JP2019094284A - Injection solution formulation containing pemetrexed - Google Patents
Injection solution formulation containing pemetrexed Download PDFInfo
- Publication number
- JP2019094284A JP2019094284A JP2017223610A JP2017223610A JP2019094284A JP 2019094284 A JP2019094284 A JP 2019094284A JP 2017223610 A JP2017223610 A JP 2017223610A JP 2017223610 A JP2017223610 A JP 2017223610A JP 2019094284 A JP2019094284 A JP 2019094284A
- Authority
- JP
- Japan
- Prior art keywords
- pemetrexed
- solution
- cysteine
- concentration
- less
- 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.)
- Pending
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- 239000000243 solution Substances 0.000 title claims abstract description 92
- 229960005079 pemetrexed Drugs 0.000 title claims abstract description 65
- 239000000203 mixture Substances 0.000 title claims abstract description 41
- 238000009472 formulation Methods 0.000 title claims abstract description 38
- 238000002347 injection Methods 0.000 title claims abstract description 27
- 239000007924 injection Substances 0.000 title claims abstract description 27
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 title claims abstract 8
- 238000002360 preparation method Methods 0.000 claims abstract description 55
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims abstract description 43
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims abstract description 43
- 235000018417 cysteine Nutrition 0.000 claims abstract description 43
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 33
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000011975 tartaric acid Substances 0.000 claims abstract description 29
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 29
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims description 36
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
- 229940102223 injectable solution Drugs 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000011800 void material Substances 0.000 claims description 9
- 238000010828 elution Methods 0.000 claims description 8
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052710 silicon Inorganic materials 0.000 claims description 5
- 239000010703 silicon Substances 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 4
- 238000004659 sterilization and disinfection Methods 0.000 claims description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 abstract description 24
- 238000003860 storage Methods 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 11
- 238000004040 coloring Methods 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 6
- 230000007774 longterm Effects 0.000 abstract description 5
- 238000004090 dissolution Methods 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 63
- 229960002433 cysteine Drugs 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000000052 comparative effect Effects 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 229920001971 elastomer Polymers 0.000 description 15
- 239000000126 substance Substances 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000008215 water for injection Substances 0.000 description 12
- 239000003963 antioxidant agent Substances 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 235000006708 antioxidants Nutrition 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- -1 alkali metal salts Chemical class 0.000 description 9
- 230000003078 antioxidant effect Effects 0.000 description 9
- 239000005388 borosilicate glass Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- NYDXNILOWQXUOF-UHFFFAOYSA-L disodium;2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)NC(CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-UHFFFAOYSA-L 0.000 description 8
- 239000011521 glass Substances 0.000 description 8
- 239000000654 additive Substances 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 229910021645 metal ion Inorganic materials 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 6
- 229960001305 cysteine hydrochloride Drugs 0.000 description 6
- 239000011148 porous material Substances 0.000 description 6
- 238000011146 sterile filtration Methods 0.000 description 6
- LCOBNBPKWCKAKF-UHFFFAOYSA-N 1-[3,6-dihydroxy-2,4-bis(phenylmethoxy)phenyl]ethanone Chemical compound OC1=C(OCC=2C=CC=CC=2)C(C(=O)C)=C(O)C=C1OCC1=CC=CC=C1 LCOBNBPKWCKAKF-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 150000003863 ammonium salts Chemical class 0.000 description 5
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- 239000011261 inert gas Substances 0.000 description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 229940009662 edetate Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 229940095064 tartrate Drugs 0.000 description 4
- 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 description 3
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 230000009918 complex formation Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000007872 degassing Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910003002 lithium salt Inorganic materials 0.000 description 3
- 159000000002 lithium salts Chemical class 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 229940037001 sodium edetate Drugs 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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- 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 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 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 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
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- 239000002246 antineoplastic agent Substances 0.000 description 2
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- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
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Abstract
Description
本発明は、ペメトレキセドの安定性が保持された注射用溶液製剤に関する。 The present invention relates to injectable solution formulations in which the stability of pemetrexed is maintained.
ペメトレキセドは、化学名をＮ−［４−［２−（２−アミノ−４−オキソ−４，７−ジヒドロ−１Ｈ−ピロロ［２，３−ｄ］ピリミジン−５−イル）エチル］ベンゾイル］Ｌ−グルタミン酸であり、その２ナトリウム塩が代謝拮抗性抗悪性腫瘍剤として、悪性胸膜中皮腫及び切除不能な進行・再発の非小細胞肺癌の治療剤として用いられている。ペメトレキセドの医薬製剤は、有効成分のペメトレキセドナトリウム水和物と添加剤のＤ−マンニトールとを含む凍結乾燥粉製剤が、ペメトレキセド注射用製剤（アリムタ（ＡＬＩＭＴＡ 登録商標））として提供されている。該製剤は、投与時に生理食塩液を加えて充分に溶解し、必要量の溶解液を抜き取り、生理食塩液に混和し１００ｍＬとして用いられる。 Pemetrexed has the chemical name N- [4- [2- (2-amino-4-oxo-4,7-dihydro-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] L -Glutamic acid, and its disodium salt is used as an antimetabolite antineoplastic agent, as a therapeutic agent for malignant pleural mesothelioma and unresectable, advanced / recurrent non-small cell lung cancer. The pharmaceutical preparation of pemetrexed is provided as a freeze-dried powder formulation containing the active ingredient pemetrexed sodium hydrate and the additive D-mannitol as a preparation for injection of pemetrexed (ALIMTA (registered trademark)). At the time of administration, the preparation is sufficiently dissolved by adding physiological saline, and the required amount of solution is withdrawn, mixed with the physiological saline and used as 100 mL.
一般的に凍結乾燥製剤は保存安定性に優れるものの、用時に溶解工程が必要であり、完全に溶解させるため十分な混和操作が必要となる。したがって、医療現場において、煩雑な溶解工程が不要で、希釈してすぐ投与できる溶液形態のＲＴＵ（Ｒｅａｄｙ−ｔｏ−ｕｓｅ）製剤が求められている。 In general, lyophilized preparations are excellent in storage stability, but require a dissolution step at the time of use, and a sufficient mixing operation is required for complete dissolution. Therefore, there is a need for an RTU (Ready-to-use) preparation in the form of a solution which can be diluted and immediately administered without complicated dissolution steps at medical sites.
ペメトレキセドは溶液安定性が低い物性であることが知られており、水溶液中で主に酸化反応を伴う分解反応が進行する。そこで、ペメトレキセドの水溶液中での分解を抑制した水溶液製剤処方物が報告されている。特許文献１は、酸素分圧が０．２％以下のペメトレキセド二ナトリウム溶液製剤を開示しており、減圧脱気、蒸留脱気、窒素バブリング、膜脱気や触媒樹脂脱気方法が用いられることを記載している。
一方、種々の抗酸化性添加剤を用いてペメトレキセドの安定性を向上させた水溶液製剤も報告されている。特許文献２は、抗酸化剤としてモノチオグリセロール、システインまたはチオグリコール酸を用いたペメトレキセド水溶液製剤を開示している。特許文献３には、リポ酸、ジヒドロリポ酸、メチオニンまたはこれらの混合物から選択される抗酸化剤、及びラクトビオン酸、三塩基性クエン酸ナトリウムまたはこれらの混合物から選択されるキレート剤を含有するペメトレキセド溶液製剤が記載されている。特許文献４には、クエン酸及びシステインから選択される抗酸化剤を含むペメトレキセド溶液製剤が記載されている。特許文献５には、システイン、アルギニン及びプロピレングリコールを含有するペメトレキセド溶液製剤が記載されている。特許文献６には、システイン及びチオグリセリンを含有するペメトレキセド溶液製剤が記載されている．特許文献７には、アセチルシステイン及びクエン酸ナトリウムを含有するペメトレキセド溶液製剤が記載されている。
It is known that pemetrexed is a material having low solution stability, and a decomposition reaction mainly involving an oxidation reaction proceeds in an aqueous solution. Therefore, there have been reported aqueous solution formulations in which degradation of pemetrexed in an aqueous solution is suppressed. Patent Document 1 discloses a pemetrexed disodium solution preparation having an oxygen partial pressure of 0.2% or less, and a vacuum degassing, distillation degassing, nitrogen bubbling, membrane degassing or catalyst resin degassing method is used. Is listed.
