WO2024253189A1 - がん化学療法剤に起因する末梢神経障害の予防剤及び／又は改善剤 - Google Patents

がん化学療法剤に起因する末梢神経障害の予防剤及び／又は改善剤 Download PDF

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WO2024253189A1
WO2024253189A1 PCT/JP2024/020890 JP2024020890W WO2024253189A1 WO 2024253189 A1 WO2024253189 A1 WO 2024253189A1 JP 2024020890 W JP2024020890 W JP 2024020890W WO 2024253189 A1 WO2024253189 A1 WO 2024253189A1
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iron
ferrous
agent
peripheral neuropathy
compound
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French (fr)
Japanese (ja)
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祥弘 瀬戸
秀人 藤
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University of Toyama NUC
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University of Toyama NUC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies

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  • the present invention relates to an agent for preventing and/or improving peripheral neuropathy caused by cancer chemotherapy agents.
  • Peripheral neuropathy caused by cancer chemotherapy drugs includes symptoms such as numbness, hypoesthesia, dysesthesias, paresthesia, anesthesia, and hyperesthesia, and in some cases cold stimuli may be felt as pain.
  • oxaliplatin a platinum drug
  • has long been widely used in cancer chemotherapy and is a key drug in major regimens such as FOLFOX therapy, SOX therapy, and XELOX therapy, particularly in the fields of gastric cancer and colorectal cancer.
  • FOLFOX therapy SOX therapy
  • XELOX therapy XELOX therapy
  • iron compounds e.g., saccharified iron oxide, ferric citrate, etc.
  • iron deficiency anemia e.g., saccharified iron oxide, ferric citrate, etc.
  • chronic kidney disease e.g., Patent Documents 1 and 2
  • Patent Documents 1 and 2 e.g., Patent Documents 1 and 2
  • the present invention aims to provide an effective preventive and/or ameliorative agent for peripheral neuropathy caused by cancer chemotherapy agents.
  • the agent for preventing and/or improving peripheral neuropathy caused by cancer chemotherapy agents in the present invention contains an iron compound as an active ingredient.
  • the iron compound is a sugar-containing iron oxide or an iron oligosaccharide compound, such as a sugar-containing ferric hydroxide and a ferric hydroxide oligosaccharide compound.
  • an iron oligosaccharide compound such as a sugar-containing ferric hydroxide and a ferric hydroxide oligosaccharide compound.
  • the iron compounds contained in Fesin (registered trademark), Monovar (registered trademark), which contains ferric delisomaltose as an active ingredient, and Feinject (registered trademark), which contains ferric carboxymaltose as an active ingredient are also included in the iron compounds.
  • cancer chemotherapy agent is not limited to any chemotherapy agent used in cancer treatment, and may be, for example, one or more agents selected from the group consisting of taxane drugs, vinca alkaloid drugs, platinum preparations, anthracycline drugs, and proteasome inhibitors, and is preferably a platinum preparation.
  • Peripheral neuropathy refers to a functional disorder of a single or multiple peripheral nerves (parts of the nervous system distal to the nerve root and nerve plexus), and examples thereof include numbness, hypoesthesia, dysesthesia, paresthesia, anesthesia, neuropathic pain (e.g., mechanical allodynia, cold allodynia), and hyperesthesia (preferably cold hypersensitivity). Peripheral neuropathy may involve multiple disorders at the same time, so the term peripheral neuropathy may include one or more of the above examples. Examples of peripheral neuropathy caused by cancer chemotherapy agents include numbness, hypoesthesia, dysesthesia, paresthesia, anesthesia, neuropathic pain, hyperesthesia, and the like. Preferred peripheral neuropathy is neuropathic pain and/or hyperesthesia.
  • the present invention is a preventive and/or ameliorative agent that contains sugar-containing iron oxide or an iron oligosaccharide compound as an active ingredient and is effective against platinum-based (e.g., oxaliplatin)-induced cold hypersensitivity or neuropathic pain.
  • platinum-based e.g., oxaliplatin
  • the present invention makes it possible to effectively prevent and/or improve peripheral neuropathy caused by cancer chemotherapy agents.
  • 1 shows the diurnal variations in serum iron, unsaturated iron binding capacity, and total iron binding capacity in mice.
