JP2021123530A - Multiple myeloma treatment agent - Google Patents
Multiple myeloma treatment agent Download PDFInfo
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- JP2021123530A JP2021123530A JP2020015201A JP2020015201A JP2021123530A JP 2021123530 A JP2021123530 A JP 2021123530A JP 2020015201 A JP2020015201 A JP 2020015201A JP 2020015201 A JP2020015201 A JP 2020015201A JP 2021123530 A JP2021123530 A JP 2021123530A
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- curcumin
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Abstract
Description
本発明は、多発性骨髄腫の治療剤に関する。 The present invention relates to a therapeutic agent for multiple myeloma.
多発性骨髄腫（MM：Multiple Myeloma）は、形質細胞（血液細胞の一つ）が癌化した骨髄腫細胞が主に骨髄中で異常増殖する疾患である。骨髄腫細胞の異常増殖により、造血抑制に伴う貧血、感染症、出血傾向など、Mタンパク（異常免疫グロブリン）産生に伴う腎障害、血液循環障害など、あるいは、骨破壊によって骨痛、骨折、高カルシウム血症などの症状を引き起こす。
多発性骨髄腫の治療は薬物療法が中心である。従来用いられているメルファランなどの抗がん剤とステロイド剤に加えて、現在では、さまざまな薬剤を適切に組み合わせた治療が行われている。そのような薬剤としては、例えばプロテアソーム阻害薬：ボルテゾミブ、カルフィルゾミブ、イキサゾミブ、免疫調整薬：レナリドミド、サリドマイド、ポマリドミド、抗体医薬：エロツズマブ、ダラツムマブなどがある。
これらの薬剤のなかでも、ボルテゾミブがkey drugとして用いられるが、治療を受けた症例の約７０〜８０％がボルテゾミブ耐性となり重篤な状態になると推定されている。
従って、多発性骨髄腫、さらには再発・難治性の多発性骨髄腫に対する安全で有効な治療剤が求められている。
Multiple Myeloma (MM) is a disease in which myeloma cells, in which plasma cells (one of the blood cells) have become cancerous, proliferate mainly in the bone marrow. Abnormal proliferation of myeloma cells causes anemia, infections, bleeding tendency associated with hematopoiesis suppression, renal disorders associated with M protein (abnormal immunoglobulin) production, blood circulation disorders, etc., or bone pain, fractures, hypercalcemia due to bone destruction. Causes symptoms such as hypercalcemia.
Treatment of multiple myeloma is centered on drug therapy. In addition to the conventionally used anticancer agents such as melphalan and steroids, treatments are now being performed with an appropriate combination of various agents. Such agents include, for example, proteasome inhibitors: bortezomib, carfilzomib, ixazomib, immunomodulators: lenalidomide, thalidomide, pomalidomide, antibody drugs: elotuzumab, daratumumab and the like.
Among these drugs, bortezomib is used as a key drug, but it is estimated that about 70 to 80% of treated cases become bortezomib resistant and become seriously ill.
Therefore, there is a need for a safe and effective therapeutic agent for multiple myeloma and relapsed / refractory multiple myeloma.
クルクミンは、近年、腫瘍形成阻害作用、抗酸化作用、抗炎症作用、コレステロール低下作用、抗アレルギー作用、脳疾患予防作用、心疾患予防治療作用などの薬理作用を有することが明らかとなり、食品（例えば、機能性食品）、医薬品や化粧品などへの利用が検討されている。
クルクミンと多発性骨髄腫との関連性については、「クルクミンによるヒト多発性骨髄腫の治療」として、４つの多発性骨髄腫細胞株（U266、RPMI8226、MM.1およびMM.1R）を用い、クルクミンは多発性骨髄腫細胞によって発現する恒常的なNF-κB を抑制したこと、またクルクミンはビンクリスチンの細胞毒性効果を増強したとの報告がある（特許文献１）。しかしながら、この特許文献１には、クルクミンによる多発性骨髄腫治療に関するin vivoデータなど、具体的な作用効果は全く開示されていない。
一方、クルクミンを水溶性物質（例えばグルクロン酸、硫酸、グルタチオンおよびアミノ酸など）との抱合体とし、この抱合体を有効成分とする非経口投与用医薬治療剤が、水難溶性なクルクミンの吸収性を改善した結果、クルクミンが有する抗腫瘍作用などの薬理作用が十分に得られることが報告されている（特許文献２）。
In recent years, it has been clarified that curcumin has pharmacological actions such as tumorigenesis inhibitory action, antioxidant action, anti-inflammatory action, cholesterol lowering action, antiallergic action, brain disease preventive action, and heart disease preventive and therapeutic action, and foods (for example, , Functional foods), pharmaceuticals and cosmetics are being considered for use.
