JP6292267B2 - Docetaxel formulation - Google Patents
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- JP6292267B2 JP6292267B2 JP2016179034A JP2016179034A JP6292267B2 JP 6292267 B2 JP6292267 B2 JP 6292267B2 JP 2016179034 A JP2016179034 A JP 2016179034A JP 2016179034 A JP2016179034 A JP 2016179034A JP 6292267 B2 JP6292267 B2 JP 6292267B2
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- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 title claims description 43
- 229960003668 docetaxel Drugs 0.000 title claims description 36
- 239000000203 mixture Substances 0.000 title claims description 23
- 238000009472 formulation Methods 0.000 title claims description 21
- 238000002360 preparation method Methods 0.000 claims description 42
- 239000002202 Polyethylene glycol Substances 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical group OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 7
- 238000001802 infusion Methods 0.000 claims description 7
- 238000001990 intravenous administration Methods 0.000 claims description 7
- 239000003381 stabilizer Substances 0.000 claims description 5
- 229960004543 anhydrous citric acid Drugs 0.000 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 4
- 229950008882 polysorbate Drugs 0.000 claims 1
- 229920000136 polysorbate Polymers 0.000 claims 1
- 239000000126 substance Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 229940063683 taxotere Drugs 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 5
- 229920000053 polysorbate 80 Polymers 0.000 description 5
- 229940068968 polysorbate 80 Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 102000029749 Microtubule Human genes 0.000 description 3
- 108091022875 Microtubule Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 210000004688 microtubule Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WQNHWIYLCRZRLR-UHFFFAOYSA-N 2-(3-hydroxy-2,5-dioxooxolan-3-yl)acetic acid Chemical compound OC(=O)CC1(O)CC(=O)OC1=O WQNHWIYLCRZRLR-UHFFFAOYSA-N 0.000 description 2
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003978 infusion fluid Substances 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- VOXXWSYKYCBWHO-UHFFFAOYSA-N 3-phenyllactic acid Chemical compound OC(=O)C(O)CC1=CC=CC=C1 VOXXWSYKYCBWHO-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- -1 polyoxyethylene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、ドセタキセル製剤に関する。 The present invention relates to docetaxel formulations.
サノフィ・アベンティス株式会社が製造販売する抗癌剤のタキソテール（登録商標）点滴静注用製剤（非特許文献１）は、有効成分のドセタキセル水和物をポリソルベート８０に溶解した主薬バイアルと１３％エタノール溶液の添付溶解液とからなる二液製剤である。用時は、あらかじめ主薬バイアルに添付溶解液を加えるか、もしくはアルコールに過敏な患者には輸液を加えて均一になるまで混和し、輸液に混注して点滴静注する。 Taxotere (registered trademark) intravenous infusion preparation (Non-patent Document 1), an anticancer agent manufactured and sold by Sanofi-aventis Co., Ltd., consists of an active ingredient docetaxel hydrate dissolved in polysorbate 80 and a 13% ethanol solution. It is a two-part preparation consisting of an attached dissolution solution. At the time of use, add the attached dissolution solution to the main drug vial in advance, or add the infusion solution to patients who are sensitive to alcohol, mix until uniform, mix the infusion solution, and infuse intravenously.
このように、タキソテール（登録商標）は、用時製剤調製が必要であり、混和操作などが煩雑で時間を要し、混和操作で発生する泡立ちが消失するまで１時間以上要するなどの問題がある。 As described above, Taxotere (registered trademark) requires preparation preparation at the time of use, and the mixing operation is complicated and takes time, and there is a problem that it takes 1 hour or more until foaming generated by the mixing operation disappears. .
これらの問題を改善するために、同社から一液製剤であるワンタキソテール（登録商標）点滴静注用製剤（非特許文献２）が発売された。ワンタキソテール（登録商標）は、あらかじめ無水エタノールで希釈されているため、混和操作が不要であり、製剤調製に伴う問題は解消されたものの、アルコールに過敏な患者には投与できないという問題がある。 In order to remedy these problems, the company has released One-Taxotere (registered trademark) intravenous infusion preparation (Non-patent Document 2), which is a one-part preparation. Since One Taxotere (registered trademark) is diluted with absolute ethanol in advance, mixing operation is not necessary, and although problems associated with preparation of the preparation have been solved, there is a problem that it cannot be administered to patients who are sensitive to alcohol.
本発明は、アルコールに過敏な患者にも投与可能な一液製剤であるドセタキセル製剤を提供することを目的とする。 An object of this invention is to provide the docetaxel formulation which is a one-component formulation which can be administered also to the patient hypersensitive to alcohol.
