JP7423028B2 - Lyophilized pharmaceutical composition containing bortezomib - Google Patents
Lyophilized pharmaceutical composition containing bortezomib Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 39
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title claims description 28
- 229960001467 bortezomib Drugs 0.000 title claims description 26
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 10
- 238000003860 storage Methods 0.000 description 18
- 238000012360 testing method Methods 0.000 description 13
- 238000001035 drying Methods 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 239000000463 material Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- 235000010355 mannitol Nutrition 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229920000089 Cyclic olefin copolymer Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 2
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- -1 pH adjusters Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 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
- 229910019142 PO4 Inorganic materials 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Description
本発明は、再調製時間の遅延が抑制され、良好な再調製を示すボルテゾミブ又はその誘導体を含有する凍結乾燥医薬組成物およびその製造方法を提供する。 The present invention provides a lyophilized pharmaceutical composition containing bortezomib or a derivative thereof that exhibits good reconstitution with suppressed delay in reconstitution time, and a method for producing the same.
一般に、凍結乾燥は、医薬品分野のみならず、多種の分野において広く利用される技術である。当該技術は、溶液を凍結後に真空化状態で溶媒を昇華させることにより、乾燥固体または粉末を形成する方法である。そのため、凍結乾燥の技術は医薬品分野において、溶液状態で不安定な薬物などを長期に保管しなければならない場合に多く利用されている。そして、凍結乾燥医薬組成物は注射剤の分野で多く利用されているが、凍結乾燥した注射剤を患者に投与する場合、投与する前に凍結乾燥医薬組成物を生理食塩液などの輸液等で再調製して溶液化する。この際、作業性の観点などから、再調製は短時間且つ容易であることが要求される。 Generally, freeze-drying is a technique widely used not only in the pharmaceutical field but also in various fields. The technique involves freezing a solution and then sublimating the solvent under vacuum to form a dry solid or powder. Therefore, freeze-drying technology is often used in the pharmaceutical field when drugs and the like that are unstable in a solution state must be stored for a long period of time. Freeze-dried pharmaceutical compositions are widely used in the field of injections, but when administering freeze-dried injections to patients, the freeze-dried pharmaceutical composition is injected into an infusion solution such as physiological saline before administration. Reconstitute and dissolve. At this time, from the viewpoint of workability, it is required that the re-preparation be quick and easy.
ボルテゾミブは、プロテアソームを選択的かつ可逆的に阻害して抗腫瘍作用を発揮する分子標的薬であり、多発性骨髄腫の治療薬として知られている。現在、ボルテゾミブを含む凍結乾燥製剤は、ベルケイド（登録商標）注射用３ｍｇの商品名で市販されている。そして、ボルテゾミブを含有した凍結乾燥医薬組成物については、酒石酸を含有させることで安定性及び溶出性を改善した医薬組成物（特許文献１参照）、グルコン酸ナトリウムを含有させることで良好な物理特性を有する医薬組成物（特許文献２参照）などが開示されている。 Bortezomib is a molecular targeted drug that selectively and reversibly inhibits the proteasome to exhibit antitumor effects, and is known as a therapeutic drug for multiple myeloma. Currently, a lyophilized formulation containing bortezomib is commercially available under the trade name Velcade® 3 mg for injection. Regarding lyophilized pharmaceutical compositions containing bortezomib, there are pharmaceutical compositions with improved stability and dissolution properties by containing tartaric acid (see Patent Document 1), and good physical properties by containing sodium gluconate. A pharmaceutical composition having the following has been disclosed (see Patent Document 2).
しかしながら、これら知見は、あくまでもボルテゾミブを含有した凍結乾燥医薬組成物に関する安定性等について開示されているにとどまり、ボルテゾミブを含有した凍結乾燥医薬組成物の再調製時間の遅延に関しては言及していない。 However, these findings only disclose the stability etc. of lyophilized pharmaceutical compositions containing bortezomib, and do not mention the delay in reconstitution time of lyophilized pharmaceutical compositions containing bortezomib.