Regarding the association between curcumin and multiple myeloma, four multiple myeloma cell lines (U266, RPMI8226, MM.1 and MM.1R) were used as "treatment of human multiple myeloma with curcumin". It has been reported that curcumin suppressed the constitutive NF-κB expressed by multiple myeloma cells, and that curcumin enhanced the cytotoxic effect of bincristine (Patent Document 1). However,
On the other hand, a pharmaceutical therapeutic agent for parenteral administration containing curcumin as a conjugate with a water-soluble substance (for example, glucuronic acid, sulfuric acid, glutathione, amino acid, etc.) and containing this conjugate as an active ingredient can absorb curcumin which is poorly soluble in water. As a result of the improvement, it has been reported that sufficient pharmacological actions such as antitumor action of curcumin can be obtained (Patent Document 2).
本発明の課題は、安全で有効な多発性骨髄腫の治療剤、さらにプロテアソーム阻害薬耐性の多発性骨髄腫の治療剤などを提供することにある。 An object of the present invention is to provide a safe and effective therapeutic agent for multiple myeloma, a therapeutic agent for multiple myeloma resistant to a proteasome inhibitor, and the like.
そこで、本発明者は、種々の多発性骨髄腫、特にボルテゾミブなどのプロテアソーム阻害薬耐性の多発性骨髄腫に対して有効な治療剤を開発すべく種々検討したところ、クルクミン類の水溶性物質抱合体がプロテアソーム阻害薬耐性の多発性骨髄腫に対して優れた増殖阻害作用を有することを見出し、本発明を完成した。 Therefore, the present inventor has conducted various studies to develop effective therapeutic agents for various multiple myeloma, particularly multiple myeloma resistant to proteasome inhibitors such as bortezomib. We have found that the coalescence has an excellent growth inhibitory effect on multiple myeloma resistant to proteasome inhibitors, and completed the present invention.
すなわち本発明は、次の発明［１］〜［１１］を提供するものである。
［１］クルクミン類の水溶性物質抱合体を有効成分とする多発性骨髄腫の治療剤。
［２］クルクミン類が、クルクミンおよびその誘導体から選ばれる１種以上である上記［１］記載の治療剤。
［３］クルクミンの誘導体が、ビスデメトキシクルクミン、デメトキシクルクミンおよびテトラヒドロクルクミンから選ばれる１種以上である上記［２］記載の治療剤。
［４］前記水溶性物質が、グルクロン酸、硫酸、グルタチオンおよびアミノ酸から選ばれる１種以上である上記［１］〜［３］のいずれかに記載の治療剤。
［５］前記水溶性物質が、グルクロン酸および硫酸から選ばれる１種以上である上記［１］〜［３］のいずれかに記載の治療剤。
［６］前記クルクミン類の水溶性物質抱合体が、クルクミンモノグルクロニドである上記［１］記載の治療剤。
［７］前記多発性骨髄腫が、プロテアソーム阻害薬耐性の多発性骨髄腫である、上記［１］〜［６］のいずれかに記載の治療剤。
［８］前記多発性骨髄腫が、ボルテゾミブ耐性の多発性骨髄腫である、上記［１］〜［６］のいずれかに記載の治療剤。
［９］他の多発性骨髄腫治療薬と組み合わせたことを特徴とする、上記［１］〜［８］のいずれかに記載の治療剤。
［１０］前記他の多発性骨髄腫治療薬が、プロテアソーム阻害薬から選ばれる１種以上である［９］に記載の治療剤。
［１１］非経口投与用治療剤である、上記［１］〜［１０］のいずれかに記載の治療剤。
That is, the present invention provides the following inventions [1] to [11].