On the other hand, aqueous solution formulations in which the stability of pemetrexed is improved using various antioxidant additives have also been reported. Patent Document 2 discloses an aqueous solution preparation of pemetrexed using monothioglycerol, cysteine or thioglycolic acid as an antioxidant. Patent Document 3 discloses a pemetrexed solution containing an antioxidant selected from lipoic acid, dihydrolipoic acid, methionine or a mixture thereof, and a chelating agent selected from lactobionic acid, tribasic sodium citrate or a mixture thereof The formulation is described. Patent Document 4 describes a pemetrexed solution formulation containing an antioxidant selected from citric acid and cysteine. Patent Document 5 describes a pemetrexed solution formulation containing cysteine, arginine and propylene glycol. Patent Document 6 describes a pemetrexed solution formulation containing cysteine and thioglycerin. Patent Document 7 describes a pemetrexed solution formulation containing acetylcysteine and sodium citrate.
本発明が解決しようとする課題は、長期保存においても、類縁物質の生成を抑制すると共に不溶性異物の生成及び溶液の着色が抑制されたペメトレキセドを含む注射用溶液製剤を提供することにある。特には、ペメトレキセドの溶液形態のＲＴＵ製剤として、有機溶剤等の不溶性類縁物質可溶化剤を用いなくても良い単純な組成のペメトレキセド溶液製剤を提供することを課題とする。 The problem to be solved by the present invention is to provide a solution preparation for injection containing pemetrexed in which the formation of insoluble substances and the coloration of the solution are suppressed while suppressing the formation of related substances even in long-term storage. In particular, it is an object of the present invention to provide a pemetrexed solution preparation of a simple composition which does not need to use an insoluble analogue solubilizing agent such as an organic solvent as an RTU preparation of a solution form of pemetrexed.
本発明は、ペメトレキセド有効成分とする注射用溶液製剤において、システイン又はその塩をシステイン換算で０．０５ｍｇ／ｍＬ以上で０．２ｍｇ／ｍＬ未満で用い、酒石酸又はその塩を酒石酸換算で０．０１ｍｇ／ｍＬ以上で２ｍｇ／ｍＬ以下で含む処方が、有機溶剤を用いなくても、有効成分であるペメトレキセドの分解を抑制するとともに、不溶性異物の生成及び溶液着色を抑制できることを見出したことに基づく。以下の［１］〜［５］に記載の発明を要旨とする。
［１］ペメトレキセド又は薬学的に許容できるその塩、システイン又はその塩、並びに酒石酸又はその塩、を含有する注射用溶液製剤であって、システイン又はその塩の濃度がシステイン換算で０．０５ｍｇ／ｍＬ以上で０．２ｍｇ／ｍＬ未満であり、酒石酸又はその塩の濃度が酒石酸換算で０．０１ｍｇ／ｍＬ以上で２ｍｇ／ｍＬ以下である、有機溶剤を含まないペメトレキセドを含有する注射用溶液製剤。
［２］密閉容器に封入され、容器内の空隙酸素濃度が１％以下である前記［１］に記載の注射用溶液製剤。
［３］ペメトレキセドの濃度が５ｍｇ／ｍＬ以上で５０ｍｇ／ｍＬ以下である前記［１］又は［２］に記載の注射用溶液製剤
［４］ｐＨが７．０〜８．０である前記［１］〜［３］の何れか一項に記載の注射用溶液製剤
［５］水を充填し封をした後、１２１℃で１時間高圧蒸気滅菌処理後の水へのケイ素の溶出量が１ｐｐｍ以下のガラスバイアルを使用した前記［１］〜［４］の何れか一項に記載の注射用溶液製剤
The present invention uses a cysteine or its salt in an amount of 0.05 mg / mL or more and less than 0.2 mg / mL in terms of cysteine and 0.01 mg of tartaric acid or a salt thereof in terms of tartaric acid in an injectable solution preparation containing pemetrexed as an active ingredient. It is based on the finding that a formulation containing 2 mL / mL or more and 2 mg / mL or more can suppress the decomposition of pemetrexed, which is an active ingredient, and can suppress the formation of insoluble foreign matter and solution coloring, even without using an organic solvent. The inventions described in the following [1] to [5] are summarized.
[1] An injectable solution preparation containing pemetrexed or pharmaceutically acceptable salt thereof, cysteine or salt thereof, and tartaric acid or salt thereof, wherein the concentration of cysteine or salt thereof is 0.05 mg / mL in terms of cysteine An injectable solution preparation containing pemetrexed containing no organic solvent, wherein the concentration is less than 0.2 mg / mL and the concentration of tartaric acid or a salt thereof is 0.01 mg / mL or more and 2 mg / mL or less in terms of tartaric acid.
[2] The injectable solution preparation according to the above [1], which is enclosed in a closed container, and the void oxygen concentration in the container is 1% or less.
[3] The injectable solution preparation according to the above [1] or [2], wherein the concentration of pemetrexed is 5 mg / mL or more and 50 mg / mL or less [4] the above [1] whose pH is 7.0 to 8.0 The solution preparation for injection [5] according to any one of [1] to [3], filled with water and sealed, and then the amount of eluted silicon in water after high-pressure steam sterilization treatment at 121 ° C. for 1 hour is 1 ppm or less Solution preparation for injection according to any one of the above [1] to [4] using a glass vial of
本発明のペメトレキセドを含有する注射用溶液製剤は、システイン及び酒石酸の添加によりペメトレキセドの分解物である類縁物質の生成を抑制することができ、且つ不溶性異物及び溶液変色を抑制することができ、保存安定性に優れたペメトレキセドのＲＴＵ製剤を提供することができる。特にプロピレングリコール等の有機溶剤を用いることのない製剤処方とすることができ、ペメトレキセドの効能および安全性を長期に亘って保持することができ、安全性に優れ、投与溶液の調製が容易な製剤を提供することができる。 The injectable solution preparation containing pemetrexed according to the present invention can suppress the formation of an analogue which is a degradation product of pemetrexed by addition of cysteine and tartaric acid, and can suppress insoluble foreign substances and solution discoloration, An RTU preparation of pemetrexed with excellent stability can be provided. In particular, it can be formulated without using organic solvents such as propylene glycol, can maintain the efficacy and safety of pemetrexed for a long time, is excellent in safety, and is easy to prepare administration solutions. Can be provided.
本発明は、ペメトレキセドを有効成分とする注射用溶液製剤において、有機溶剤を含まず、システイン又はその塩をシステイン換算で０．０５〜０．２ｍｇ／ｍＬ及び酒石酸又はその塩を酒石酸換算で０．０１ｍｇ／ｍＬ〜２ｍｇ／ｍＬになるように用いたペメトレキセドを含有する注射用溶液製剤である。以下にその詳細をについて説明する。 The present invention is a solution formulation for injection comprising pemetrexed as an active ingredient, wherein the organic solvent is not contained, cysteine or a salt thereof is 0.05 to 0.2 mg / mL in terms of cysteine and tartaric acid or a salt thereof is 0. 0 in terms of tartaric acid. It is a solution formulation for injection containing pemetrexed used to be 01 mg / mL to 2 mg / mL. The details will be described below.