本発明者らは、上記課題を解決するために鋭意検討した結果、ポリエチレングリコールを共存させることによって、アルコールに過敏な患者にも投与可能な一液製剤であるドセタキセル製剤を提供できることを見出し、本発明を完成させた。 As a result of diligent studies to solve the above problems, the present inventors have found that by coexisting polyethylene glycol, a docetaxel preparation that is a one-part preparation that can be administered to alcohol-sensitive patients can be provided. Completed the invention.
本発明のドセタキセル製剤は、ドセタキセルとポリエチレングリコールとを含有し、アルコールを含有しない。 The docetaxel formulation of the present invention contains docetaxel and polyethylene glycol and does not contain alcohol.
１つの実施態様では、上記ポリエチレングリコールは、４３０〜６５０ｍｇ／ｍＬの濃度で含有される。 In one embodiment, the polyethylene glycol is contained at a concentration of 430-650 mg / mL.
１つの実施態様では、上記製剤は、ｐＨが２．９〜４．２である。 In one embodiment, the formulation has a pH of 2.9-4.2.
本発明によれば、アルコールに過敏な患者にも投与可能な一液製剤であるドセタキセル製剤を提供することができる。本発明のドセタキセル製剤は、従来製剤よりもドセタキセル由来の類縁物質の生成が少ないため、安全性が高い。 ADVANTAGE OF THE INVENTION According to this invention, the docetaxel formulation which is a 1 liquid formulation which can be administered also to the patient hypersensitive to alcohol can be provided. The docetaxel formulation of the present invention is highly safe because it produces less related substances derived from docetaxel than the conventional formulation.
本発明のドセタキセル製剤は、ドセタキセルとポリエチレングリコールとを含有する。 The docetaxel formulation of the present invention contains docetaxel and polyethylene glycol.
ドセタキセルは、タキソイド類に属する化合物であり、分子式Ｃ４３Ｈ５３ＮＯ１４、分子量８０７．８７９、化学名（−）−（１Ｓ，２Ｓ，３Ｒ，４Ｓ，５Ｒ，７Ｓ，８Ｓ，１０Ｒ，１３Ｓ）−４−アセトキシ−２−ベンゾイルオキシ−５，２０−エポキシ−１，７，１０−トリヒドロキシ−９−オキソタキサ−１１−エン−１３−イル（２Ｒ，３Ｓ）−３−ｔｅｒｔ−ブトキシカルボニルアミノ−２−ヒドロキシ−３−フェニルプロピオネートの白色の粉末である。高い親油性を有し、水にほとんど溶けない。抗癌作用の機序としては、チューブリンの重合を促進し、安定な微小管を形成するとともに、微小管の脱重合を抑制することによって、異常な形態の微小管束を形成し、細胞の有糸分裂を阻害する。 Docetaxel is a compound belonging to taxoids, molecular formula C 43 H 53 NO 14 , molecular weight 807.879, chemical name (−)-(1S, 2S, 3R, 4S, 5R, 7S, 8S, 10R, 13S) — 4-Acetoxy-2-benzoyloxy-5,20-epoxy-1,7,10-trihydroxy-9-oxotaxa-11-en-13-yl (2R, 3S) -3-tert-butoxycarbonylamino-2 -White powder of hydroxy-3-phenylpropionate. Highly lipophilic and hardly soluble in water. The mechanism of anticancer action is to promote tubulin polymerization to form stable microtubules and to suppress depolymerization of microtubules, thereby forming abnormally shaped microtubule bundles and the presence of cells. Inhibits mitosis.
ドセタキセルは、イチイ属の植物から抽出された前駆体（タキソイド１０−デアセチルバッカチンＩＩＩ）を原料に製造することができる。ドセタキセル水和物をポリソルベート８０に溶解した溶解液が、タキソテール（登録商標）点滴静注用製剤としてサノフィ・アベンティス株式会社から市販されている。本発明のドセタキセルは、誘導体や類似の化合物も含み、無水物、水和物、塩などの形態も含む。ドセタキセルの濃度としては、特に限定されず、例えば１０〜３０ｍｇ／ｍＬ、好ましくは１５〜２５ｍｇ／ｍＬ、より好ましくは１８〜２２ｍｇ／ｍＬである。 Docetaxel can be produced from a precursor (taxoid 10-deacetylbaccatin III) extracted from a yew plant. A solution obtained by dissolving docetaxel hydrate in polysorbate 80 is commercially available from Sanofi-aventis Co., Ltd. as a formulation for intravenous injection of Taxotere (registered trademark). The docetaxel of the present invention includes derivatives and similar compounds, and includes forms such as anhydrides, hydrates and salts. It does not specifically limit as a density | concentration of docetaxel, For example, it is 10-30 mg / mL, Preferably it is 15-25 mg / mL, More preferably, it is 18-22 mg / mL.