  • the results of serum iron and the number of escapes induced by cold stimulation after administration of an iron compound are shown.
  • the results of the number of escapes caused by cold stimulation after administration of a cancer chemotherapy agent and saccharified iron oxide are shown.
  • 1 shows the results of the number of escapes associated with cold stimulation after administration of a cancer chemotherapy agent and ferric delisomaltose.
  • 1 shows the results of the number of escapes induced by cold stimulation after administration of a cancer chemotherapy agent and ferric carboxymaltose.
  • the iron compound can be appropriately formulated to be used as an iron preparation.
  • the iron compound is generally formulated using a formulation technique known as a pharmaceutical.
  • commercially available iron preparations such as Fesin (registered trademark), Monovar (registered trademark) containing ferric delisomaltose as an active ingredient, and Feinject (registered trademark) containing ferric carboxymaltose as an active ingredient can be used as is or with modification.
  • the dosage of the iron compound varies depending on the administration form, age, body weight, symptoms, and the like, but for example, for an adult, for oral agents, it may be about 50 to 400 mg/day, preferably about 100 to 200 mg/day, calculated as iron, for injections, about 20 to 240 mg/day, calculated as iron, or 500 to 1000 mg per dose once a week, or up to 500 mg per dose twice a week, preferably about 40 to 120 mg/day, or in one embodiment, an amount effective for reaching and/or maintaining a serum iron concentration of about 60 to 180 ⁇ g/dL, or a hemoglobin value of about 12 g/dL or more, or a serum fetilin value of about 12 ng/mL or more.
  • the drug may be administered once or twice or even several times a day.
  • Cancer chemotherapy drugs can cause peripheral neuropathy (CIPN) as a side effect, and examples of these include taxane drugs (paclitaxel, docetaxel, etc.), vinca alkaloid drugs (vincristine, vinblastine, vindesine, vinorelbine, etc.), platinum preparations (oxaliplatin, cisplatin, carboplatin, nedaplatin, etc.), anthracycline drugs (adriamycin, etc.), and proteasome inhibitors (bortezomib, carfilzomib, ixazomib, etc.), and also peripheral neuropathy caused by combination therapy containing one or more of these drugs.
  • CIPN peripheral neuropathy
  • taxane drugs paclitaxel, docetaxel, etc.
  • vinca alkaloid drugs vincristine, vinblastine, vindesine, vinorelbine, etc.
  • platinum preparations oxaliplatin, cisplatin, carboplatin, ned
  • combination therapies include, but are not limited to, FOLFOX therapy, SOX therapy, and XELOX therapy.
  • the iron compound may be administered prophylactically before administration of a cancer chemotherapeutic agent, simultaneously with administration of a cancer chemotherapeutic agent, or therapeutically after administration of a cancer chemotherapeutic agent, where "simultaneous" does not only mean at the same time, but also means that the iron compound and the cancer chemotherapeutic agent are administered without a significant interval, even if not at the same time.
  • the method of administration of the iron compound may be the same as or different from the method of administration of the cancer chemotherapeutic agent, for example, the iron compound may be administered orally and the cancer chemotherapeutic agent may be administered intravenously, or both the iron compound and the cancer chemotherapeutic agent may be administered intravenously.
  • the prophylactic or ameliorative agent may be used as a combination drug containing an iron compound and a cancer chemotherapeutic agent, or as separate kits, or each may be administered alone.
  • a person skilled in the art can appropriately determine the dosage, timing, frequency, duration, etc. of a cancer chemotherapy agent while taking into consideration the nature and type of the agent.
  • oxaliplatin the present inventors have demonstrated that when oxaliplatin or its metabolite, oxalate, is administered once to mice at any of six time points (1:00, 5:00, 9:00, 13:00, 17:00, and 21:00), the cold hypersensitivity reaction two hours after administration is greatest in the group administered at 9:00.
  • the present invention is a preventive and/or ameliorative agent that is also effective in chronopharmacological therapy.
  • the preventive and/or ameliorative agents of the present invention can be used as medicines, quasi-drugs, health functional foods (nutritional functional foods, foods for specified health uses, foods with functional claims), general foods, etc., and there are no particular limitations on the dosage form, but tablets, granules, injections, etc. are preferred, and there are no particular limitations on the manufacturing method, but in manufacturing, pharmacologically acceptable carriers, excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, glidants, lubricants, flavoring agents, sweeteners, solubilizers, solvents, gelling agents, nutrients, etc. can be added as necessary.