今般、本発明者らは、ボルテゾミブ又はその誘導体を含有する凍結乾燥医薬組成物において、一定期間貯蔵することにより、再調製に要する時間が貯蔵前と比べて遅延してしまうことを確認した。本発明の課題は、当該貯蔵後における再調製時間の遅延を抑制したボルテゾミブ又はその誘導体を含有する凍結乾燥医薬組成物を提供することにある。 Recently, the present inventors have confirmed that when a lyophilized pharmaceutical composition containing bortezomib or a derivative thereof is stored for a certain period of time, the time required for reconstitution is delayed compared to before storage. An object of the present invention is to provide a lyophilized pharmaceutical composition containing bortezomib or a derivative thereof that suppresses the delay in reconstitution time after storage.
本発明者らは、上記課題を解決すべく鋭意研究した結果、驚くべきことに、ボルテゾミブ又はその誘導体を含有する凍結乾燥医薬組成物において、当該組成物中の水分含量を１．０％以下とすることにより本発明の課題を解決できることを見出し、本発明を完成するに至った。 As a result of intensive research to solve the above problems, the present inventors surprisingly found that in a freeze-dried pharmaceutical composition containing bortezomib or its derivatives, the water content in the composition is 1.0% or less. The inventors have discovered that the problems of the present invention can be solved by doing so, and have completed the present invention.
本発明によれば、貯蔵後における再調製時間の遅延が抑制されることにより良好な再調製が可能であるボルテゾミブ又はその誘導体を含有する凍結乾燥医薬組成物を提供することができる。 According to the present invention, it is possible to provide a lyophilized pharmaceutical composition containing bortezomib or a derivative thereof that can be reconstituted satisfactorily by suppressing the delay in reconstitution time after storage.
ボルテゾミブとは、[(1R)‐3‐メチル‐1‐[[(2S)‐1‐オキソ‐3‐フェニル‐2‐[(2‐ピラジニルカルボニル)アミノ]プロピル]アミノ]ブチル]ボロン酸である。そして、ボルテゾミブはプロテアソームを選択的かつ可逆的に阻害して抗腫瘍作用を発揮する分子標的薬であり、多発性骨髄腫の治療薬である。本発明において、ボルテゾミブ又はその誘導体は医薬的に許容される程度の純度を有するものであれば、特に制限なく使用することができる。また凍結乾燥医薬組成物中のボルテゾミブ又はその誘導体の量は、特に限定されるものではないが、例えば、１製剤あたり１～５ｍｇの量で使用することができ、更に好ましくは１～３ｍｇであり、更に好ましくは２ｍｇ又は３ｍｇである。 Bortezomib is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(2-pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid. It is. Bortezomib is a molecular targeting drug that selectively and reversibly inhibits the proteasome and exhibits antitumor effects, and is a therapeutic drug for multiple myeloma. In the present invention, bortezomib or a derivative thereof can be used without any particular restriction as long as it has a pharmaceutically acceptable degree of purity. Further, the amount of bortezomib or its derivative in the lyophilized pharmaceutical composition is not particularly limited, but it can be used, for example, in an amount of 1 to 5 mg, more preferably 1 to 3 mg per preparation. , more preferably 2 mg or 3 mg.
本発明の凍結乾燥医薬組成物には、有効成分であるボルテゾミブ又はその誘導体以外に、本発明の効果を損なわない限りにおいて、賦形剤、ｐＨ調整剤、緩衝剤、等張化剤などを適宜使用することができる。 In addition to the active ingredient bortezomib or its derivative, the lyophilized pharmaceutical composition of the present invention may contain excipients, pH adjusters, buffers, isotonic agents, etc., as long as they do not impair the effects of the present invention. can be used.
本発明において、賦形剤としては、特に限定されるものではないが、例えばジヒドロキシ化合物などを使用することができる。ジヒドロキシ化合物としては、特に限定されるものではないが、単糖類、二糖類、多糖類、糖アルコールおよびアミノ糖から選択される少なくとも１種以上の糖類であることが好ましい。糖類としては、好ましくはグルコース、スクロース、フルクトース、トレハロース、キシリトール、マンニトール及びソルビトールなどであり、更に好ましくはマンニトールである。また、マンニトールをはじめとするポリオールを使用するとボルテゾミブとのエステル体を形成することもある。 In the present invention, the excipient is not particularly limited, but for example, dihydroxy compounds and the like can be used. The dihydroxy compound is not particularly limited, but is preferably at least one type of saccharide selected from monosaccharides, disaccharides, polysaccharides, sugar alcohols, and amino sugars. Preferable sugars include glucose, sucrose, fructose, trehalose, xylitol, mannitol, and sorbitol, and more preferably mannitol. Furthermore, when polyols such as mannitol are used, they may form esters with bortezomib.