ポリエチレングリコールとしては、特に限定されないが、好ましくはマクロゴール、より好ましくはマクロゴール４００である。マクロゴールとは、日本薬局方（局方）または医薬品添加物規格（薬添規）に収載された規格を満たすポリエチレングリコールをいう。マクロゴール４００は、平均分子量が４００の分子で構成される常温で粘稠性の液体であり、製剤において、安定化剤、界面活性剤、可塑剤、滑沢剤、基剤、結合剤、光沢化剤、コーティング剤、溶解補助剤、乳化剤、崩壊剤、溶解補助剤などとして用いられる。ポリエチレングリコールの濃度としては、特に限定されないが、好ましくは４３０〜６５０ｍｇ／ｍＬ、より好ましくは４９０〜６００ｍｇ／ｍＬである。 The polyethylene glycol is not particularly limited, but is preferably macrogol, more preferably macrogol 400. Macrogol refers to polyethylene glycol that meets the standards listed in the Japanese Pharmacopoeia (Pharmacopeia) or Pharmaceutical Additives Standard (Pharmaceutical Addendum). Macrogol 400 is a viscous liquid at room temperature composed of molecules having an average molecular weight of 400. In the preparation, stabilizer, surfactant, plasticizer, lubricant, base, binder, gloss It is used as an agent, coating agent, solubilizer, emulsifier, disintegrant, solubilizer and the like. Although it does not specifically limit as a density | concentration of polyethyleneglycol, Preferably it is 430-650 mg / mL, More preferably, it is 490-600 mg / mL.
本発明のドセタキセル製剤は、アルコールを含有しない。 The docetaxel formulation of the present invention does not contain alcohol.
本発明のドセタキセル製剤は、通常の製剤などに用いられる緩衝剤、ｐＨ調節剤、安定化剤などを必要に応じて含んでいてもよい。緩衝剤としては、特に限定されない。ｐＨ調整剤としては、特に限定されず、例えば、無水クエン酸、リン酸が挙げられる。好ましくは、無水クエン酸である。安定化剤としては、特に限定されず、例えば、ポリソルベート８０、ポリオキシエチレンヒマシ油が挙げられる。好ましくは、ポリソルベート８０である。 The docetaxel formulation of the present invention may contain a buffer, a pH adjuster, a stabilizer and the like used in a normal formulation as necessary. The buffer is not particularly limited. The pH adjuster is not particularly limited, and examples thereof include anhydrous citric acid and phosphoric acid. Preferably, it is anhydrous citric acid. The stabilizer is not particularly limited, and examples thereof include polysorbate 80 and polyoxyethylene castor oil. Polysorbate 80 is preferable.
本発明のドセタキセル製剤のｐＨは、特に限定されないが、好ましくは２．９〜４．２、より好ましくは３．１〜３．９である。ｐＨが２．９未満または４．２を超えると、製剤の保存中にドセタキセルの分解産物である類縁物質の生成が促進される。類縁物質としては、１０−オキソ体、７−エピ体、７−エピ−１０−オキソ体が挙げられる。ｐＨ２．９〜４．２では、製剤の保存中に７−エピ−１０−オキソ体がほとんど生成しない。 Although pH of the docetaxel formulation of this invention is not specifically limited, Preferably it is 2.9-4.2, More preferably, it is 3.1-3.9. A pH below 2.9 or above 4.2 facilitates the production of related substances that are degradation products of docetaxel during storage of the formulation. Related substances include 10-oxo, 7-epi, and 7-epi-10-oxo. At pH 2.9 to 4.2, almost no 7-epi-10-oxo form is produced during storage of the formulation.
本発明のドセタキセル製剤は、通常バイアルなどのガラス容器に封入されて、室温にて、好ましくは冷所にて保存される。用時、必要に応じて、生理食塩液またはブドウ糖液にて希釈して用いる。 The docetaxel preparation of the present invention is usually sealed in a glass container such as a vial and stored at room temperature, preferably in a cold place. At the time of use, it is diluted with a physiological saline solution or a glucose solution as necessary.
本発明のドセタキセル製剤は、例えば、非小細胞肺癌に適用する場合、成人に１日１回、ドセタキセルとして６０ｍｇ／ｍ２（体表面積）を１時間以上かけて３〜４週間間隔で点滴静注する。 When applied to non-small cell lung cancer, for example, the docetaxel preparation of the present invention is intravenously infused once daily to adults at 60 mg / m 2 (body surface area) as docetaxel at intervals of 3 to 4 weeks over 1 hour. To do.