[1] A therapeutic agent for multiple myeloma containing a conjugate of a water-soluble substance of curcumin as an active ingredient.
[2] The therapeutic agent according to the above [1], wherein the curcumins are one or more selected from curcumin and its derivatives.
[3] The therapeutic agent according to the above [2], wherein the curcumin derivative is at least one selected from bisdemethoxycurcumin, demethoxycurcumin and tetrahydrocurcumin.
[4] The therapeutic agent according to any one of the above [1] to [3], wherein the water-soluble substance is one or more selected from glucuronic acid, sulfuric acid, glutathione and amino acids.
[5] The therapeutic agent according to any one of the above [1] to [3], wherein the water-soluble substance is one or more selected from glucuronic acid and sulfuric acid.
[6] The therapeutic agent according to the above [1], wherein the water-soluble substance conjugate of the curcumins is curcumin monoglucuronide.
[7] The therapeutic agent according to any one of the above [1] to [6], wherein the multiple myeloma is a proteasome inhibitor-resistant multiple myeloma.
[8] The therapeutic agent according to any one of the above [1] to [6], wherein the multiple myeloma is a bortezomib-resistant multiple myeloma.
[9] The therapeutic agent according to any one of the above [1] to [8], which is characterized by being combined with another therapeutic agent for multiple myeloma.
[10] The therapeutic agent according to [9], wherein the other therapeutic agent for multiple myeloma is one or more selected from proteasome inhibitors.
[11] The therapeutic agent according to any one of the above [1] to [10], which is a therapeutic agent for parenteral administration.
本発明のクルクミン類の水溶性物質抱合体を有効成分とする多発性骨髄腫の治療剤は、後記実施例に示すように、種々の多発性骨髄腫、特にプロテアソーム阻害薬耐性の多発性骨髄腫に対して安全で有効な治療効果を得ることができる。 The therapeutic agent for multiple myeloma containing a water-soluble substance conjugate of curcumins of the present invention as an active ingredient is, as shown in Examples below, various multiple myeloma, particularly proteasome inhibitor-resistant multiple myeloma. A safe and effective therapeutic effect can be obtained.
以下，本発明を実施するための形態について説明する。本発明は，以下に説明する形態に限定されるものではなく，以下の形態から当業者が自明な範囲で適宜修正したものも含む。 Hereinafter, embodiments for carrying out the present invention will be described. The present invention is not limited to the forms described below, but also includes those which are appropriately modified by those skilled in the art from the following forms to the extent obvious to those skilled in the art.
クルクミンは、ウコン色素に含まれるクルクミノイドの主成分であり、下記構造式（１）で表される化合物である。 Curcumin is the main component of curcuminoid contained in turmeric pigment, and is a compound represented by the following structural formula (1).
本発明のクルクミン類は、クルクミンおよびその誘導体から選ばれる１種以上である。クルクミンの誘導体としては、ビスデメトキシクルクミン、デメトキシクルクミンおよびテトラヒドロクルクミンが挙げられる。
本発明においてクルクミンは、化学合成されたクルクミンを用いてもよいし、ウコン色素として流通しているものを用いてもよい。ウコン色素としては、ショウガ科ウコン（Ｃｕｒｃｕｍａ ｌｏｎｇａ ＬＩＮＮＥ）の根茎の乾燥物を粉末にしたウコン末、該ウコン末を適当な溶媒（例えば、エタノール、油脂、プロピレングリコール、ヘキサン、アセトンなど）を用いて抽出して得られる粗製クルクミン或いはオレオレジン（ターメリックオレオレジン）、および精製したクルクミンを挙げることができる。
なお、クルクミンには、互変異性体であるケト型およびエノール型のいずれも含まれる。
The curcumins of the present invention are one or more selected from curcumin and its derivatives. Derivatives of curcumin include bisdemethoxycurcumin, demethoxycurcumin and tetrahydrocurcumin.