本発明において、賦形剤の使用量は、特に限定されるものではないが、例えば、ボルテゾミブ又はその誘導体の重量を１００重量％とした場合に対して、７５重量％以上であることが好ましく、更に好ましくは８３重量％以上であり、更に好ましくは８８重量％以上である。 In the present invention, the amount of excipient used is not particularly limited, but for example, it is preferably 75% by weight or more with respect to 100% by weight of bortezomib or its derivative, More preferably, it is 83% by weight or more, and still more preferably 88% by weight or more.
本発明において、ｐＨ調整剤としては、特に限定されるものではないが、例えば水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、リン酸水素ナトリウム、塩酸、クエン酸、酢酸などを使用することができる。本発明の凍結乾燥医薬組成物では、特に限定されないが、再調製後のｐＨが２．０～７．０であることが好ましく、更に好ましくはｐＨが４．０～７．０である。 In the present invention, the pH adjuster is not particularly limited, but for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydrogen phosphate, hydrochloric acid, citric acid, acetic acid, etc. can be used. . The lyophilized pharmaceutical composition of the present invention preferably has a pH of 2.0 to 7.0, more preferably 4.0 to 7.0, after reconstitution, although it is not particularly limited.
本発明において、緩衝剤としては、特に限定されるものではないが、例えばリン酸塩、炭酸塩などを使用することができる。 In the present invention, the buffering agent is not particularly limited, but for example, phosphates, carbonates, etc. can be used.
本発明において、等張化剤としては、特に限定されるものではないが、例えば塩化ナトリウム、グリセロールなどを使用することができる。 In the present invention, the tonicity agent is not particularly limited, but for example, sodium chloride, glycerol, etc. can be used.
本発明の凍結乾燥医薬組成物では、当該組成物中の水分含量が好ましくは１．０％以下である。更に好ましくは０．９％以下であり、更には０．８％以下であり、更には０．７％以下であり、更には０．６％以下であり、更には０．５％以下であり、更には０．４５％以下であり、更には０．４％以下であり、更には０．３５％以下である。組成物中の水分含量の測定方法は、特に限定されないが、例えば、カールフィッシャー水分計（例えば、微量水分測定装置 AQ-2200（平沼産業株式会社製））を用いて測定することができる。 In the lyophilized pharmaceutical composition of the present invention, the water content in the composition is preferably 1.0% or less. More preferably, it is 0.9% or less, further preferably 0.8% or less, further preferably 0.7% or less, further preferably 0.6% or less, and even more preferably 0.5% or less. , more preferably 0.45% or less, further 0.4% or less, and further 0.35% or less. The method for measuring the water content in the composition is not particularly limited, but it can be measured using, for example, a Karl Fischer moisture meter (eg, trace moisture measuring device AQ-2200 (manufactured by Hiranuma Sangyo Co., Ltd.)).
本発明において「再調製」とは、凍結乾燥医薬組成物を生理食塩液などの溶解液で溶液化することを意味する。本発明において「再調製時間」とは、凍結乾燥医薬組成物に対して溶解液を加えたときから、該組成物が完全に溶解して無色澄明の液になるまでの再調製に要した時間を意味する。本発明の凍結乾燥医薬組成物は、医薬的に許容される期間貯蔵後も再調製時間の遅延が抑制されている。例えば、温度４０℃、相対湿度７５％、１ヶ月間貯蔵した後、又は温度６０℃、７日間貯蔵した後であっても、試験開始時と比べて、再調製時間の大幅な遅延は見られない。 In the present invention, "reconstitution" means to dissolve the lyophilized pharmaceutical composition in a solution such as physiological saline. In the present invention, "reconstitution time" refers to the time required for reconstitution from the time when a dissolving solution is added to a lyophilized pharmaceutical composition until the composition is completely dissolved and becomes a clear colorless liquid. means. The lyophilized pharmaceutical composition of the present invention exhibits suppressed reconstitution time delay even after storage for a pharmaceutically acceptable period of time. For example, after one month of storage at 40°C and 75% relative humidity, or after 7 days of storage at 60°C, there was no significant delay in reconstitution time compared to the start of the test. do not have.