本発明におけるペメトレキセドは、代謝拮抗性抗腫瘍剤の有効成分として用いられている、化学名でＮ−［４−［２−（２−アミノ−４−オキソ−４，７−ジヒドロ−１Ｈ−ピロロ［２，３−ｄ］ピリミジン−５−イル）エチル］ベンゾイル］Ｌ−グルタミン酸であり、その薬学的に許容できるその塩である。前記薬学的に許容できる塩とは、ナトリウム塩、カリウム塩、リチウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩、トリメチルアンモニウム塩、トリエチルアンモニウム塩、モノエタノールアンモニウム塩、トリエタノールアンモニウム塩、ピリジニウム塩、置換ピリジニウム塩などの医薬的に許容し得るアルカリ金属塩、アルカリ土類金属塩、アンモニウム塩および置換アンモニウム塩などが挙げられる。ナトリウム塩を用いることが好ましく、２ナトリウム塩であることが好ましい。すなわち、本発明において、ペメトレキセド２ナトリウム塩を用いることが好ましい。前記ペメトレキセド又は薬学的に許容できるその塩は、無水物又は水和物や溶媒和物であっても良い。水和物としては２．５水和物や７水和物が知られており、特に限定なく用いることができる。 Pemetrexed in the present invention is N- [4- [2- (2-amino-4-oxo-4,7-dihydro-1H-pyrrolo) by the chemical name, which is used as an active ingredient of the antimetabolite antitumor agent. [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] L-glutamic acid, a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt includes sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, ammonium salt, trimethyl ammonium salt, triethyl ammonium salt, monoethanol ammonium salt, triethanol ammonium salt, pyridinium salt, substitution Pharmaceutically acceptable alkali metal salts such as pyridinium salts, alkaline earth metal salts, ammonium salts and substituted ammonium salts and the like. It is preferred to use a sodium salt, preferably a disodium salt. That is, in the present invention, it is preferable to use pemetrexed disodium salt. The pemetrexed or pharmaceutically acceptable salt thereof may be an anhydride or a hydrate or a solvate. As the hydrate, 2.5 hydrate and heptahydrate are known, and can be used without particular limitation.
本発明は、システイン又はシステイン塩を用いる。該システイン塩は、塩酸塩、硫酸塩、リン酸塩、メシル酸塩、トシル酸塩、等の酸との塩、若しくはナトリウム塩、カリウム塩、リチウム塩、アンモニウム塩、アミン塩、ピリジニウム塩等の薬学的に許容できる塩で用いることができる。本発明の溶液製剤を調製する場合ためには、システイン又はシステイン塩酸塩を用いることが好ましい。 The present invention uses cysteine or cysteine salts. The cysteine salt is a salt with an acid such as hydrochloride, sulfate, phosphate, mesylate, tosylate or the like, or sodium salt, potassium salt, lithium salt, ammonium salt, amine salt, pyridinium salt, etc. It can be used as a pharmaceutically acceptable salt. It is preferred to use cysteine or cysteine hydrochloride when preparing the solution formulation of the present invention.
前記システインの濃度は、０．０５ｍｇ／ｍＬ以上で用いることが好ましく、上限は０．２ｍｇ／ｍＬ未満で用いることが好ましい。システインの濃度とは、システイン又はその塩の添加量から、システイン換算とした濃度を示す。システイン濃度が０．０５ｍｇ／ｍＬ未満である場合、保存期間中における十分な類縁物質生成抑制効果が得られない可能性がある。一方、システイン濃度が０．２ｍｇ／ｍＬ以上である場合、ペメトレキセド類縁物質の生成抑制効果は得られるものの、不溶性異物の生成が起こり得る可能性がある。好ましくは、システイン換算濃度として０．０５ｍｇ／ｍＬ以上で０．１５ｍｇ／ｍＬ以下の濃度である。さらに好ましくは、０．１ｍｇ／ｍＬ以上で０．１３ｍｇ／ｍＬ以下の濃度である。 The concentration of cysteine is preferably 0.05 mg / mL or more, and the upper limit is preferably less than 0.2 mg / mL. The concentration of cysteine refers to the concentration converted to cysteine from the added amount of cysteine or its salt. If the concentration of cysteine is less than 0.05 mg / mL, it may not be possible to obtain a sufficient analog substance production inhibitory effect during the storage period. On the other hand, when the cysteine concentration is 0.2 mg / mL or more, although the effect of suppressing the formation of the pemetrexed analogue can be obtained, the formation of insoluble foreign matter may occur. Preferably, the concentration in terms of cysteine is 0.05 mg / mL or more and 0.15 mg / mL or less. More preferably, the concentration is 0.1 mg / mL or more and 0.13 mg / mL or less.
ペメトレキセド注射用溶液製剤中の類縁物質を抑制するための抗酸化剤として、システイン又はその塩を用いることは広く知られている。しかしながら、該溶液製剤の長期保存中にペメトレキセドが二価の金属イオンと錯体を形成し、不溶性の微粒子を形成することが報告されている。そこで金属捕捉剤としてＥＤＴＡ等のキレート剤やクエン酸等の有機酸類を共存させる製剤例や、さらにプロピレングリコール等の可溶化剤となる有機溶剤及び酒石酸を添加した溶液製剤が知られていた。
しかしながら、製剤用添加剤であっても人体に対して望ましくない副作用を示す場合がある。例えばＥＤＴＡや有機溶剤は静脈内投与による炎症作用やアレルギー作用の可能性等の副作用が知られている。したがって、注射用溶液製剤としては、有効成分とその溶媒である水以外の添加剤は極力少なくし、もし添加剤が必要であったとしても身体に対する刺激性や炎症作用の少ない添加剤を選択することが望ましいといえる。
本発明は、抗酸化剤としてシステイン又はその塩を用いたペメトレキセドを含有する溶液製剤において、酒石酸又はその塩を最適な濃度で添加し、容器内の空隙の酸素濃度を低減することで、ペメトレキセド由来の類縁物質生成を抑制すると共に、ペメトレキセドと二価金属イオンとの錯体形成による不溶性の微粒子形成を抑制できる。したがって、可溶化剤等の有機溶剤を用いなくても、長期保存期間中も安定性を維持した注射用溶液製剤を見出した。
It is widely known to use cysteine or its salts as an antioxidant to inhibit analogues in pemetrexed injectable solution formulations. However, it has been reported that pemetrexed forms a complex with divalent metal ions during long-term storage of the solution preparation to form insoluble microparticles. Therefore, there have been known formulation examples in which a chelating agent such as EDTA or an organic acid such as citric acid coexists as a metal capture agent, and a solution formulation further containing an organic solvent as a solubilizing agent such as propylene glycol and tartaric acid.
However, even pharmaceutical additives may exhibit undesirable side effects on the human body. For example, EDTA and organic solvents are known to have side effects such as the inflammatory action and the possibility of allergic action by intravenous administration. Therefore, as the solution preparation for injection, the active ingredient and its solvent other than water should be minimized, and the additive with little irritation and inflammation to the body should be selected even if the additive is required. Is desirable.
The present invention relates to a solution preparation containing pemetrexed using cysteine or a salt thereof as an antioxidant, wherein tartaric acid or a salt thereof is added at an optimum concentration to reduce the oxygen concentration of the void in the container, thereby obtaining pemetrexed origin. Formation of insoluble fine particles due to complex formation between pemetrexed and a divalent metal ion. Therefore, the present inventors have found a solution formulation for injection that maintains its stability during long-term storage without using organic solvents such as solubilizers.
