JP2018024584A - Pharmaceutical preparation comprising bortezomib - Google Patents
Pharmaceutical preparation comprising bortezomib Download PDFInfo
- Publication number
- JP2018024584A JP2018024584A JP2016155242A JP2016155242A JP2018024584A JP 2018024584 A JP2018024584 A JP 2018024584A JP 2016155242 A JP2016155242 A JP 2016155242A JP 2016155242 A JP2016155242 A JP 2016155242A JP 2018024584 A JP2018024584 A JP 2018024584A
- Authority
- JP
- Japan
- Prior art keywords
- bortezomib
- pharmaceutical preparation
- solution
- acid
- preparation
- 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.)
- Granted
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- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title claims abstract description 100
- 229960001467 bortezomib Drugs 0.000 title claims abstract description 78
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 57
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000002360 preparation method Methods 0.000 claims abstract description 42
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 28
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- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 17
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 14
- 239000011570 nicotinamide Substances 0.000 claims abstract description 14
- 239000007864 aqueous solution Substances 0.000 claims description 21
- 150000007514 bases Chemical class 0.000 claims description 14
- 150000007513 acids Chemical class 0.000 claims description 13
- 229960003966 nicotinamide Drugs 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
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Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、ボルテゾミブを含有する医薬製剤について、ボルテゾミブの安定性を保持し、再溶解性を良好にした医薬製剤に関する。 The present invention relates to a pharmaceutical preparation containing bortezomib, which retains the stability of bortezomib and has good resolubility.
ボルテゾミブは、化学名（Ｎ‐（２‐ピラジンカルボニル）‐Ｌ‐フェニルアラニン‐Ｌ‐ロイシンボロン酸）とするプロテアソーム阻害作用を有する抗悪性腫瘍剤であり、現在、多発性骨髄腫及びマントル細胞リンパ腫の治療剤として用いられている。臨床に供されているボルテゾミブの医薬製剤は、有効成分であるボルテゾミブと添加剤のＤ−マンニトールを含む凍結乾燥製剤であって、ボルテゾミブ注射用製剤（ベルケイド（Ｖｅｌｃａｄｅ）（登録商標））として提供されている。該製剤は、静脈内投与と皮下投与で承認がなされており、その投与方法によって溶解液の量が異なる。静脈内投与を行う場合は生理食塩水３ｍＬに、皮下投与を行う場合は生理食塩水１．２ｍＬに溶解して用いられている。 Bortezomib is an antineoplastic agent having a proteasome inhibitory action with the chemical name (N- (2-pyrazinecarbonyl) -L-phenylalanine-L-leucine boronic acid), and is currently used in multiple myeloma and mantle cell lymphoma It is used as a therapeutic agent. A pharmaceutical preparation of bortezomib used in clinical practice is a lyophilized preparation containing bortezomib as an active ingredient and D-mannitol as an additive, and is provided as a bortezomib injectable preparation (Velcade (registered trademark)). ing. The preparation is approved for intravenous administration and subcutaneous administration, and the amount of the solution varies depending on the administration method. In the case of intravenous administration, it is dissolved in 3 mL of physiological saline, and in the case of subcutaneous administration, it is dissolved in 1.2 mL of physiological saline.
アミノアルキルボロン酸であるボルテゾミブは、酸化や化学的な分解を受けやすく、不安定な物性であることが知られている。また、ボロン酸自体が脱水的に反応して酸無水物化をして多量体化する物性である。このため、ボルテゾミブを有効成分とする医薬製剤を調製する場合、酸化や分解に対する安定化、酸無水物化による多量体化を抑制するための対策が必要である。
例えば、特許文献１には、ボルテゾミブのボロン酸とマンニトール等の糖類とのボロン酸エステル誘導体を開示しており、これを用いた医薬製剤が教唆されている。これは、ボルテゾミブ及びマンニトールのｔｅｒｔ−ブタノール溶液又はｔｅｒｔ−ブタノール含水溶液を凍結乾燥することで調製されている。また、特許文献２には、ボルテゾミブとトロメタミンを含む凍結乾燥製剤が記載されている。これは、強いＢ−Ｎ結合を有するボルテゾミブのトロメタミン塩であることが記載されている。特許文献３には、ボルテゾミブ誘導体の凍結乾燥製剤であって、シクロデキストリン及び単糖を有する増量剤と界面活性剤とからなる群から選択される医薬製剤が記載されている。
ボルテゾミブは安定性に問題があるため、通常は凍結乾燥製剤を検討されているが、特許文献４には、プロピレングリコールを添加することにより安定化された水溶液製剤が開示されている。また、特許文献５には、クエン酸等のα‐ヒドロキシ‐β‐カルボン酸とボルテゾミブとの酸無水物‐エステル誘導体が開示されており、それを医薬製剤にできることが記載されている。
このように、ボロン酸はアルコールやカルボン酸と反応してボロン酸エステルや酸無水物を形成することが知られている。このようなボロン酸エステルや酸無水物は、水溶液中で加水分解を受けてボルテゾミブが再構成される。また現在販売されているボルテゾミブ凍結乾燥製剤は凍結乾燥ケーキの濡れ性が悪く、非特許文献１には溶解に最大120秒程度要することが記載されている。そのため安定であり、再溶解性が良好である医薬製剤が望まれている。
Bortezomib, an aminoalkylboronic acid, is known to be unstable and susceptible to oxidation and chemical degradation. In addition, the boronic acid itself reacts dehydratingly to form an acid anhydride and multimerize. For this reason, when preparing a pharmaceutical preparation containing bortezomib as an active ingredient, it is necessary to take measures to stabilize against oxidation and decomposition and to prevent multimerization due to acid anhydride formation.