本発明において、貯蔵後の再調製時間は、特に限定されるものではない。例えば、温度４０℃、相対湿度７５％、１ヶ月間貯蔵した後の場合、好ましくは５０秒以内であり、更に好ましくは４０秒以内であり、更に好ましくは３０秒以内であり、更に好ましくは２０秒以内である。また温度６０℃、７日間貯蔵した後の場合、特に限定されるものではないが、好ましくは７０秒以内であり、更に好ましくは６０秒以内であり、更に好ましくは５０秒以内である。 In the present invention, the reconditioning time after storage is not particularly limited. For example, after storage for one month at a temperature of 40°C and a relative humidity of 75%, it is preferably within 50 seconds, more preferably within 40 seconds, even more preferably within 30 seconds, and even more preferably 20 seconds. Within seconds. Furthermore, after storage at a temperature of 60° C. for 7 days, the storage time is not particularly limited, but is preferably within 70 seconds, more preferably within 60 seconds, and still more preferably within 50 seconds.
本発明では、再調製時間の遅延の程度を「遅延率」によって表すこともできる。本発明において、「遅延率」とは安定性試験における試験開始時の凍結乾燥医薬組成物の再調製時間を１００％とした場合に対するある一定期間貯蔵した後の再調製時間との比率を意味する。なお、当該試験開始時の凍結乾燥医薬組成物は、医薬品として適切に保管された製造から６ヶ月以内の製品が好ましく、更には３ヶ月以内の製品が好ましく、更には１ヶ月以内の製品が好ましい。凍結乾燥医薬組成物である。本発明における「遅延率」については特に限定されるものではない。例えば、温度４０℃、相対湿度７５％、１ヶ月間貯蔵した後の場合、好ましい遅延率は３００％以下であり、更に好ましくは２５０％以下であり、更に好ましくは２００％以下であり、更に好ましくは１５０％以下であり、更に好ましくは１００％以下である。また温度６０℃、７日間貯蔵した後の場合、特に限定されるものではないが、好ましい遅延率は５００％以下であり、更に好ましくは４００％以下であり、更に好ましくは３００％以下であり、更に好ましくは２５０％以下である。 In the present invention, the degree of delay in readjustment time can also be expressed by a "delay rate." In the present invention, "delay rate" means the ratio of the reconstitution time after storage for a certain period of time to the reconstitution time of the lyophilized pharmaceutical composition at the start of the stability test, set as 100%. . The lyophilized pharmaceutical composition at the start of the test is preferably a product that has been stored appropriately as a pharmaceutical product and has been manufactured within 6 months, more preferably within 3 months, and even more preferably within 1 month. . A lyophilized pharmaceutical composition. The "delay rate" in the present invention is not particularly limited. For example, after storage for one month at a temperature of 40°C and a relative humidity of 75%, the retardation rate is preferably 300% or less, more preferably 250% or less, even more preferably 200% or less, and even more preferably is 150% or less, more preferably 100% or less. Furthermore, after storage at a temperature of 60° C. for 7 days, the retardation rate is not particularly limited, but is preferably 500% or less, more preferably 400% or less, still more preferably 300% or less, More preferably, it is 250% or less.
本発明の凍結乾燥医薬組成物の投与経路は、特に限定されないが、例えば、静脈内投与又は皮下投与などによって投与することができる。 The route of administration of the lyophilized pharmaceutical composition of the present invention is not particularly limited, but it can be administered, for example, intravenously or subcutaneously.