本発明は、酒石酸又は酒石酸塩を用いる。該酒石酸塩とは、ナトリウム塩、カリウム塩、リチウム塩、アンモニウム塩、アミン塩、ピリジニウム塩等の薬学的に許容できる塩で用いることができる。本発明の溶液製剤を調製する場合ためには、酒石酸又は酒石酸ナトリウム塩を用いることが好ましい。
本発明の注射用溶液製剤中のペメトレキセドと二価金属イオンとの錯体形成を抑制する酒石酸又はその塩の濃度は、酒石酸として０．０１ｍｇ／ｍＬ以上で用いることが好ましく、上限は２ｍｇ／ｍＬ以下で用いることである。酒石酸の濃度とは、酒石酸又はその塩の添加量から、酒石酸換算とした濃度を示す。酒石酸濃度が０．０１ｍｇ／ｍＬ未満である場合、保存期間中における十分な不溶性微粒子の抑制効果が得られない可能性がある。好ましくは、酒石酸換算濃度として０．０５ｍｇ／ｍＬ以上で１．５ｍｇ／ｍＬ以下の濃度である。さらに好ましくは、０．１ｍｇ／ｍＬ以上で１．２ｍｇ／ｍＬ以下の濃度である。
The present invention uses tartaric acid or tartrate. The tartrate may be used as a pharmaceutically acceptable salt such as sodium salt, potassium salt, lithium salt, ammonium salt, amine salt, pyridinium salt and the like. When preparing the solution formulation of the present invention, it is preferred to use tartaric acid or tartrate sodium salt.
The concentration of tartaric acid or a salt thereof which suppresses the complex formation between pemetrexed and divalent metal ion in the injectable solution preparation of the present invention is preferably 0.01 mg / mL or more as tartaric acid, and the upper limit is 2 mg / mL or less It is to use in The concentration of tartaric acid refers to the concentration of tartaric acid or its salt added in terms of tartaric acid. When the tartaric acid concentration is less than 0.01 mg / mL, a sufficient inhibitory effect on insoluble microparticles during storage may not be obtained. Preferably, it is a concentration of 0.05 mg / mL or more and 1.5 mg / mL or less as a tartaric acid equivalent concentration. More preferably, the concentration is 0.1 mg / mL or more and 1.2 mg / mL or less.
本発明の注射用溶液製剤において、医薬品の添加物として許容される有機溶剤は含まない。医薬品の添加物として許容される有機溶剤としては、例えば、エタノール、ベンジルアルコール、ジブチルヒドロキシトルエン、ソルビタン脂肪酸エステル、ソルビタンセスキオレイン酸エステル、プロピレングリコール、ベンジルアルコール、ポリオキシエチレン硬化ヒマシ油、ポリソルベート２０、ポリソルベート８０、マクロゴール類、モノエタノールアミンなどが知られている。すなわち、本発明の注射用溶液製剤は、前記有機溶剤を含まず、水を唯一の溶剤として含有する水溶液製剤である。 The injectable solution preparation of the present invention does not contain an organic solvent acceptable as a pharmaceutical additive. Examples of organic solvents acceptable as additives for pharmaceuticals include ethanol, benzyl alcohol, dibutylhydroxytoluene, sorbitan fatty acid ester, sorbitan sesquioleate ester, propylene glycol, benzyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 20, Polysorbate 80, macrogols, monoethanolamine and the like are known. That is, the injectable solution preparation of the present invention is an aqueous solution preparation which does not contain the organic solvent and contains water as a sole solvent.
本発明の注射用溶液製剤において、システイン又はその塩、並びに酒石酸又はその塩以外の他の製剤用添加剤を、ペメトレキセドの安定性を維持する範囲において用いても良い。該他の製剤用添加剤としては、通常の医薬製剤に用いられる抗酸化剤、緩衝剤、ｐＨ調整剤、等張化剤、キレート剤、安定化剤等を添加しても良い。
抗酸化剤としては、例えば、アスコルビン酸、亜硫酸ナトリウム、亜硫酸水素ナトリウム、ピロ亜硫酸ナトリウム、クエン酸、チオグリコール酸ナトリウム、αチオグリセリン、エデト酸ナトリウム、メチオニン、アセチルシステインなどがあげられる。
緩衝剤としては、例えば、リン酸塩、クエン酸塩、酢酸塩等を挙げることができる。
ｐＨ調節剤としては、例えば、塩酸、水酸化ナトリウム、酢酸やその塩、リン酸やその塩、クエン酸やその塩などがあげられる。
キレート剤としては、例えば、エデト酸ナトリウム（ＥＤＴＡ）があげられる。
等張化剤としては、塩化ナトリウム、塩化カルシウム、塩化マグネシウム、グリセリン、果糖、キシリトール、ソルビトール、トレハロース、ニコチンアミド、ブドウ糖、精製白糖、マンニトールなどがあげられる。
安定化剤としては、例えば、アセチルトリプトファン、アラニン、アルブミン、安息香酸やその塩、イノシトール、ヒスチジンやその塩、果糖、カルジアミドナトリウム、カルバゾクロムスルホン酸ナトリウム、炭酸ナトリウム、キシリトール、グリシン、グルタミン酸やその塩、クレアチニン、リン酸二水素ナトリウム、コンドロイチン硫酸ナトリウム、ジエチレントリアミン五酢酸、シスチン、臭化カルシウム、ゼラチン、ソルビトール、炭酸水素ナトリウム、チオシアン酸カリウム、デキストラン、糖酸カルシウム、ナトリウムホルムアルデヒドスルホシレート、ニコチン酸アミド、乳酸、乳糖、尿素、パラオキシ安息香酸プロピル、パラオキシ安息香酸メチル、氷酢酸、ベンザルコニウム、ベンゼトニウム、マルトース、ピロリン酸ナトリウム、マレイン酸、リン酸やその塩、メグルミン、メタスルホ安息香酸ナトリウム、リジン塩酸塩、硫酸マグネシウムなどがあげられる。
但し、これらの添加剤は、必須としない任意成分である。より好ましくは、本発明の溶液製剤はキレート剤であるエデト酸ナトリウム（ＥＤＴＡ）を含まない製剤であることが好ましい。更に、本発明の溶液製剤は、他の抗酸化剤を含有せずに、システインを唯一の抗酸化剤として用いることが好ましい。また、安定化剤としてアルギニン又はその塩を含まない処方であることが好ましい。
In the injectable solution preparation of the present invention, other pharmaceutical additives other than cysteine or a salt thereof and tartaric acid or a salt thereof may be used as long as the stability of pemetrexed is maintained. As the other pharmaceutical additive, an antioxidant, a buffer, a pH adjuster, a tonicity agent, a chelating agent, a stabilizer and the like used in a usual pharmaceutical preparation may be added.
Examples of the antioxidant include ascorbic acid, sodium sulfite, sodium bisulfite, sodium pyrosulfite, citric acid, sodium thioglycolate, α-thioglycerin, sodium edetate, methionine, acetylcysteine and the like.
As the buffer, for example, phosphate, citrate, acetate and the like can be mentioned.
Examples of pH adjusters include hydrochloric acid, sodium hydroxide, acetic acid and salts thereof, phosphoric acid and salts thereof, and citric acid and salts thereof.
Examples of chelating agents include sodium edetate (EDTA).
As tonicity agents, sodium chloride, calcium chloride, magnesium chloride, glycerin, fructose, xylitol, sorbitol, trehalose, nicotinamide, glucose, refined sucrose, mannitol and the like can be mentioned.