In the present invention, as the curcumin, chemically synthesized curcumin may be used, or those commercially available as a turmeric pigment may be used. As the turmeric pigment, turmeric powder obtained by powdering the dried rhizome of Curcuma longa LINE, and the turmeric powder using an appropriate solvent (for example, ethanol, fat, propylene glycol, hexane, acetone, etc.) are used. Examples thereof include crude curcumin or oleoresin (turmeric oleoresin) obtained by extraction, and purified curcumin.
In addition, curcumin includes both keto type and enol type which are tautomers.
本発明のクルクミン類の水溶性物質抱合体の水溶性物質としては、グルクロン酸、硫酸、グルタチオンおよびアミノ酸から選ばれる１種以上が挙げられる。アミノ酸としては、生体内に存在するアミノ酸、例えば必須アミノ酸が挙げられる。クルクミン類の水溶性物質抱合体は、遊離型クルクミンの血中濃度を高い値で維持することができる。これにより、クルクミンが有する薬理作用が十分に得られ、またクルクミン抱合体はクルクミンの生体内代謝産物であることから、安全性が非常に高いので好ましい。
クルクミン抱合体におけるクルクミンと前記水溶性物質との結合モル比は、クルクミン：水溶性物質＝１：１〜１：３であるのが好ましく、１：１〜１：２がより好ましく、１：１がさらに好ましい。
Examples of the water-soluble substance of the water-soluble substance conjugate of curcumins of the present invention include one or more selected from glucuronic acid, sulfuric acid, glutathione and amino acids. Examples of amino acids include amino acids existing in the living body, for example, essential amino acids. The water-soluble substance conjugate of curcumins can maintain a high blood concentration of free curcumin. As a result, the pharmacological action of curcumin can be sufficiently obtained, and since the curcumin conjugate is a metabolite of curcumin in vivo, it is preferable because it is very safe.
The binding molar ratio of curcumin to the water-soluble substance in the curcumin conjugate is preferably curcumin: water-soluble substance = 1: 1 to 1: 3, more preferably 1: 1 to 1: 2, 1: 1. Is even more preferable.
クルクミンと前記水溶性物質の抱合形態（結合形態）は、例えば式（２）の形態である。 The conjugation form (binding form) of curcumin and the water-soluble substance is, for example, the form of the formula (2).
（式中、Ｒ１およびＲ２の少なくとも一方は前記水溶性物質の残基であり、残余は水素原子である。） (In the formula, at least one of R 1 and R 2 is a residue of the water-soluble substance, and the remainder is a hydrogen atom.)
前記式（２）中、Ｒ１およびＲ２の一方または両方はグルクロン酸残基または硫酸残基が好ましく、残余は水素原子が好ましい。なかでも、Ｒ１がグルクロン酸残基でＲ２が水素原子であるクルクミンモノグルクロニドの場合がより好ましい。
クルクミン類の水溶性物質抱合体は、前記特許文献２記載の方法によって製造することができる。
In the formula (2), one or both of R 1 and R 2 are preferably glucuronic acid residues or sulfuric acid residues, and the remainder is preferably a hydrogen atom. Of these, curcumin monoglucuronide in which R 1 is a glucuronic acid residue and R 2 is a hydrogen atom is more preferable.
The water-soluble substance conjugate of curcumins can be produced by the method described in Patent Document 2.
本発明の治療剤が対象とする多発性骨髄腫は、通常の多発性骨髄腫、さらには再発・難治性の多発性骨髄腫、なかでもプロテアソーム阻害薬耐性の多発性骨髄腫に好ましく用いられる。とくに、この治療剤は、ボルテゾミブを対象に継続的に投与した結果ボルテゾミブ耐性が生じた多発性骨髄腫患者に対する多発性骨髄腫の治療剤として好ましく用いられる。 The multiple myeloma targeted by the therapeutic agent of the present invention is preferably used for ordinary multiple myeloma, relapsed / refractory multiple myeloma, and particularly proteasome inhibitor-resistant multiple myeloma. In particular, this therapeutic agent is preferably used as a therapeutic agent for multiple myeloma in patients with multiple myeloma who have developed resistance to bortezomib as a result of continuous administration of bortezomib to a subject.