以下、実施例を挙げて本発明を説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited to these Examples.
（実施例１）
ドセタキセル水和物２１．３４ｍｇ（ドセタキセルとして２０ｍｇおよび無水クエン酸（小松屋株式会社製、日本薬局方）１．２ｍｇをポリソルベート８０（三洋化成工業株式会社製、日本薬局方）５４０ｍｇに溶かし、マクロゴール４００（三洋化成工業株式会社、日本薬局方）５６０ｍｇを混合して製剤を得た。
Example 1
21.34 mg docetaxel hydrate (20 mg as docetaxel and 1.2 mg citric anhydride (manufactured by Komatsuya, Japan Pharmacopoeia) dissolved in 540 mg polysorbate 80 (manufactured by Sanyo Chemical Industries, Japan Pharmacopoeia), Macrogol 400 (Sanyo Chemical Industries, Japanese Pharmacopoeia) 560 mg was mixed to obtain a preparation.
（比較例１および２）
市販のタキソテール（登録商標）点滴静注用製剤５００μＬに無水エタノール３９５ｍｇを添加した製剤を比較例１とした。マクロゴール４００に代えてプロピレングリコールにしたこと以外は実施例１と同様にして調製した製剤を比較例２とした。
(Comparative Examples 1 and 2)
A comparative example 1 was prepared by adding 395 mg of absolute ethanol to 500 μL of a commercially available Taxotere (registered trademark) intravenous infusion preparation. A preparation prepared in the same manner as in Example 1 except that propylene glycol was used in place of Macrogol 400 was used as Comparative Example 2.
（試験例１）
実施例１ならびに比較例１および２の製剤を６０℃にて２週間保存し、保存後の製剤について、ドセタキセルの分解産物であるドセタキセル類縁物質をＨＰＬＣにて定量した。結果を製剤調製時のｐＨとともに表１に示す。なお、ＨＰＬＣ分析条件は以下のとおりである。
(Test Example 1)
The preparations of Example 1 and Comparative Examples 1 and 2 were stored at 60 ° C. for 2 weeks, and docetaxel-related substances, which are degradation products of docetaxel, were quantified by HPLC. The results are shown in Table 1 together with the pH at the preparation of the preparation. The HPLC analysis conditions are as follows.
＜ＨＰＬＣ分析条件＞
カラム：株式会社資生堂製ＣＡＰＣＥＬＬＰＡＫ Ｃ１８ＭＧII（４．６×２５０ｍｍ）
移動相：水／メタノール／アセトニトリル（２１／１６／１３）
流量：ドセタキセルの保持時間が約２４分になるように調整した。
温度：２８℃付近の一定温度
検出波長：２３２ｎｍ
<HPLC analysis conditions>
Column: CAPCELLPAK C 18 MGII (4.6 × 250 mm) manufactured by Shiseido Co., Ltd.
Mobile phase: water / methanol / acetonitrile (21/16/13)
Flow rate: The docetaxel retention time was adjusted to about 24 minutes.
Temperature: Constant temperature around 28 ° C Detection wavelength: 232 nm
表１から明らかなように、製剤保存後、実施例１の製剤は、比較例１の従来製剤と同等の類縁物質増加量であった。類縁物質としては、１０−オキソ体、７−エピ体、７−エピ−１０−オキソ体が主に認められた。一方、比較例２の製剤は、析出物が認められた。 As is apparent from Table 1, after the preparation was stored, the preparation of Example 1 had an increased amount of related substances equivalent to the conventional preparation of Comparative Example 1. As related substances, 10-oxo, 7-epi and 7-epi-10-oxo were mainly observed. On the other hand, precipitates were observed in the preparation of Comparative Example 2.
（実施例２〜７）
無水クエン酸の添加量を以下の表２に記載の処方にしたことおよびドセタキセル水和物をドセタキセルに変更したこと以外は実施例１と同様に調製した製剤を実施例２〜７とした。市販のワンタキソテール（登録商標）点滴静注用製剤を比較例３とした。
(Examples 2 to 7)
Examples 2 to 7 were prepared in the same manner as in Example 1 except that the amount of citric anhydride added was changed to the formulation shown in Table 2 below and that docetaxel hydrate was changed to docetaxel. A commercially available one-taxotere (registered trademark) intravenous infusion preparation was designated as Comparative Example 3.