本発明の凍結乾燥医薬組成物の製造方法は、本発明の効果を損なわない限り特に制限されないが、例えば、ボルテゾミブをマンニトールなどの賦形剤と共に注射用水などの溶媒に溶解し、得られた水溶液を凍結乾燥することにより得ることができる。なお、凍結乾燥の条件は、本発明の効果を損なわない限り特に制限されず、医薬分野における通常の知識を有するものによって適宜設定することが可能である。また、本発明の凍結乾燥医薬組成物を調製する際に用いる溶媒としては、本発明の効果を損なわない限りにおいて特に限定されるものでないが、水（例えば、注射用水など）や有機溶媒（例えばエタノール又はｔｅｒｔ－ブタノールなどのアルコール類など）を単独又は組み合わせて適宜使用することができる。 The method for producing the lyophilized pharmaceutical composition of the present invention is not particularly limited as long as it does not impair the effects of the present invention. can be obtained by freeze-drying. Note that the freeze-drying conditions are not particularly limited as long as they do not impair the effects of the present invention, and can be appropriately set by those with ordinary knowledge in the pharmaceutical field. In addition, the solvent used when preparing the lyophilized pharmaceutical composition of the present invention is not particularly limited as long as it does not impair the effects of the present invention, but water (e.g., water for injection) and organic solvents (e.g. Alcohols such as ethanol or tert-butanol) can be used alone or in combination as appropriate.
本発明に用いることができる容器としては、特に限定されないが、アンプル、バイアル、プレフィルドシリンジ等を選択することができる。最善な容器はバイアルである。本発明に用いることができる容器の材質としては、本発明の効果を損なわない限り特に限定されるものでないが、例えば、ガラス、シクロオレフィンポリマー（ＣＯＰ）などからなる容器を使用することができる。また、本発明に用いることができる蓋材としては、特に限定されないが、例えば、ゴム栓などである。当該蓋材の材質としては、本発明の効果を損なわない限り特に限定されるものでないが、例えば、ブチル、塩化ブチルなどからなる蓋材を使用することができる。 Containers that can be used in the present invention are not particularly limited, but ampoules, vials, prefilled syringes, and the like can be selected. The best container is a vial. The material of the container that can be used in the present invention is not particularly limited as long as it does not impair the effects of the present invention, but for example, containers made of glass, cycloolefin polymer (COP), etc. can be used. Moreover, the lid material that can be used in the present invention is not particularly limited, but includes, for example, a rubber stopper. The material of the lid material is not particularly limited as long as it does not impair the effects of the present invention, but for example, lid materials made of butyl, butyl chloride, etc. can be used.
本発明の凍結乾燥医薬組成物中の水分含量を制御する方法は、本発明の効果を損なわない限りにおいて特に限定されるものでない。一例としては、凍結乾燥時の乾燥条件を適宜設定することにより水分含量を制御することも可能であるし、他には、予め乾燥処理された容器等を用いて本発明の凍結乾燥医薬組成物を保管することなどによっても水分含量を低く制御することが可能である。なお、当該容器等への乾燥処理は、容器又は蓋材のいずれに対して行ってもよく、またその両方を乾燥処理することも可能であるが、特には、蓋材に対して乾燥処理を行うことが好ましい。 The method for controlling the water content in the lyophilized pharmaceutical composition of the present invention is not particularly limited as long as it does not impair the effects of the present invention. For example, it is possible to control the moisture content by appropriately setting the drying conditions during freeze-drying, or alternatively, the freeze-dried pharmaceutical composition of the present invention can be prepared using a pre-drying container or the like. It is also possible to control the moisture content to a low level by storing. Note that the drying treatment for the container, etc. may be performed on either the container or the lid material, and it is also possible to dry both of them, but in particular, drying treatment may be performed on the lid material. It is preferable to do so.
本発明の凍結乾燥医薬組成物中の水分含量を制御するために、容器若しくは蓋材又はその両方を乾燥処理する場合、これら容器等における水分値は、本発明の効果を損なわない限りにおいて特に限定されるものでない。例えば、蓋材であるゴム栓を乾燥処理する場合、ゴム栓の水分値が０．２５％以下になるまで乾燥処理されていることが好ましく、更に好ましくは０．２０％以下であり、更に好ましくは０．１７％以下であり、更に好ましくは０．１３％以下であり、更に好ましくは０．１０％以下である。水分値の測定方法は、特に限定されないが、例えば、カールフィッシャー水分計（例えば、微量水分測定装置 AQ-2200（平沼産業株式会社製））を用いて測定することができる。 In order to control the moisture content in the freeze-dried pharmaceutical composition of the present invention, when the container or the lid material or both are subjected to drying treatment, the moisture value of these containers, etc. is particularly limited as long as it does not impair the effects of the present invention. It is not something that can be done. For example, when drying a rubber stopper that is a lid material, it is preferable that the moisture value of the rubber stopper is dried until it becomes 0.25% or less, more preferably 0.20% or less, and even more preferably is 0.17% or less, more preferably 0.13% or less, even more preferably 0.10% or less. The method for measuring the moisture value is not particularly limited, but it can be measured using, for example, a Karl Fischer moisture meter (eg, trace moisture measuring device AQ-2200 (manufactured by Hiranuma Sangyo Co., Ltd.)).