本発明の治療剤は，安全とされている投与量の範囲内において，ヒトを含む哺乳動物に対して，必要量（有効量）が投与される。本発明の治療剤中のクルクミン類の水溶性物質抱合体の含有量は、多発性骨髄腫の種類、患者の性別、年齢、症状などに応じて最終的には医師または獣医師の判断により適宜決定されるため、一概に決定することはできないが、例えば、１日当たり１回〜数回対象に投与される。例えば、１回あたり本発明の治療剤中のクルクミン類の水溶性物質抱合体の含有量が１〜１００質量％のものを有効量投与してもよく、該クルクミン類の水溶性物質抱合体の含有量が５〜１００質量％のものを有効量投与してもよい。さらに、１回あたり該クルクミン類の水溶性物質抱合体の含有量が１０〜１００質量％のものを有効量投与してもよい。 The therapeutic agent of the present invention is administered in a required amount (effective amount) to mammals including humans within a safe dose range. The content of the water-soluble substance conjugate of curcumin in the therapeutic agent of the present invention is appropriately determined by a doctor or a veterinarian depending on the type of multiple myeloma, the sex, age, symptoms, etc. of the patient. Since it is determined, it cannot be unconditionally determined, but it is administered to the subject once to several times a day, for example. For example, an effective amount of curcumin containing a water-soluble substance conjugate in the therapeutic agent of the present invention may be administered in an effective amount of 1 to 100% by mass. An effective amount of curcumin having a content of 5 to 100% by mass may be administered. Further, an effective amount of the curcumin containing 10 to 100% by mass of the water-soluble substance conjugate may be administered at one time.
本発明の治療剤の投与経路は、疾患、症状などに応じて、全身投与および局所投与や、経口経路および非経口経路のいずれも選択することができる。それらの投与方法や経路により、本発明の治療剤も、好適な剤形、例えば錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤などの形態での経口投与、または注射剤（例えば、静注、筋注など）、坐剤、経皮剤、経鼻剤、吸入剤などの形態での非経口投与を選択できる。 The administration route of the therapeutic agent of the present invention can be selected from systemic administration and topical administration, and oral route and parenteral route, depending on the disease, symptoms and the like. Depending on their administration method and route, the therapeutic agent of the present invention may also be orally administered in a suitable dosage form, for example, in the form of tablets, pills, capsules, granules, powders, solutions, or injections (eg, intravenous). Parenteral administration in the form of injections, intramuscular injections, etc.), suppositories, transdermal agents, nasal agents, inhalants, etc. can be selected.
投与経路が経口投与の場合には、本発明の治療剤は、主成分であるクルクミン類の水溶性物質抱合体を不活性な賦形剤、滑沢剤、崩壊剤、溶解補助剤、不活性な溶剤（例えば、精製水、エタノールなど）などと混合することにより常法に従って製造される。賦形剤は、例えば、乳糖（ラクトース）、セルロース、マンニトール、ブドウ糖であり得る。滑沢剤は、例えば、ステアリン酸マグネシウムであり得る。崩壊剤は、例えば、カルボキシメチルスターチナトリウムであり得る。錠剤または丸剤は、必要により糖衣または胃溶性若しくは腸溶性コーティング剤で被膜してもよい。液剤は、必要により可溶化剤、湿潤剤、懸濁化剤、甘味剤、矯味剤、芳香剤、緩衝剤（例えば、クエン酸ナトリウムなど）、安定化剤または防腐剤を含有してもよい。 When the route of administration is oral administration, the therapeutic agent of the present invention contains an inactive excipient, a lubricant, a disintegrant, a solubilizing agent, and an inert substance of a water-soluble substance conjugate of curcumins, which are the main components. It is produced according to a conventional method by mixing with a various solvent (for example, purified water, ethanol, etc.). Excipients can be, for example, lactose, cellulose, mannitol, glucose. The lubricant can be, for example, magnesium stearate. The disintegrant can be, for example, sodium carboxymethyl starch. Tablets or pills may be coated with a sugar coating or a gastric or enteric coating, if desired. The liquid may optionally contain solubilizers, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances, buffers (eg, sodium citrate, etc.), stabilizers or preservatives.