  • mice Five-week-old male C57BL/6J mice were housed for 7 days under conditions with free access to food and water, constant temperature (24 ⁇ 1°C), constant humidity (50 ⁇ 10%) and a 12/12-hour light/dark cycle (hereinafter referred to as "household conditions"). On the 8th day, blood was collected from the heart under sevoflurane anesthesia at 9:00 and 21:00. Serum was collected by centrifugation (3000 G, 10 minutes), and serum iron and unsaturated iron binding capacity were measured by contract with Oriental Yeast Co., Ltd. Total iron binding capacity was calculated as the sum of serum iron and unsaturated iron binding capacity. The results are shown in Figure 1.
  • iron compound administration on serum iron and the number of escapes due to cold stimuli
  • Five-week-old male C57BL/6J mice were kept under the above-mentioned conditions for 7 days, and on the 8th day at 9:00 am, a single dose of the iron compound was intraperitoneally administered.
  • the iron compound used was an iron preparation (Fesin (registered trademark)) diluted with 20% glucose solution and then further diluted with 5% glucose solution to give final iron concentrations of 0.5 mg/kg, 2 mg/kg, or 5 mg/kg (hereinafter referred to as "Fe 0.5 mg/kg,”"Fe 2 mg/kg,” and “Fe 5 mg/kg”).
  • the serum iron concentrations 2 hours after administration of the iron compound were significantly higher in the Fe 2 mg/kg and Fe 5 mg/kg dose groups compared to the control group. Furthermore, the groups administered 2 mg/kg Fe and 5 mg/kg Fe had serum iron concentrations higher than the values at 9 p.m. shown in FIG. 1( a ). From this, it was confirmed that the serum iron concentration can be rapidly increased by administering an iron compound, and the serum iron concentration at 9:00, which is lower than that at 21:00, can be compensated for. Furthermore, as shown in FIG. 2(b), the number of escapes associated with cold stimuli after administration of the iron compound showed no significant difference among all groups, confirming that administration of the iron compound does not significantly affect the evaluation of cold hypersensitivity reaction. One-way analysis of variance was used for comparison between multiple groups, and Scheffe's test was used for comparison between two specific groups.
  • a 5% glucose solution was administered intraperitoneally in a single dose, followed immediately by administration of a 5% glucose solution in a single dose via the tail vein.
  • the above-mentioned sugar-containing iron oxide was administered intraperitoneally in a single dose, and immediately thereafter, a 5% glucose solution was administered in a single dose into the tail vein.
  • L-OHP a 5% glucose solution was administered intraperitoneally in a single dose, followed immediately by administration of the above-mentioned L-OHP in a single dose via the tail vein.
  • the above-mentioned saccharified iron oxide was administered in a single dose intraperitoneally, and immediately thereafter, the above-mentioned L-OHP was administered in a single dose via the tail vein. Two hours after a single intravenous administration, the number of escapes associated with cold stimulation was measured under the above-mentioned conditions. The results are shown in FIG.
  • FD+L-OHP administration group a group in which ferric delisomaltose (FD, Monovar (registered trademark)) was administered at 2 mg/kg in terms of iron into the tail vein one hour before the administration of L-OHP was hereinafter referred to as the FD+L-OHP administration group.
  • FD+L-OHP administration group Two hours after administration, the number of escape attempts was measured for each group under the above-mentioned conditions. The results are shown in Figure 4. One-way analysis of variance was used for comparison between multiple groups, and Scheffe's test was used for comparison between two specific groups.
  • the L-OHP-administered group exhibited a significant increase in the number of escapes compared to the control group, and exhibited cold hypersensitivity.
  • the FD+L-OHP group in which FD was administered before L-OHP administration, had a significantly lower number of escape attempts compared to the L-OHP alone group, and the results were almost the same as those of the control group, indicating that the cold hypersensitivity reaction was suppressed by the prophylactic administration of an iron compound.