本発明において、容器若しくは蓋材又はその両方を乾燥処理する方法としては、本発明の効果を損なわない限り、その手段は特には制限されないが、例えば、高圧蒸気滅菌機などを用いて乾燥処理することができる。 In the present invention, the method for drying the container or the lid material or both is not particularly limited as long as the effects of the present invention are not impaired, but for example, drying may be performed using a high-pressure steam sterilizer or the like. be able to.
以下、実施例を挙げて本発明を具体的に説明するが、本発明はこれら実施例に限定されるものではない。 EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.
下記表１の処方に従い、実施例１～６及び比較例１のボルテゾミブ凍結乾燥医薬組成物を得た。 Freeze-dried bortezomib pharmaceutical compositions of Examples 1 to 6 and Comparative Example 1 were obtained according to the formulations shown in Table 1 below.
実施例１～６及び比較例１は、いずれも以下の製造方法により組成物を調製した。
注射用水を予め入れたステンレス容器内にＤ－マンニトールを加え、これを撹拌、溶解してＤ－マンニトール溶解液を調製した。次に、注射用水を予め入れたステンレス容器中にボルテゾミブを加え、これを撹拌してボルテゾミブ懸濁液を調製した。先に調整したＤ－マンニトール溶解液中にボルテゾミブ懸濁液を加えて、更に注射用水を加えて、これを撹拌した。得られた溶解液を無菌濾過した後、バイアルに充填し、高圧蒸気滅菌器（YRD-E18SLJPCWZ（サクラ精機株式会社製））を用いて滅菌及び乾燥処理を施したゴム栓を半打栓して、凍結乾燥を行った。なお、上記高圧蒸気滅菌器を用いた乾燥処理は、実施例１～６では真空乾燥タイマー９０分、パルス乾燥カウンター３０回、比較例１では真空乾燥タイマー９０分、パルス乾燥カウンター３回の条件に設定して行った。その後、ゴム栓を全打栓し、キャップの巻締めを行ってボルテゾミブ凍結乾燥組成物を得た。
In Examples 1 to 6 and Comparative Example 1, compositions were prepared by the following manufacturing method.
D-mannitol was added to a stainless steel container previously filled with water for injection, and stirred and dissolved to prepare a D-mannitol solution. Next, bortezomib was added to a stainless steel container previously filled with water for injection, and the mixture was stirred to prepare a bortezomib suspension. The bortezomib suspension was added to the previously prepared D-mannitol solution, water for injection was further added, and this was stirred. After the obtained solution was sterile-filtered, it was filled into a vial, which was sterilized and dried using a high-pressure steam sterilizer (YRD-E18SLJPCWZ (manufactured by Sakura Seiki Co., Ltd.)), and half-closed with a rubber stopper. , freeze-dried. The drying process using the above-mentioned high-pressure steam sterilizer was carried out under the conditions of a vacuum drying timer of 90 minutes and a pulse drying counter 30 times in Examples 1 to 6, and a vacuum drying timer of 90 minutes and a pulse drying counter 3 times in Comparative Example 1. I set it up and went. Thereafter, the rubber stopper was completely plugged, and the cap was tightened to obtain a bortezomib lyophilized composition.
実施例１～６及び比較例１の乾燥処理後のゴム栓水分値及び凍結乾燥医薬組成物中の水分値を表２に示す。 The moisture values of the rubber stoppers and the moisture values of the freeze-dried pharmaceutical compositions after drying in Examples 1 to 6 and Comparative Example 1 are shown in Table 2.
