystallization can be prevented even during storage, means for suppressing the formation of N-oxide We examined. That is, the above amorphous body containing sodium benzoate and dibutylhydroxytoluene as a lipophilic antioxidant has been found to strongly suppress the formation of N-oxide form in the search section for the above-mentioned stabilizer The stabilization effect of incorporating as an additional stabilizer into solifenacin succinate containing tablets was investigated as follows.
（１）安息香酸ナトリウム及びジブチルヒドロキシトルエンを含有する非晶質体コハク酸ソリフェナシン錠の製造
表６に示す組成に従って，下記の手順で錠剤６（対照）及びジブチルヒドロキシトルエンを含有する錠剤７を製造した。
(1) Preparation of Amorphous Solifenacin Succinate Tablet Containing Sodium Benzoate and Dibutyl Hydroxytoluene According to the composition shown in Table 6, manufacture Tablet 6 (control) and tablet 7 containing dibutylhydroxytoluene according to the following procedure did.
流動層造粒装置にＤ−マンニトールを投入し，その流動層に，５０％エタノール水溶液中にコハク酸ソリフェナシン，ヒドロキシプロピルメチルセルロース及び安息香酸ナトリウムを含む溶液を噴霧して造粒し，乾燥させ，更にこれにジブチルヒドロキシトルエンを含むエタノール溶液を噴霧して，乾燥，整粒して顆粒を得た。この顆粒とステアリン酸マグネシウムを混合して打末とし，これを打錠して錠剤７を素錠として得た。また，同様の手順で，但しジブチルヒドロキシトルエン添加工程を含めずに，錠剤６を対照として得た。 D-mannitol is charged into a fluid bed granulator, and the fluid bed is granulated by spraying a solution containing solifenacin succinate, hydroxypropyl methylcellulose and sodium benzoate in 50% aqueous ethanol, granulated and dried, and further The mixture was sprayed with an ethanol solution containing dibutylhydroxytoluene, dried and sized to obtain granules. The granules and magnesium stearate were mixed to give a powder, which was then compressed to obtain tablets 7 as uncoated tablets. Tablet 6 was obtained as a control in a similar procedure, but without the dibutyl hydroxytoluene addition step.
（２）安定性の検討
製造直後の錠剤６及び７につき，Ｎ−オキシド体の量を測定した。また，両錠剤をポリエチレン瓶に入れ，表７に示すように７０℃で３，６及び９日間，７０℃で１及び２週間，２５℃７５％ＲＨ（開放）で２週間，４０℃７５％ＲＨ（開放）で２週間，及び４０℃７５％（密閉）で２週間，それぞれ保存した後，Ｎ−オキシド体の量を測定した。結果を表７に併せて示す。
(2) Examination of stability About the tablet 6 and 7 immediately after manufacture, the quantity of N-oxide body was measured. Also, both tablets are placed in polyethylene bottles, as shown in Table 7, for 3 or 6 days at 70 ° C., 1 and 2 weeks at 70 ° C., 2 weeks at 25 ° C. 75% RH (open), 40 ° C. 75% After storage for 2 weeks at RH (open) and 2 weeks at 40 ° C. 75% (sealed), respectively, the amount of N-oxide was measured. The results are shown in Table 7 together.
表７に見られるように，Ｎ−オキシド体の生成は，ジブチルヒドロキシトルエンの配合により著しく抑制され，表３に示した結晶体コハク酸ソリフェナシンを主として含む錠剤１とほぼ同等の安定性を達成できることが判明した。また，錠剤７についてＸＲＤ法による測定の結果，コハク酸ソリフェナシンの結晶化が見られず，非晶質体の状態に維持されていることが確認された。前述の「安定化剤の検索」の部において，ジブチルヒドロキシトルエンの配合はコハク酸ソリフェナシンの結晶化を促進し得ることが確認されているが，錠剤７においてコハク酸ソリフェナシンの結晶化が認められないのは，同時に配合されている安息香酸ナトリウムの強い結晶化防止効果によると考えられ，その結果Ｎ−オキシド体の生成抑制という化学的安定化の作用のみが現れたものと推測される。 As seen in Table 7, the formation of the N-oxide is significantly suppressed by the incorporation of dibutyl hydroxytoluene, and the stability almost equivalent to that of the tablet 1 mainly containing the crystalline solifenacin succinate shown in Table 3 can be achieved. There was found. Further, as a result of measurement of the tablet 7 by the XRD method, it was confirmed that crystallization of solifenacin succinate was not observed, and was maintained in an amorphous state. In the "Stabilizer Search" section above, it has been confirmed that the incorporation of dibutylhydroxytoluene can promote the crystallization of solifenacin succinate, but no crystallization of solifenacin succinate is observed in tablet 7. The reason is considered to be due to the strong anti-crystallization effect of sodium benzoate compounded at the same time, and as a result, it is presumed that only the action of chemical stabilization to suppress the formation of N-oxide forms.