For example, Patent Document 1 discloses a boronic acid ester derivative of a bortezomib boronic acid and a saccharide such as mannitol, and a pharmaceutical preparation using the boronic acid ester derivative is taught. This is prepared by freeze-drying a tert-butanol solution or an aqueous solution containing tert-butanol of bortezomib and mannitol. Patent Document 2 describes a lyophilized preparation containing bortezomib and tromethamine. This is described as a tromethamine salt of bortezomib with a strong BN bond. Patent Document 3 describes a lyophilized preparation of bortezomib derivative, which is a pharmaceutical preparation selected from the group consisting of a bulking agent having a cyclodextrin and a monosaccharide and a surfactant.
Since bortezomib has a problem in stability, a freeze-dried preparation is usually studied. However, Patent Document 4 discloses an aqueous solution preparation stabilized by adding propylene glycol. Patent Document 5 discloses an acid anhydride-ester derivative of α-hydroxy-β-carboxylic acid such as citric acid and bortezomib, and describes that it can be used as a pharmaceutical preparation.
Thus, it is known that boronic acid reacts with alcohol or carboxylic acid to form boronic acid ester or acid anhydride. Such boronic acid esters and acid anhydrides undergo hydrolysis in an aqueous solution to reconstitute bortezomib. Moreover, the freeze-dried bortezomib preparation currently sold has poor wettability of the freeze-dried cake, and Non-Patent Document 1 describes that it takes about 120 seconds at maximum for dissolution. Therefore, a pharmaceutical preparation that is stable and has good re-dissolvability is desired.
本発明は、類縁物質の生成が抑制され、更に再溶解性が良好であるボルテゾミブを含む医薬製剤を提供することを課題とする。 This invention makes it a subject to provide the pharmaceutical formulation containing the bortezomib which the production | generation of a related substance is suppressed and re-solubility is favorable.
本発明者らは、ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体と共に、グリセリンを用いることで、類縁物質の生成が抑制され、更に再溶解性が良好であるボルテゾミブを含む医薬製剤を提供できることを見出した。本願は、以下の［１］〜［５］に記載の発明を要旨とする。
［１］ （Ａ）ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体、及び（Ｂ）グリセリン、を含有する医薬製剤。
［２］ （Ｃ）ニコチン酸アミドを含有する、［１］に記載の医薬製剤。
［３］ （Ｄ）ｐＨ調整剤を含み、その（Ｄ）ｐＨ調整剤が塩基性化合物と酸性化合物からなり、塩基性化合物が１当量のとき酸性化合物の当量が１〜４当量である［１］又は［２］に記載の医薬製剤。
［４］ （Ｄ）ｐＨ調整剤を含み、（Ａ）ボルテゾミブ濃度として１〜２．５ｍｇ／ｍＬとしたときの医薬製剤水溶液のｐＨが４．０〜７．０である、［１］〜［３］に記載の医薬製剤。
［５］ 凍結乾燥製剤である、［１］〜［４］の何れか一項に記載の医薬製剤。
The present inventors have used bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib, a pharmaceutical preparation containing bortezomib that suppresses the formation of related substances and has good resolubility by using glycerin. Found that can provide. The gist of the present application is the invention described in [1] to [5] below.
[1] A pharmaceutical preparation comprising (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib, and (B) glycerin.
[2] The pharmaceutical preparation according to [1], which contains (C) nicotinic acid amide.
[3] (D) A pH adjuster is included, the (D) pH adjuster is composed of a basic compound and an acidic compound, and when the basic compound is 1 equivalent, the equivalent of the acidic compound is 1 to 4 equivalents [1 ] Or the pharmaceutical preparation of [2].
[4] The pH of the pharmaceutical preparation aqueous solution is 4.0 to 7.0 when (D) a pH adjusting agent is included, and (A) the bortezomib concentration is 1 to 2.5 mg / mL, [3] The pharmaceutical preparation according to [3].
[5] The pharmaceutical preparation according to any one of [1] to [4], which is a lyophilized preparation.