As a stabilizer, for example, acetyl tryptophan, alanine, albumin, benzoic acid and salts thereof, inositol, histidine and salts thereof, fructose, sodium caldiamide sodium, carbazochrome sodium sulfonate, sodium carbonate, xylitol, glycine, glutamic acid and salts thereof Creatine, sodium dihydrogen phosphate, sodium chondroitin sulfate, diethylenetriaminepentaacetic acid, cystine, calcium bromide, gelatin, sorbitol, sodium hydrogencarbonate, potassium thiocyanate, dextran, calcium phosphate, sodium formaldehyde sulfosylate, nicotinamide Lactic acid, lactose, urea, propyl parahydroxybenzoate, methyl parahydroxybenzoate, glacial acetic acid, benzalkonium, benzethonium, maltose, pyrophosphate Thorium, maleic acid, phosphoric acid and its salts, meglumine, sodium metasulfobenzoate, lysine hydrochloride, such as magnesium sulfate.
However, these additives are optional components which are not essential. More preferably, the solution preparation of the present invention is a preparation which does not contain the chelating agent sodium edetate (EDTA). Furthermore, the solution formulation of the present invention preferably uses cysteine as the sole antioxidant, without containing other antioxidants. Moreover, it is preferable that it is a prescription which does not contain arginine or its salt as a stabilizer.
本発明の注射用溶液製剤におけるペメトレキセドの濃度は５ｍｇ／ｍＬ以上で５０ｍｇ／ｍＬ以下に設定することが好ましい。より好ましくは、ペメトレキセド濃度として１０ｍｇ／ｍＬ以上で４０ｍｇ／ｍＬ以下である。 The concentration of pemetrexed in the injectable solution preparation of the present invention is preferably set to 5 mg / mL or more and 50 mg / mL or less. More preferably, it is 10 mg / mL or more and 40 mg / mL or less as a pemetrexed concentration.
本発明の注射用溶液製剤は、バイアル状容器に無菌的に充填され、気密性のゴム栓で封止した密封充填製剤として調製される。
使用される容器としては、ゴム栓等で密封可能であれば、バイアル状、シリンジ状等の形状は特に限定されないが、バイアル状の形状が好ましい。容器の材質としては、例えばソーダライムガラス製、ホウケイ酸ガラス製、環状ポリオレフィンポリマー製、環状ポリオレフィンコポリマー製があげられる。
ペメトレキセドは、二価金属イオンと錯体を形成し、不溶性微粒子を形成することから、ガラス成分の溶出が抑制されたバイアルを使用する方が好ましい。特に水を充填し、封をしたバイアルに対して、１２１℃で高圧蒸気滅菌処理を１時間行った後に水へ溶出するケイ素が１ｐｐｍ以下であるバイアルが好ましい。このようなケイ素の溶出が抑制されたガラスバイアルとしては、ガラス成分の溶出抑制等の目的に応じて表面処理された容器を用いることが好ましい。特に、シリコート内面処理したホウケイ酸ガラスバイアルを用いることが好ましい。シリコート表面処理されたバイアルの例として、シリコートバイアル（不二硝子（株）製）が挙げられる。その他ガラス成分の溶出が抑制されるバイアルとしてＶＩＳＴバイアル（大和特殊硝子（株）製）、ＶＩＡＬＥＸ（ニプロ（株）製）、ｔｙｐｅ１ ｐｌｕｓ（ＳＣＨＯＴＴ（株）製）などが挙げられる。
この容器を用いて、本発明の方法で脱酸素処理を行い、気密性のゴム栓で封止することにより、高度に脱酸素された注射用溶液製剤を調製することができる。ゴム栓の材質としては、ブチルゴム製のもの、さらにフッ素樹脂によりラミネートされたブチルゴム製のゴム栓を使用するのが好ましい。
これらの封止可能な容器は、容器及びゴム栓共に適当な方法により滅菌処理を施した包材であることが好ましい。
The injectable solution preparation of the present invention is aseptically filled in a vial-like container and prepared as a sealed filling preparation sealed with an airtight rubber stopper.
The container to be used is not particularly limited in the form of a vial, a syringe or the like, as long as it can be sealed by a rubber stopper or the like, but a vial is preferable. Examples of the material of the container include soda lime glass, borosilicate glass, cyclic polyolefin polymer, and cyclic polyolefin copolymer.
Since pemetrexed forms a complex with a divalent metal ion to form insoluble fine particles, it is preferable to use a vial in which the elution of the glass component is suppressed. In particular, a vial filled with water and sealed by high-pressure steam sterilization at 121 ° C. for one hour is preferably a vial having 1 ppm or less of silicon eluting into water. As such a glass vial in which the elution of silicon is suppressed, it is preferable to use a container which has been surface-treated according to the purpose such as the suppression of the elution of a glass component. In particular, it is preferable to use a borosilicate glass vial which has been treated with silico coat. An example of a silicoated surface-treated vial is a silicoated vial (manufactured by Fuji Glass Co., Ltd.). As vials in which the elution of other glass components is suppressed, VIST vials (Daiwa Special Glass Co., Ltd.), VIALEX (Nipro Co., Ltd.), type 1 plus (SCHOTT Co., Ltd.) and the like can be mentioned.
Using this container, deoxygenation treatment is carried out according to the method of the present invention, and sealing with an airtight rubber stopper makes it possible to prepare a highly deoxygenated injectable solution preparation. As a material of the rubber plug, it is preferable to use one made of butyl rubber, and further a rubber plug made of butyl rubber laminated with a fluorine resin.
These sealable containers are preferably packaging materials that have been sterilized by an appropriate method for both the container and the rubber stopper.
ペメトレキセドは、主に酸化によって類縁物質を生成することが知られている。従って、本発明の注射用溶液製剤は、溶液中の溶存酸素の濃度を制御することが好ましい。該製剤の容器の空隙の酸素濃度が１％以下であることが好ましい。より好ましくは、容器の空隙の酸素濃度が０．５％以下の注射用溶液製剤である。
溶液中の溶存酸素濃度は、酸素センサーを用いた酸素濃度測定器により測定することができる。例えば、ニードル式酸素センサーを接続した酸素濃度計（ＭｉｃｒｏｘＴＸ３、製造元：ＰｒｅＳｅｎｓ社）を用い、当該注射用溶液製剤の溶液に酸素濃度計の酸素センサーを接液させることで、本発明に係る密封状態のバイアル製剤中の溶存酸素濃度を測定することができる。
なお、本発明の注射用製剤は、バイアル充填された溶液以外の空間（ヘッドスペース）は、窒素やアルゴン等の不活性ガスが充填されていることが好ましい。溶存酸素濃度は、ヘッドスペース内の酸素分圧に影響する。溶存酸素濃度を減少させるためには、ヘッドスペース内の酸素を除去することが有効であり、窒素やアルゴン等の不活性ガスを充填しておくことが好ましい。
Pemetrexed is known to produce analogues mainly by oxidation. Therefore, for the injectable solution preparation of the present invention, it is preferable to control the concentration of dissolved oxygen in the solution. It is preferable that the oxygen concentration of the space of the container of the preparation is 1% or less. More preferably, it is an injectable solution preparation in which the concentration of oxygen in the space of the container is 0.5% or less.
The dissolved oxygen concentration in the solution can be measured by an oxygen concentration meter using an oxygen sensor. For example, a sealed state according to the present invention is achieved by bringing the oxygen sensor of the oximeter into contact with the solution of the solution preparation for injection using an oximeter (Microx TX3, manufacturer: PreSens) to which a needle type oxygen sensor is connected. The dissolved oxygen concentration in the vial formulation of
In the preparation for injection of the present invention, the space (head space) other than the solution filled with the vial is preferably filled with an inert gas such as nitrogen or argon. Dissolved oxygen concentration affects the partial pressure of oxygen in the head space. In order to reduce the concentration of dissolved oxygen, it is effective to remove oxygen in the head space, and it is preferable to be filled with an inert gas such as nitrogen or argon.