＜試験例１＞
実施例１～６及び比較例１について、貯蔵後の再調製時間の遅延を確認するための試験を実施した。試験例１では、試験開始時と温度４０℃、相対湿度７５％の条件下で１ヶ月の期間貯蔵した時の再調製時間をそれぞれ測定した。再調製は、上記で調製した各実施例の凍結乾燥医薬組成物に対して、ボルテゾミブの濃度が１ｍｇ／ｍｌになるように、実施例１、実施例２、実施例３及び比較例１では生理食塩液３ｍＬを、実施例４、実施例５及び実施例６では生理食塩液２ｍＬを加え、これを軽く２、３回振盪させた。再調製時間は、生理食塩液を加えてから、凍結乾燥医薬組成物が完全に溶解するまでの時間を測定した。
試験例１の結果について、表３に示す。
<Test Example 1>
For Examples 1 to 6 and Comparative Example 1, tests were conducted to confirm the delay in reconditioning time after storage. In Test Example 1, the reconditioning time was measured at the start of the test and when stored for one month under conditions of a temperature of 40° C. and a relative humidity of 75%. Reconstitution was carried out in Example 1, Example 2, Example 3, and Comparative Example 1 so that the concentration of bortezomib was 1 mg/ml for the freeze-dried pharmaceutical composition of each Example prepared above. 3 mL of saline solution was added, and in Examples 4, 5, and 6, 2 mL of physiological saline solution was added, and the mixture was gently shaken two or three times. The reconstitution time was measured as the time from the addition of physiological saline until the lyophilized pharmaceutical composition was completely dissolved.
The results of Test Example 1 are shown in Table 3.
表３の結果より、比較例１では、試験開始時に比べて、貯蔵後の再調製時間が大幅に遅延した。一方、実施例１～６では、比較例１で見られた再調製時間の遅延が顕著に抑制されていた。 From the results in Table 3, in Comparative Example 1, the reconditioning time after storage was significantly delayed compared to the time at the start of the test. On the other hand, in Examples 1 to 6, the delay in reconditioning time observed in Comparative Example 1 was significantly suppressed.
＜試験例２＞
実施例１及び比較例１について、貯蔵条件を温度６０℃、７日間に変更したこと以外は試験例１と同様の方法で安定性試験を実施した。そして、試験前後の凍結乾燥医薬組成物の再調製時間については、試験例１と同様に測定した。その結果を表４に示す。
<Test Example 2>
Regarding Example 1 and Comparative Example 1, a stability test was conducted in the same manner as Test Example 1 except that the storage conditions were changed to a temperature of 60° C. for 7 days. The re-preparation time of the freeze-dried pharmaceutical composition before and after the test was measured in the same manner as in Test Example 1. The results are shown in Table 4.
表４の結果より、比較例１では、試験開始時に比べて、貯蔵後の再調製時間が大幅に遅延した。一方、実施例１では、比較例１で見られた再調製時間の遅延が顕著に抑制された。 From the results in Table 4, in Comparative Example 1, the reconditioning time after storage was significantly delayed compared to the time at the start of the test. On the other hand, in Example 1, the delay in reconditioning time observed in Comparative Example 1 was significantly suppressed.
本発明は貯蔵後における再調製時間の遅延が抑制されており、良好な再調製が可能であるボルテゾミブ又はその誘導体を含有する凍結乾燥医薬組成物を提供するものであり、医薬品等の分野において産業上の利用可能性を有する。 The present invention provides a freeze-dried pharmaceutical composition containing bortezomib or its derivatives, which has a suppressed delay in reconstitution time after storage and can be easily reconstituted. With availability above.
Claims (1)
前記凍結乾燥医薬組成物の水分含量が１．０％以下であり、
前記ゴム栓の水分値は０．２５％以下であり、
温度４０℃、相対湿度７５％下で１ヶ月貯蔵した後の再調製時間の遅延率が３００％以下に抑制されている、凍結乾燥医薬組成物。 A lyophilized pharmaceutical composition in which a pharmaceutical composition containing 3 mg of bortezomib and 30 mg of D- mannitol is filled into a vial and sealed with a rubber stopper ,
The moisture content of the freeze-dried pharmaceutical composition is 1.0% or less,
The moisture value of the rubber stopper is 0.25% or less,
A lyophilized pharmaceutical composition having a reconstitution time delay rate of 300% or less after being stored for one month at a temperature of 40° C. and a relative humidity of 75%.
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