５．ジブチルヒドロキシトルエンの配合量の検討。
ジブチルヒドロキシトルエンの配合によりコハク酸ソリフェナシンの分解が抑制されること，及びジブチルヒドロキシトルエンを配合しても，安息香酸ナトリウムによるコハク酸ソリフェナシンの物理的安定化効果（結晶化防止）が妨げられないことも判明したため，安息香酸ナトリウム及びジブチルヒドロキシトルエンを含む非晶質体コハク酸ソリフェナシン錠における，ジブチルヒドロキシトルエンの適した配合量につき，以下の通り検討した。
5. Examination of the compounding quantity of dibutyl hydroxytoluene.
The compounding of dibutylhydroxytoluene suppresses the decomposition of solifenacin succinate, and the compounding of dibutylhydroxytoluene does not prevent the physical stabilization effect (anticrystallisation) of solifenacin succinate by sodium benzoate Since it also turned out, the suitable compounding quantity of dibutyl hydroxytoluene in the amorphous form solifenacin succinate tablet containing sodium benzoate and dibutyl hydroxy toluene was examined as follows.
（１）錠剤８〜１１の製造
次の表８に示す組成に従って，ジブチルヒドロキシトルエンを含有しない錠剤８及びこれを０．５，１及び２ｍｇ／１５０ｍｇ量（組成物全量に対し，０．３，０．６７，及び１．３３重量％）の量でそれぞれ含有する錠剤９，１０，及び１１を下記の通り製造した。
(1) Production of Tablets 8 to 11 According to the composition shown in Table 8 below, Tablet 8 containing no dibutylhydroxytoluene and its amount of 0.5, 1 and 2 mg / 150 mg (relative to the total amount of the composition, 0.3, Tablets 9, 10 and 11 were prepared as follows, containing respectively in amounts of 0.67 and 1.33% by weight).
コハク酸ソリフェナシン，ヒドロキシプロピルメチルセルロース，及び安息香酸ナトリウムの３０％エタノール溶液（１液）と，ジブチルヒドロキシトルエンのエタノール溶液（２液）とを調製し，低置換度ヒドロキシプロピルセルロースに１液及び２液を（但し，錠剤８では１液のみを）加え，練合し，乾燥させた。この乾燥末を粉砕し，整粒して顆粒とした。この顆粒に乳糖水和物，低置換度ヒドロキシプロピルセルロース，ヒドロキシプロピルセルロース及びステアリン酸マグネシウムを加えて混合し，打錠して錠剤８〜１１を得た。 A solution of solifenacin succinate, hydroxypropyl methylcellulose, and sodium benzoate in 30% ethanol solution (1 solution) and an ethanol solution of dibutylhydroxytoluene (2 solution) were prepared, and 1 solution and 2 solutions to low substituted hydroxypropyl cellulose (However, for tablet 8, only one solution) was added, kneaded and dried. The dried powder was crushed and sized into granules. Lactose hydrate, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose and magnesium stearate were added to the granules, mixed and compressed to obtain tablets 8-11.
（２）錠剤の安定性の検討
錠剤８〜１１につき，表９に示すように製造直後（初期値）及び各条件での保存後にＮ−オキシド体の量を測定した。結果を表９に併せて示す。
(2) Examination of stability of tablet As shown in Table 9, about the tablet 8-11, the quantity of N-oxide body was measured immediately after manufacture (initial value) and after storage in each condition. The results are shown in Table 9 together.
表９に見られる通り，ジブチルヒドロキシトルエンを含まない錠剤８と比べて，これを配合（０．５〜２ｍｇ／１５０ｍｇ）した錠剤９〜１１において，Ｎ−オキシド体の生成が何れも著しく抑制されていることが判明した。 As seen in Table 9, N-oxide formation is significantly suppressed in tablets 9 to 11 containing (0.5 to 2 mg / 150 mg) compared to tablet 8 not containing dibutylhydroxytoluene. It turned out that it was.