本発明の注射用溶液製剤における溶液中の溶存酸素の濃度を制御する方法として、溶液が充填された容器内に、窒素やアルゴン等の不活性ガスを直接注入し、一定量の不活性ガスを注入した後に、容器をゴム栓等で密封する方法が挙げられる。この方法を用いることで、注射用溶液中の酸素濃度を１．０ｐｐｍ以下に制御することが可能となる。
また、本発明に係る注射用溶液を充填した容器を密閉空間に設置し、空間内を薬液の任意の温度における蒸気圧を下回らない程度まで減圧し、その後、窒素やアルゴン等の不活性ガスを大気圧になるまで注入し、数時間静置した後、ゴム栓等で密栓する方法を用いても良い。この方法を用いることで、溶液中の酸素濃度を１．０ｐｐｍ以下に制御することが可能となる。
As a method of controlling the concentration of dissolved oxygen in the solution in the injectable solution preparation of the present invention, an inert gas such as nitrogen or argon is directly injected into a container filled with the solution, and a fixed amount of inert gas is injected. After filling, the container may be sealed with a rubber stopper or the like. By using this method, it is possible to control the oxygen concentration in the solution for injection to 1.0 ppm or less.
In addition, a container filled with the solution for injection according to the present invention is installed in a sealed space, the pressure in the space is reduced to a level not lower than the vapor pressure at any temperature of the drug solution, and then inert gas such as nitrogen or argon is After pouring to atmospheric pressure and leaving it to stand for several hours, a method of sealing with a rubber plug or the like may be used. By using this method, it is possible to control the oxygen concentration in the solution to 1.0 ppm or less.
本発明の注射用溶液製剤は、室温、好ましくは冷所にて保存される。また、遮光下で保存することが好ましい。 The injectable solution preparation of the present invention is stored at room temperature, preferably in a cold place. Moreover, it is preferable to preserve | save under light-shielding.
本発明の注射用溶液製剤は、ペメトレキセドを治療剤とする疾病に対する医薬品として使用することができる。 The injectable solution preparation of the present invention can be used as a medicine for diseases in which pemetrexed is used as a therapeutic agent.
以下に、本発明を実施例により更に説明する。ただし、本発明がこれらの実施例に限定されるものではない。 The invention is further illustrated by the following examples. However, the present invention is not limited to these examples.
［実施例１］
酒石酸２ナトリウム２水和物４００ｍｇ（酒石酸に換算して２６１ｍｇ）及びシステイン塩酸塩水和物５８．０ｍｇ（システインに換算して４０ｍｇ）及びペメトレキセド２ナトリウム塩２．５水和物１２，０８２ｍｇ（ペメトレキセドに換算して１０，０００ｍｇ）を適量の注射用水に溶かし、適量の塩酸溶液および適量の水酸化ナトリウム溶液でｐＨ７．８に調整し、注射用水を加えて全量を４００ｍＬとした。
この溶液を、孔径０．２２μｍのメンブランフィルターを用いて無菌ろ過を行い、ホウケイ酸ガラス製のバイアルにろ過した液を４ｍＬ充填し、バイアルの空隙部分に窒素を注入し、ゴム栓で打栓した。その後、アルミキャップにて巻締めを行い、実施例１の注射用溶液製剤を調製した。
Example 1
400 mg of disodium tartrate dihydrate (261 mg in terms of tartaric acid) and 58.0 mg of cysteine hydrochloride hydrate (40 mg in terms of cysteine) and 12,082 mg of pemetrexed disodium salt 2.5 hydrate (pemetrexed in 10,000 mg) was dissolved in an appropriate amount of water for injection, adjusted to pH 7.8 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution, and water for injection was added to make the total volume 400 mL.
This solution was subjected to sterile filtration using a membrane filter with a pore size of 0.22 μm, 4 mL of the filtered solution was filled in a borosilicate glass vial, nitrogen was injected into the void portion of the vial, and stoppered with a rubber stopper . Then, it wound-fastened with the aluminum cap, and prepared the solution formulation for injection of Example 1.
［実施例２］
酒石酸２ナトリウム２水和物５９ｍｇ（酒石酸に換算して３８ｍｇ）及びシステイン塩酸塩水和物７．２ｍｇ（システインに換算して５ｍｇ）及びペメトレキセド２ナトリウム塩２．５水和物１，５１０ｍｇ（ペメトレキセドに換算して１，２５０ｍｇ）を適量の注射用水に溶かし、適量の塩酸溶液および適量の水酸化ナトリウム溶液でｐＨ７．５に調整し、注射用水を加えて全量を５０ｍＬとした。
この溶液を、孔径０．２２μｍのメンブランフィルターを用いて無菌ろ過を行い、シリコート内面処理したホウケイ酸ガラス製バイアルにろ過した液を４ｍＬ充填し、バイアルの空隙部分に窒素を注入し、ゴム栓で打栓した。その後、アルミキャップにて巻締めを行い、実施例２の注射用溶液製剤を調製した。
Example 2
59 mg of disodium tartrate dihydrate (38 mg in terms of tartaric acid) and 7.2 mg of cysteine hydrochloride hydrate (5 mg in terms of cysteine) and 1,510 mg of pemetrexed disodium salt 2.5 hydrate (pemetrexed The solution (1,250 mg) was dissolved in an appropriate amount of water for injection, adjusted to pH 7.5 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution, and water for injection was added to make the total volume 50 mL.
This solution is subjected to sterile filtration using a membrane filter with a pore size of 0.22 μm, 4 mL of the filtered solution is filled in a silicode inner surface treated borosilicate glass vial, nitrogen is injected into the void portion of the vial, and a rubber stopper is used. It was plugged. Then, it wound-fastened with the aluminum cap, and prepared the solution formulation for injection of Example 2.
［実施例３］
前記実施例２に記載の操作において、システイン塩酸塩水和物の添加量を８．７ｍｇ（システインに換算して６．０ｍｇ）とした以外は、実施例２と同様の操作を行い実施例３の注射用溶液製剤を調製した。
[Example 3]
In the procedure described in Example 2, the same procedure as in Example 2 was performed, except that the addition amount of cysteine hydrochloride hydrate was 8.7 mg (6.0 mg in terms of cysteine). A solution formulation for injection was prepared.
［比較例１］
ペメトレキセド２ナトリウム塩２．５水和物１５１０ｍｇ（ペメトレキセドに換算して１２５０ｍｇ）を適量の注射用水に溶かし、適量の塩酸溶液および適量の水酸化ナトリウム溶液でｐＨ７．５に調整し、注射用水を加えて全量を５０ｍＬとした。
この溶液を、孔径０．２２μｍのメンブランフィルターを用いて無菌ろ過を行い、ホウケイ酸ガラス製のバイアルにろ過した液を４ｍＬ充填し、バイアルの空隙部分に窒素を注入し、ゴム栓で打栓した。その後、アルミキャップにて巻締めを行い、比較例１の注射用溶液製剤を調製した。
Comparative Example 1
Dissolve 1510 mg of pemetrexed disodium salt 2.5 hydrate (1250 mg converted to pemetrexed) in an appropriate amount of water for injection, adjust to pH 7.5 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution, and add water for injection The total volume was 50 mL.