本発明の治療剤の投与経路としては、非経口投与が好ましく、なかでも注射剤が特に好ましい。注射剤としては、通常の静脈内投与、動脈内投与の他、関節内、皮下、皮内、筋肉内などへの注射（用時溶解型の粉末充填剤を含む）により投与できる。注射剤の主成分であるクルクミン類の水溶性物質抱合体を溶解・分散などさせる注射剤用の水性の溶剤は、例えば、蒸留水、生理食塩水、リンゲル液などであり得る。注射剤用の非水性の溶剤は、例えば、プロピレングリコール、ポリエチレングリコール、オリーブ油のような植物油、エタノールのようなアルコール類、またはポリソルベート８０（局方名）であり得る。このような製剤は、さらに等張化剤（例えば、塩化ナトリウム、ブドウ糖など）、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、ｐＨ調節剤（例えば、クエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウムなど）、緩衝剤、局所麻酔剤ないし無痛化剤（例えば、塩化ベンザルコニウム、塩酸プロカイン、塩酸リドカインなど）または溶解補助剤を含有してもよい。
これらの製剤は、例えば、バクテリア保留フィルターによる濾過、殺菌剤の配合、または放射線照射によって無菌化され得る。また、無菌の固体治療剤を使用前に無菌の水または注射用溶媒に溶解または懸濁して得られた治療剤をこれらの製剤として使用することもできる。これらの製剤は、製剤工程において通常用いられる公知の方法により製造することができる。
As the administration route of the therapeutic agent of the present invention, parenteral administration is preferable, and injection is particularly preferable. As the injection, in addition to the usual intravenous administration and intraarterial administration, it can be administered by injection into joints, subcutaneously, intradermally, intramuscularly, etc. (including a dissolution-type powder filler at the time of use). The aqueous solvent for the injection, which dissolves and disperses the water-soluble substance conjugate of curcumins, which is the main component of the injection, may be, for example, distilled water, physiological saline, Ringer's solution, or the like. The non-aqueous solvent for injections can be, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80 (Public name). Such formulations also include tonicity agents (eg, sodium chloride, glucose, etc.), preservatives, wetting agents, emulsifiers, dispersants, stabilizers, pH adjusters (eg, sodium citrate, sodium acetate, phosphorus). It may contain a buffer (such as sodium acetate), a local anesthetic or soothing agent (eg, benzalkonium chloride, prokine hydrochloride, lidocaine hydrochloride, etc.) or a solubilizer.
These formulations can be sterilized, for example, by filtration through a bacterial retention filter, formulation of a fungicide, or irradiation. Moreover, the therapeutic agent obtained by dissolving or suspending a sterile solid therapeutic agent in sterile water or an injection solvent before use can also be used as these preparations. These preparations can be produced by a known method usually used in the preparation process.
本発明の治療剤は、他の多発性骨髄腫治療薬（他の抗がん剤）と組み合わせて投与することができる。この場合、組み合わせての投与とは、両薬剤が単一製剤中に含まれた製剤が投与されてもよく、またそれぞれが別々に製剤化され、別々に投与されても良い。別々に製剤化される場合、その投与時期は特に限定されない。それらの投与は、同一回数となる場合もあり、異なる回数となる場合もある。また、それぞれが別々に製剤化される場合、各製剤の投与方法（投与経路）は同じであってもよく、異なる投与方法（投与経路）で投与されてもよい。また、両薬剤が同時に体内に存在する必要は無く、ある一定期間（例えば一ヶ月間、好ましくは１週間、さらに好ましくは数日間、さらにより好ましくは１日間）の間に体内に取り込まれていればよく、いずれかの投与時にもう一方の有効成分が体内から消失していてもよい。
本発明においては、２種の異なる製剤とした場合は、それらを含むキットとすることもできる。
The therapeutic agent of the present invention can be administered in combination with another therapeutic agent for multiple myeloma (another anticancer agent). In this case, the combined administration may be a preparation in which both agents are contained in a single preparation, or each may be separately formulated and administered separately. When they are formulated separately, the timing of administration is not particularly limited. The doses may be the same or different. In addition, when each is formulated separately, the administration method (administration route) of each preparation may be the same, or may be administered by a different administration method (administration route). In addition, both drugs do not have to be present in the body at the same time, and should be taken into the body for a certain period of time (for example, one month, preferably one week, more preferably several days, even more preferably one day). However, the other active ingredient may have disappeared from the body at the time of administration of either one.