また，結晶原薬との対比において，錠剤８〜１１の製造直後（初期値）及び４０℃７５％ＲＨ（開放）保存後の粉末Ｘ線回折の結果を示す図２に見られるとおり，何れの錠剤においても，コハク酸ソリフェナシンの結晶化は認められず，非晶質体の状態が維持されていることも確認された。 Also, as seen in FIG. 2, which shows the results of powder X-ray diffraction immediately after preparation (initial value) of tablets 8 to 11 and after storage at 40 ° C. and 75% RH (open) in comparison with crystalline drug substance. Also in the tablets, no crystallization of solifenacin succinate was observed, and it was also confirmed that the amorphous state was maintained.
６．安息香酸ナトリウム配合非晶質体コハク酸ソリフェナシン含有ＯＤ錠の製造
転動流動層装置にＤ−マンニトール（ノンパレル−１０８）１５０ｇを投入し，これにコハク酸ソリフェナシン５０ｇ，ヒプロメロース（ＴＣ−５Ｅ）５０ｇ及び安息香酸ナトリウム５０ｇを含むエタノール水溶液を噴霧してコーティングした。乾燥させ，更にこれにジブチルヒドロキシトルエン１０ｇのエタノール溶液を噴霧し，乾燥させた。形成された顆粒に，続いてヒプロメロース２４ｇ及びタルク（タルカンハヤシ）６ｇを含むエタノール水溶液を噴霧してコーティングし，更にメタクリル酸コポリマーＬ（ポリキッドＬＡ−１００）４０ｇ，ヒプロメロース５ｇ及びタルク１５ｇを含むエタノール水溶液でコーティングを施して，薬物顆粒を製造した。
6. Preparation of sodium benzoate mixed amorphous body solifenacin succinate containing OD tablet In a tumbling fluidized bed apparatus, 150 g of D-mannitol (nonpareil-108) was charged, to which 50 g of solifenacin succinate, 50 g of hypromellose (TC-5E) and It coated by spraying the ethanol aqueous solution containing 50 g of sodium benzoate. It was dried and further sprayed with a solution of 10 g of dibutylhydroxytoluene in ethanol for drying. The formed granules are subsequently coated by spraying with an aqueous solution of ethanol containing 24 g of hypromellose and 6 g of talc (Talkan Hayashi) and further coated with an aqueous solution of ethanol containing 40 g of methacrylic acid copolymer L (Polykid LA-100), 5 g of hypromellose and 15 g of talc Coated to produce drug granules.
薬物顆粒とは別に，速崩壊性顆粒を調製した。速崩壊性顆粒は，トレハロース５００ｇを流動層造粒装置に投入し，トウモロコシデンプン１００ｇの水分散液をスプレーして造粒することにより調製した。 Apart from drug granules, fast disintegrating granules were prepared. The rapidly disintegrating granules were prepared by charging 500 g of trehalose into a fluid bed granulator and spraying an aqueous dispersion of 100 g of corn starch to granulate.
上記の薬物顆粒４０ｇ及び速崩壊性顆粒９７ｇと，エチルセルロース１０．５ｇ，アスパルテーム１．５ｇ及びステアリン酸マグネシウム１ｇを混合して打錠末とした。打錠末をロータリー式打錠機を用いて打錠し，非晶質コハク酸ソリフェナシン５ｍｇを含有する素錠を得た。 40 g of the above drug granules and 97 g of rapidly disintegrating granules were mixed with 10.5 g of ethyl cellulose, 1.5 g of aspartame and 1 g of magnesium stearate to prepare a tablet. The tableted powder was tableted using a rotary tableting machine to obtain a core tablet containing 5 mg of amorphous solifenacin succinate.
このＯＤ錠につき，上記と同様に安定性試験を行った。その結果，コハク酸ソリフェナシンの結晶化は認められず，非晶質体の状態が維持されており，また，Ｎ−オキシド体の生成も著しく抑制されているのが確認された。 The stability test was carried out on this OD tablet in the same manner as described above. As a result, it was confirmed that the crystallization of solifenacin succinate was not observed, the state of the amorphous form was maintained, and the formation of the N-oxide form was also significantly suppressed.
本発明は，十分な安定性を有する非晶質体コハク酸ソリフェナシン含有固形医薬組成物の提供を可能にするものとして有用である。
The present invention is useful as it enables provision of an amorphous solifenacin succinate-containing solid pharmaceutical composition having sufficient stability.
Claims (26)
26. The method of any of claims 14-25, further comprising the step of applying a coating to the obtained tablet.
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| JP7430937B1 (en) | 2022-10-12 | 2024-02-14 | 浩 坂本 | Method for manufacturing premix particles |
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