This solution was subjected to sterile filtration using a membrane filter with a pore size of 0.22 μm, 4 mL of the filtered solution was filled in a borosilicate glass vial, nitrogen was injected into the void portion of the vial, and stoppered with a rubber stopper . Then, it wound-fastened with the aluminum cap, and prepared the solution formulation for injection of the comparative example 1.
［比較例２］
バイアルについて、シリコート内面処理したホウケイ酸ガラス製バイアルを使用したこと以外については，比較例１と同様の操作を行い、比較例２の注射用溶液製剤を調製した。
Comparative Example 2
The same procedure as in Comparative Example 1 was performed, except that a borosilicate glass vial with inner surface treated with silicoat was used for the vial, to prepare a solution preparation for injection of Comparative Example 2.
［比較例３］
酒石酸２ナトリウム２水和物２５０ｍｇ（酒石酸に換算して１６３ｍｇ）及びペメトレキセド２ナトリウム塩２．５水和物１，５１０ｍｇ（ペメトレキセドに換算して１，２５０ｍｇ）を適量の注射用水に溶かし、適量の塩酸溶液および適量の水酸化ナトリウム溶液でｐＨ７．５に調整し、注射用水を加えて全量を５０ｍＬとした。
この溶液を、孔径０．２２μｍのメンブランフィルターを用いて無菌ろ過を行い、ホウケイ酸ガラス製のバイアルにろ過した液を４ｍＬ充填し、バイアルの空隙部分に窒素を注入し、ゴム栓で打栓した。その後、アルミキャップにて巻締めを行い、比較例３の注射用溶液製剤を調製した。
Comparative Example 3
Dissolve 250 mg of disodium tartrate dihydrate (163 mg in terms of tartaric acid) and 1,510 mg of pemetrexed disodium salt 2.5 hydrate (1,250 mg in terms of pemetrexed) in an appropriate amount of water for injection The pH was adjusted to 7.5 with a hydrochloric acid solution and an appropriate amount of sodium hydroxide solution, and water for injection was added to make the total volume 50 mL.
This solution was subjected to sterile filtration using a membrane filter with a pore size of 0.22 μm, 4 mL of the filtered solution was filled in a borosilicate glass vial, nitrogen was injected into the void portion of the vial, and stoppered with a rubber stopper . Then, it wound-fastened with the aluminum cap, and prepared the solution formulation for injection of the comparative example 3.
［比較例４］
酒石酸２ナトリウム２水和物５９ｍｇ（酒石酸に換算して３８ｍｇ）及びシステイン塩酸塩水和物１４．５ｍｇ（システインに換算して１０ｍｇ）及びペメトレキセド２ナトリウム塩２．５水和物１，５１０ｍｇ（ペメトレキセドに換算して１，２５０ｍｇ）を適量の注射用水に溶かし、適量の塩酸溶液および適量の水酸化ナトリウム溶液でｐＨ７．８に調整し、注射用水を加えて全量を５０ｍＬとした。
この溶液を、孔径０．２２μｍのメンブランフィルターを用いて無菌ろ過を行い、ホウケイ酸ガラス製のバイアルにろ過した液を４ｍＬ充填し、バイアルの空隙部分に窒素を注入し、ゴム栓で打栓した。その後、アルミキャップにて巻締めを行い、比較例４の注射用溶液製剤を調製した。
Comparative Example 4
59 mg of disodium tartrate dihydrate (38 mg in terms of tartaric acid) and 14.5 mg of cysteine hydrochloride hydrate (10 mg in terms of cysteine) and 1,510 mg of pemetrexed disodium salt 2.5 hydrate (pemetrexed The solution (1,250 mg) was dissolved in an appropriate amount of water for injection, adjusted to pH 7.8 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution, and water for injection was added to make the total volume 50 mL.
This solution was subjected to sterile filtration using a membrane filter with a pore size of 0.22 μm, 4 mL of the filtered solution was filled in a borosilicate glass vial, nitrogen was injected into the void portion of the vial, and stoppered with a rubber stopper . Then, it wound-fastened with the aluminum cap, and prepared the solution formulation for injection of the comparative example 4.
［比較例５］
酒石酸２ナトリウム２水和物５０ｍｇ（酒石酸に換算して３３ｍｇ）及びシステイン塩酸塩水和物７．２ｍｇ（システインに換算して５．０ｍｇ）、プロピレングルコール５，０００ｍｇ及びペメトレキセド２ナトリウム塩２．５水和物１，５１０ｍｇ（ペメトレキセドに換算して１，２５０ｍｇ）を適量の注射用水に溶かし、適量の塩酸溶液および適量の水酸化ナトリウム溶液でｐＨ７．８に調整し、注射用水を加えて全量を５０ｍＬとした。
この溶液を、孔径０．２２μｍのメンブランフィルターを用いて無菌ろ過を行い、ホウケイ酸ガラス製のバイアルにろ過した液を４ｍＬ充填し、バイアルの空隙部分に窒素を注入し、ゴム栓で打栓した。その後、アルミキャップにて巻締めを行い、比較例５の注射用溶液製剤を調製した。
Comparative Example 5
50 mg of disodium tartrate dihydrate (33 mg in terms of tartaric acid) and 7.2 mg of cysteine hydrochloride hydrate (5.0 mg in terms of cysteine), 5,000 mg of propylene glycol and pemetrexed disodium salt 2.5 Dissolve 1,510 mg of hydrate (1,250 mg converted to pemetrexed) in an appropriate amount of water for injection, adjust to pH 7.8 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution, add water for injection, and add the total amount to 50 mL.
This solution was subjected to sterile filtration using a membrane filter with a pore size of 0.22 μm, 4 mL of the filtered solution was filled in a borosilicate glass vial, nitrogen was injected into the void portion of the vial, and stoppered with a rubber stopper . Then, it wound-fastened with the aluminum cap, and prepared the solution formulation for injection of the comparative example 5.
［ペメトレキセド類縁物質の分析条件］
実施例及び比較例のペメトレキセド分解由来の類縁物質を、以下の液体クロマトグラフィー（ＨＰＬＣ）条件にて分析した。
カラム：ジーエルサイエンス社製Ｉｎｅｒｔｓｉｌ ＯＤＳ―３（内径４．６ｍｍ、長さ２５ｃｍ）
カラム温度：４０℃
移動相Ａ：リン酸塩緩衝液（ｐＨ ６．８）／アセトニトリル混液（４７：３）
移動相Ｂ：アセトニトリル
送液量：１．０ｍＬ／ｍｉｎ．
波長：２２５ｎｍ
移動相の送液：表１に示す条件で送液した。
[Analytical conditions of pemetrexed analogues]
The analogs derived from pemetrexed degradation of the examples and comparative examples were analyzed under the following liquid chromatography (HPLC) conditions.
Column: GL Science Inertsil ODS-3 (inner diameter 4.6 mm, length 25 cm)
Column temperature: 40 ° C
Mobile phase A: phosphate buffer (pH 6.8) / acetonitrile mixed solution (47: 3)
Mobile phase B: acetonitrile flow rate: 1.0 mL / min.
Wavelength: 225 nm
Delivery of mobile phase: Delivery was performed under the conditions shown in Table 1.
［表１］
［溶存酸素の測定］
ニードル式酸素センサーを接続した酸素濃度計（ＭｉｃｒｏｘＴＸ３、製造元：ＰｒｅＳｅｎｓ社）を使用した。ニードルの先端に酸素に感度を持つ蛍光染料（酸素センサー）がコートされたファイバーがあり、実施例及び比較例の注射用溶液製剤のゴム栓にニードル式酸素センサーを刺し、バイアル中の空隙部分の酸素を測定した。
[Measurement of dissolved oxygen]
An oximeter (Microx TX3, manufacturer: PreSens) connected to a needle type oxygen sensor was used. There is a fiber coated with a fluorescent dye (oxygen sensor) sensitive to oxygen at the tip of the needle, and the rubber stopper of the solution preparation for injection of the example and comparative example is pierced with the needle type oxygen sensor. Oxygen was measured.