In the present invention, when two different preparations are used, a kit containing them can also be used.
前記のように組み合わせて投与される薬剤としては、例えばプロテアソーム阻害薬：ボルテゾミブ、カルフィルゾミブ、イキサゾミブ、免疫調節薬：レナリドミド、サリドマイド、ポマリドミド、抗体医薬：エロツズマブ、ダラツムマブなどを挙げることができる。これらのなかでもプロテアソーム阻害薬、特にボルテゾミブ、カルフィルゾミブ、イキサゾミブなどが好ましい。 Examples of the drugs administered in combination as described above include proteasome inhibitors: bortezomib, carfilzomib, ixazomib, immunomodulators: lenalidomide, thalidomide, pomalidomide, antibody drugs: elotuzumab, daratumumab and the like. Among these, proteasome inhibitors, particularly bortezomib, carfilzomib, ixazomib and the like are preferable.
次に実施例を挙げて本発明を更に具体的に説明するが、本発明の範囲は下記に説明する特定の態様に限定されることはない。 Next, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited to the specific aspects described below.
製造例１
（クルクミンの水溶性物質抱合体（クルクミンモノグルクロニド）の調製方法）
ＷＯ２０１８／０３８５７号公報記載の方法に準じて、クルクミンモノグルクロニドを合成した。すなわち、アセトブロモ−α−Ｄ−グルクロン酸メチルエステル１．０ｇ（２．５２ｍｍｏｌ）とバニリン３２６．０ｍｇ（２．１５ｍｍｏｌ）を原料として反応させて得られた化合物（１）（β−Ｄ−グルコピラノシドウロン酸，４−ホルミル−2−メトキシフェニル，メチルエステル，トリアセタート）４９１．６ｍｇ（収率４９％）と、２，４−ペンタジオン３．３ｍＬ（３２．０７ｍｍｏｌ）とバニリン２．２ｇを原料として反応させて得られた化合物（２）（５−ヒドロキシ−１−（4−ヒドロキシ−3−メトキシフェニル）−１，４−ヘキサジエン−３−オン）とを反応させて、得られた化合物（３）（クルクミンβ−D−グルコピラノシドウロン酸２，３，４−トリ−O−アセチル，メチルエステル）の脱アセチル化・精製によりクルクミンモノグルクロニド（２５３．１ｍｇ）を得た。
Manufacturing example 1
(Preparation method of curcumin water-soluble substance conjugate (curcumin monoglucuronide))
Curcumin monoglucuronide was synthesized according to the method described in WO2018 / 03857. That is, the compound (1) (β-D-glucopyranoside uronic acid) obtained by reacting 1.0 g (2.52 mmol) of acetbromo-α-D-glucuronic acid methyl ester with 326.0 mg (2.15 mmol) of vanillin as raw materials. Reaction of 491.6 mg (49% yield) of acid, 4-formyl-2-methoxyphenyl, methyl ester, triacetate, 3.3 mL (32.07 mmol) of 2,4-pentadione and 2.2 g of vanillin as raw materials. The obtained compound (2) (5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -1,4-hexadiene-3-one) was reacted with the obtained compound (3) ( Curcumin monoglucuronide (253.1 mg) was obtained by deacetylation and purification of curcumin β-D-glucopyranoside uronic acid (2,3,4-tri-O-acetyl, methyl ester).