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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PCT/JP2024/020890 2023-06-09 2024-06-07 がん化学療法剤に起因する末梢神経障害の予防剤及び／又は改善剤 Ceased WO2024253189A1 (ja)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009510083A (ja) * 2005-09-28 2009-03-12 イノテック ファーマシューティカルズ コーポレイション Ｎ−ベンジル置換ピリジルポルフィリン化合物およびその使用方法
JP2011516419A (ja) * 2008-03-28 2011-05-26 カイナ エルエルシー 鉄欠乏性障害を治療するためのフェリチンの使用
WO2013054756A1 (ja) * 2011-10-12 2013-04-18 Ｓｂｉファーマ株式会社 抗ガン剤の副作用の予防剤及び／又は治療剤
JP2015512420A (ja) * 2012-03-30 2015-04-27 ステルス ペプチドズ インターナショナル インコーポレイテッド 神経障害を予防および処置するための方法および組成物
US20170360866A1 (en) * 2016-06-15 2017-12-21 Dai-Ming Kuo Pharmaceutical composition for decreasing the side effects of cancer drug, and manufacturing method and uses thereof
WO2018079701A1 (ja) * 2016-10-28 2018-05-03 株式会社Ｎｒｌファーマ ラクトフェリン活性を有するタンパク質を含む、抗ガン治療補助剤
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Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009510083A (ja) * 2005-09-28 2009-03-12 イノテック ファーマシューティカルズ コーポレイション Ｎ−ベンジル置換ピリジルポルフィリン化合物およびその使用方法
JP2011516419A (ja) * 2008-03-28 2011-05-26 カイナ エルエルシー 鉄欠乏性障害を治療するためのフェリチンの使用
WO2013054756A1 (ja) * 2011-10-12 2013-04-18 Ｓｂｉファーマ株式会社 抗ガン剤の副作用の予防剤及び／又は治療剤
JP2015512420A (ja) * 2012-03-30 2015-04-27 ステルス ペプチドズ インターナショナル インコーポレイテッド 神経障害を予防および処置するための方法および組成物
US20170360866A1 (en) * 2016-06-15 2017-12-21 Dai-Ming Kuo Pharmaceutical composition for decreasing the side effects of cancer drug, and manufacturing method and uses thereof
WO2018079701A1 (ja) * 2016-10-28 2018-05-03 株式会社Ｎｒｌファーマ ラクトフェリン活性を有するタンパク質を含む、抗ガン治療補助剤
US20220079984A1 (en) * 2020-09-11 2022-03-17 Renibus Therapeutics, Inc. Method for treating cancer with kidney protection

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* Cited by examiner, † Cited by third party
Title
IBRAHIM FOUAD GHADHA, EL-SAYED SARA A. M., MABROUK MOSTAFA, AHMED KAWKAB A., BEHEREI HANAN H.: "Neuroprotective Potential of Intranasally Delivered Sulforaphane-Loaded Iron Oxide Nanoparticles Against Cisplatin-Induced Neurotoxicity", NEUROTOXICITY RESEARCH, HARWOOD ACADEMIC PUBLISHERS, LAUSANNE, CH, vol. 40, no. 5, 1 October 2022 (2022-10-01), CH , pages 1479 - 1498, XP093246610, ISSN: 1029-8428, DOI: 10.1007/s12640-022-00555-x *
LIU HU, QING XIN, PENG LIJUN, ZHANG DING, DAI WEI, YANG ZHILAI, ZHANG JIQIAN, LIU XUESHENG, : "Mannose-coated nanozyme for relief from chemotherapy-induced peripheral neuropathic pain", ISCIENCE, vol. 26, no. 106414, 21 April 2023 (2023-04-21), pages 1 - 16, XP093246609, DOI: 10.1016/j.isci *
OKAMOTO CHIYOMI, YUICHIRO KURONE , OKUDA AIKO, EIMURA YOICHIRO, SAORI NAKAGAWA, NAOTO HIRATA, SHIN OHTA, SADAHIKO SHIMOEDA : "Effect of Serum Erythropoietin Concentration on Chemotherapy Induced Peripheral Neuropathy Caused by Weekly Paclitaxel Therapy", JAPANESE SOCIETY OF PHARMACEUTICAL HEALTH CARE AND SCIENCES, vol. 32, 23 September 2022 (2022-09-23), XP093246614 *
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