［試験例］６０℃保存安定性試験
実施例１〜３及び比較例１〜５の注射用溶液製剤を、６０℃の条件下にて２週間まで保存した。各製剤について、性状（着色）、ｐＨ、ペメトレキセド由来の類縁物質、目視による不溶性異物の有無を評価した。また、製剤の保存試験開始時における溶液中の溶存酸素を酸素濃度計で測定した。評価結果を表２及び表３に示す。
[Test Example] 60 ° C. Storage Stability Test The injectable solution formulations of Examples 1 to 3 and Comparative Examples 1 to 5 were stored at 60 ° C. for up to 2 weeks. The properties (coloring), pH, relative substances derived from pemetrexed, and the presence or absence of insoluble foreign substances by visual observation were evaluated for each preparation. In addition, the dissolved oxygen in the solution at the start of the storage test of the preparation was measured by an oximeter. The evaluation results are shown in Tables 2 and 3.
［表２］
［表３］
表２に示した実施例の溶液製剤の保存安定性試験の結果から、システインを濃度として０．０５ｍｇ／ｍＬ以上０．２ｍｇ／ｍＬ未満で添加し、これに酒石酸塩を添加することで、ｐＨを７付近の中性域においても、不溶性異物及び類縁物質の生成を抑制し、尚且つ溶液の着色を抑えることができ、安定性が維持されることが認められた。
一方、表３に示したように、添加剤を用いない比較例１は、着色が認められた。また、数μｍ程度の不溶性の異物も確認された。これは、ペメトレキセドがバイアルから溶出された二価の金属イオンと複合体を形成したものが析出したものと考えられる。シリコートバイアルを用いた比較例２では、不溶性異物は確認されなかった。これは、バイアルの内面をシリコート処理したバイアルを使用することで、バイアルからの溶出物が抑制され、ペメトレキセドとバイアル溶出物との複合体形成が抑制されたものと考えられる。しかしながら、保存後の溶液は黄色を呈し、着色を抑制することはできなかった。比較例３では、金属イオンの捕捉能がある酒石酸ナトリウムを大量に添加することで、バイアルから溶出した二価の金属イオンを捕捉し、不溶性異物の形成が抑制されていると考えられる。しかし酒石酸ナトリウムのみでは、溶液の着色を抑制することはできなかった。比較例４は、抗酸化剤であるシステインを高濃度に添加した処方であるが、類縁物質及び着色が抑制されているが、システインに由来する不溶性の結晶の析出が確認された。比較例５は、国際公開２０１５／１９３５１７（特許文献５）の記載に基づきシステインの濃度を抑えた処方であるが、システイン由来と思われる不溶性の結晶の析出が確認された。有機溶剤であるプロピレングリコールの添加は、不溶性異物の析出を抑制をすることはできず、逆に不溶性異物を生成させてしまうと共に、溶液の着色をもたらす結果となった。
以上の結果から、有機溶剤を含まず、システインを０．０５ｍｇ／ｍＬ以上０．２ｍｇ／ｍＬ未満で含み、酒石酸塩を含有するペメトレキセド水溶液製剤は、製剤保存経過において、溶液の着色を抑え、不溶性異物を抑制し、ペメトレキセド類縁物質を最大限抑制できることが明らかとなった。
また、ガラスからの金属成分の溶出が低減されるような表面処理を行ったガラスバイアルを、当該ペメトレキセド水溶液製剤の包材に使用することで、不溶性異物の生成を抑制することが明らかとなった。本発明で使用しているガラス成分の溶出を抑制したシリコート内面処理バイアルは、水を充填し、封をしたのち、１２１℃で高圧蒸気滅菌処理を１時間行った後に水へ溶出するケイ素が１ｐｐｍ以下であった。
From the results of the storage stability test of the solution preparation of the example shown in Table 2, cysteine is added at a concentration of 0.05 mg / mL or more and less than 0.2 mg / mL, and a tartrate is added thereto to adjust the pH. Also in the neutral region around 7, it is recognized that the formation of insoluble foreign substances and related substances can be suppressed, and the coloring of the solution can be suppressed, and the stability is maintained.
On the other hand, as shown in Table 3, in Comparative Example 1 in which no additive was used, coloring was observed. In addition, insoluble foreign matter of several micrometers was also confirmed. This is considered to be that what the pemetrexed formed in the complex with the bivalent metal ion eluted from the vial was deposited. In the comparative example 2 using the sili coat vial, insoluble foreign matter was not confirmed. It is considered that the use of the vial in which the inner surface of the vial was silicoated treated suppressed the elution from the vial and suppressed the complex formation between pemetrexed and the vial eluate. However, the solution after storage turned yellow and could not suppress coloring. In Comparative Example 3, by adding a large amount of sodium tartrate capable of capturing metal ions, it is considered that the formation of insoluble foreign matter is suppressed by capturing divalent metal ions eluted from the vial. However, sodium tartrate alone could not suppress the coloration of the solution. Comparative Example 4 is a formulation in which cysteine, which is an antioxidant, is added at a high concentration, but the related substances and coloring are suppressed, but precipitation of insoluble crystals derived from cysteine was confirmed. Comparative Example 5 is a formulation in which the concentration of cysteine is suppressed based on the description of International Publication WO 2015/193517 (Patent Document 5), but the precipitation of insoluble crystals thought to be derived from cysteine was confirmed. The addition of propylene glycol, which is an organic solvent, can not suppress the precipitation of insoluble foreign matter, and on the contrary, it produces an insoluble foreign matter and results in coloring of the solution.
From the above results, the pemetrexed aqueous solution preparation containing an organic solvent and containing cysteine at 0.05 mg / mL or more and less than 0.2 mg / mL and containing tartrate reduces the coloration of the solution during the formulation storage process and is insoluble It has become clear that foreign substances can be suppressed and pemetrexed analogues can be suppressed as much as possible.
Moreover, it became clear to suppress generation | occurrence | production of an insoluble foreign material by using for the packaging material of the said pemetrexed aqueous solution formulation the glass vial which surface-treated so that elution of the metal component from glass might be reduced. . Sili coat inner surface treatment vial which suppresses elution of the glass component used in the present invention is filled with water, sealed, and subjected to high pressure steam sterilization treatment at 121 ° C. for 1 hour, and 1 ppm of silicon eluted into water It was below.
本発明によれば、ペメトレキセドの分解に伴う類縁物質の生成を抑制した保存安定性に優れるペメトレキセドを含む注射用溶液製剤を提供することができる。本発明の注射用溶液製剤で使用している添加剤は、人への使用実績があり、且つ使用実績量以下の量である。従って、医薬的に安全で、投与時の調製が簡便なペメトレキセド注射用溶液製剤を提供することができる。
According to the present invention, it is possible to provide a solution preparation for injection containing pemetrexed which is excellent in storage stability and in which the formation of a related substance accompanying the decomposition of pemetrexed is suppressed. The additive used in the injectable solution preparation of the present invention has a history of use in humans and is an amount equal to or less than the actual use amount. Therefore, a pemetrexed injectable solution preparation which is pharmaceutically safe and easy to prepare at the time of administration can be provided.
Claims (5)
The vial according to any one of claims 1 to 4, wherein a vial filled with water and subjected to high-pressure steam sterilization at 121 ° C for 1 hour after being filled with water and sealed, has a silicon elution amount of 1 ppm or less. Solution formulation for injection.
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