（試験例２）
実施例３〜７および比較例３の製剤について、試験例１と同様に試験を行った。結果を製剤調製時のｐＨとともに表２に示す。なお、ＨＰＬＣ分析条件は以下のとおりである。製剤中のドセタキセル含量も残存率（％）として併せて示す。
(Test Example 2)
The preparations of Examples 3 to 7 and Comparative Example 3 were tested in the same manner as Test Example 1. The results are shown in Table 2 together with the pH at the preparation of the preparation. The HPLC analysis conditions are as follows. The docetaxel content in the preparation is also shown as the residual rate (%).
＜ＨＰＬＣ分析条件＞
カラム：株式会社資生堂製ＣＡＰＣＥＬＬＰＡＫ Ｃ１８ＭＧII（４．６×１００ｍｍ）
移動相：水／メタノール／アセトニトリル（２１／１６／１３）
流量：ドセタキセルの保持時間が約１２分になるように調整した。
温度：４０℃付近の一定温度
検出波長：２３２ｎｍ
<HPLC analysis conditions>
Column: CAPCELLPAK C 18 MGII (4.6 × 100 mm) manufactured by Shiseido Co., Ltd.
Mobile phase: water / methanol / acetonitrile (21/16/13)
Flow rate: The docetaxel retention time was adjusted to about 12 minutes.
Temperature: Constant temperature detection around 40 ° C Wavelength: 232nm
表２から明らかなように、製剤保存後、ｐＨ２．９〜３．６の実施例４〜７の製剤は、比較例３の従来製剤よりも類縁物質増加量が少なかった。特に、ｐＨ３．３の実施例５の製剤では、類縁物質の７−エピ−１０−オキソ体がほとんど認められなかった。 As is apparent from Table 2, after the preparation was stored, the preparations of Examples 4 to 7 having a pH of 2.9 to 3.6 showed a smaller increase in the related substances than the conventional preparation of Comparative Example 3. In particular, the 7-epi-10-oxo form of a related substance was hardly observed in the preparation of Example 5 having a pH of 3.3.
（実施例８〜１２）
無水クエン酸の添加量を以下の表３に記載の処方にしたこと以外は実施例１と同様に調製した製剤を実施例８〜１２とした。
(Examples 8 to 12)
Preparations prepared in the same manner as in Example 1 except that the addition amount of anhydrous citric acid was changed to the formulation shown in Table 3 below were designated as Examples 8 to 12.
（試験例３）
実施例８〜１２および比較例３の製剤について、６０℃にて２週間保存に代えて４０℃にて１箇月または１．５箇月保存にしたこと以外は試験例１と同様に試験を行った。結果を製剤調製時のｐＨとともに表３に示す。
(Test Example 3)
The preparations of Examples 8 to 12 and Comparative Example 3 were tested in the same manner as in Test Example 1 except that they were stored at 40 ° C for 1 month or 1.5 months instead of being stored at 60 ° C for 2 weeks. . The results are shown in Table 3 together with the pH at the preparation of the preparation.
表３から明らかなように、製剤保存後、ｐＨ２．９〜３．７の実施例８〜１２の製剤は、比較例３の従来製剤よりも類縁物質増加量が少なかった。 As is apparent from Table 3, after the preparation was stored, the preparations of Examples 8 to 12 having a pH of 2.9 to 3.7 had a smaller increase in related substances than the conventional preparation of Comparative Example 3.
本発明によれば、アルコールに過敏な患者にも投与可能な一液製剤であるドセタキセル製剤を提供することができる。 ADVANTAGE OF THE INVENTION According to this invention, the docetaxel formulation which is a 1 liquid formulation which can be administered also to the patient hypersensitive to alcohol can be provided.
Claims (3)
該ドセタキセルが１０〜３０ｍｇ／ｍＬの濃度で含有されており、
該ポリエチレングリコールが４９０〜６００ｍｇ／ｍＬの濃度で含有されており、
ｐＨが２．９〜３．７であり、
該ポリエチレングリコールがマクロゴール４００であり、
該ｐＨ調整剤が無水クエン酸であり、そして
該安定化剤がポリソルベート８０である、一液製剤。 A one-part preparation for intravenous infusion consisting essentially of docetaxel, polyethylene glycol, a pH adjuster and a stabilizer,
The docetaxel is contained at a concentration of 10 to 30 mg / mL,
The polyethylene glycol is contained at a concentration of 490 to 600 mg / mL ,
pH is 2.9 to 3.7 der is,
The polyethylene glycol is Macrogol 400,
The pH adjuster is anhydrous citric acid, and
The stabilizer Ru 80 der polysorbate, one-part formulation.
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