実施例１
（クルクミンモノグルクロニドによるマウス多発性骨髄腫の腫瘍退縮効果）
Ａ．多発性骨髄細胞株移植マウスの作成
供試動物として、ＮＯＤ Ｓｃｉｄマウス（雌性６週齢、日本チャールスリバー、体重約２０ｇ）を７日環境馴化させたものを用いた。
上記供試動物の皮下に、１×１０７のＫＭＳ１１／ＢＴＺ（ボルテゾミブ耐性多発性骨髄腫細胞株、ＪＣＲＢ）を移植した。
Ｂ．投与方法
上記の多発性骨髄細胞株移植マウス（ｎ＝６）に対し、移植２週間後から薬剤投与を開始した。
薬剤投与は、クルクミンモノグルクロニドは３０ｍｇ／ｋｇで３回／週、９０ｍｇ／ｋｇで３回／週、またはボルテゾミブは１ｍｇ／ｋｇで２回／週とし、クルクミンモノグルクロニドは蒸留水、ボルテゾミブはＤＭＳＯとＰＢＳに溶解したものを注射剤として腹腔内投与した。対照群としては、各溶媒を用いた。
Ｃ．腫瘍サイズの評価方法
供試動物の腫瘍サイズは、７日おきにノギスを用い腫瘍の長径と短径を測定し、次式によって算出した。
腫瘍サイズ＝長径×短径×短径÷２。
Example 1
(Tumor regression effect of multiple myeloma in mice by curcumin monoglucuronide)
A. Preparation of Multiple Bone Marrow Cell Line Transplanted Mice As test animals, NOD Scid mice (female 6 weeks old, Japanese Charles River, body weight about 20 g) were environmentally acclimated for 7 days.
Subcutaneously of the test animals, 1 × 10 7 of KMS11 / BTZ (bortezomib resistant multiple myeloma cell line, JCRB) were transplanted.
B. Administration method The drug administration was started 2 weeks after the transplantation to the above-mentioned multiple bone marrow cell line transplanted mice (n = 6).
The drug administration was 30 mg / kg 3 times / week for curcumin monoglucuronide, 3 times / week for 90 mg / kg, or 1 mg / kg twice / week for bortezomib, distilled water for curcumin monoglucuronide, and DMSO for bortezomib. The solution dissolved in PBS was intraperitoneally administered as an injection. As a control group, each solvent was used.
C. Tumor size evaluation method The tumor size of the test animal was calculated by the following formula by measuring the major axis and minor axis of the tumor using calipers every 7 days.
Tumor size = major axis x minor axis x minor axis ÷ 2.
投与開始（Ｄａｙ０）からＤａｙ７、Ｄａｙ１４、およびＤａｙ２１の時点で、マウスの腫瘍サイズ（Ｔｕｍｏｒ ｖｏｌｕｍｅ）と体重（Ｂｏｄｙ ｗｅｉｇｈｔ）を測定し、結果を図１および図２に示した。 Tumor volume and body weight of mice were measured from the start of administration (Day 0) to Day 7, Day 14, and Day 21, and the results are shown in FIGS. 1 and 2.
図１から、ボルテゾミブ投与による効果がほとんどないにもかかわらず、本発明の９０ｍｇ／ｋｇクルクミンモノグルクロニドの投与によって、ボルテゾミブ耐性多発性骨髄腫の腫瘍の退縮が有意に起きたことがわかる（ｐ＜０．０５）。また、クルクミンモノグルクロニドの投与量３０ｍｇ／ｋｇとした場合にも、有意の腫瘍退縮効果が確認された（ｐ＜０．０５）。
さらに、図２から、クルクミンモノグルクロニドの投与は、副作用が少なく安全であることが分かる。
From FIG. 1, it can be seen that the administration of 90 mg / kg curcumin monoglucuronide of the present invention significantly caused tumor regression of bortezomib-resistant multiple myeloma, although the administration of bortezomib had little effect (p <. 0.05). A significant tumor regression effect was also confirmed when the dose of curcumin monoglucuronide was 30 mg / kg (p <0.05).
Furthermore, it can be seen from FIG. 2 that the administration of curcumin monoglucuronide is safe with few side effects.
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