本発明のボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体を有効成分とする医薬製剤は、ボルテゾミブの安定性を保持し再溶解性が良好なボルテゾミブの医薬製剤を提供することができる。したがって、ボルテゾミブ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、凍結乾燥製剤の再溶解が容易である医薬製剤を提供することができる。 The pharmaceutical preparation comprising the bortezomib of the present invention or a pharmaceutically acceptable salt thereof or a derivative of bortezomib as an active ingredient can provide a pharmaceutical preparation of bortezomib that retains the stability of bortezomib and has good resolubility. . Therefore, it is possible to provide a pharmaceutical preparation that can retain the efficacy and safety of bortezomib for a long period of time and can be easily re-dissolved in a lyophilized preparation.
本発明は、（Ａ）ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体、（Ｂ）グリセリンを含有する医薬製剤である。以下に、その詳細について説明する。 The present invention is a pharmaceutical preparation containing (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib and (B) glycerin. The details will be described below.
本発明は、ボルテゾミブ又はその誘導体を有効成分とする医薬製剤に関する。ボルテゾミブは、プロテアソーム阻害活性を有する化学名（Ｎ‐（２‐ピラジンカルボニル）‐Ｌ‐フェニルアラニン‐Ｌ‐ロイシンボロン酸）である。当該化合物は、特許第３７１７９３４号にて開示されるボロン酸誘導体であって、それに記載の方法により入手可能である。
本発明のボルテゾミブは、医薬的に許容される適当な塩であっても良い。医薬的に許容される塩とは、例えば、アルカリ金属塩（ナトリウム、カリウムなど）、アルカリ土類金属塩（マグネシウム、カルシウムなど）、アンモニウム塩及び医薬的に許容可能なアミンの塩（テトラメチルアンモニウム、トリエチルアミン、メチルアミン、ジエチルアミン、シクロペンチルアミン、ベンジルアミン、フェネチルアミン、ピペリジンモノエタノールアミン、トリス（ヒドロキシメチル）アミン、リジン、アルギニン及びＮ−メチル−Ｄ−グルカン）が含まれる。
The present invention relates to a pharmaceutical preparation comprising bortezomib or a derivative thereof as an active ingredient. Bortezomib is a chemical name (N- (2-pyrazinecarbonyl) -L-phenylalanine-L-leucine boronic acid) having proteasome inhibitory activity. The compound is a boronic acid derivative disclosed in Japanese Patent No. 3717934, and can be obtained by the method described therein.
Bortezomib of the present invention may be a suitable pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include alkali metal salts (sodium, potassium, etc.), alkaline earth metal salts (magnesium, calcium, etc.), ammonium salts, and pharmaceutically acceptable amine salts (tetramethylammonium salt). , Triethylamine, methylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine monoethanolamine, tris (hydroxymethyl) amine, lysine, arginine and N-methyl-D-glucan).
また、本発明は有効成分としてボルテゾミブの誘導体であっても良い。当該誘導体とは、ボルテゾミブのボロン酸官能基とのエステル誘導体、酸無水物誘導体、酸無水物‐エステル混合誘導体であって、水溶液中で、加水分解的に開裂してボルテゾミブを再生する物性である誘導体である。すなわち、１，２−ジオールを含むポリオール化合物、α‐ヒドロキシ‐β‐カルボン酸化合物、ジカルボン酸化合物とボルテゾミブとの反応生成物が挙げられる。例えば、ボルテゾミブとグリセリン、マンニトール、ソルビトール、キシリトール、グルコース、マルトース、スクロース、トレハロース、ラクトース、フルクトース、メグルミン、イノシトール、グルコン酸ナトリウム、シクロデキストリン等のポリオール化合物とのボロン酸エステル誘導体。クエン酸、酒石酸、リンゴ酸、サリチル酸、マンデル酸、３−ヒドロキシ酪酸等のα‐ヒドロキシ‐β‐カルボン酸とボルテゾミブとの酸無水物‐エステル混合誘導体、シュウ酸、マロン酸、コハク酸等のジカルボン酸との酸無水物等が挙げられる。
本発明において、ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体（Ａ）は、ボルテゾミブ、ボルテゾミブの塩、又はボルテゾミブの誘導体の何れか１種の化学種であっても良く、２種以上の混合物であっても良い。また、一部が、ボルテゾミブの３量体等の自己脱水縮合体を含んでいても良い。しかしながら、該３量体は難溶性であり、水溶液として投与する際に不溶性異物となるため、該３量体等の自己脱水縮合物は含まないことが好ましい。当該（Ａ）成分としては、医薬品用の有効成分として用いることができる品質レベルである事が好ましい。
The present invention may also be a derivative of bortezomib as an active ingredient. The derivative is an ester derivative, an acid anhydride derivative, or an acid anhydride-ester mixed derivative of bortezomib with a boronic acid functional group, and has physical properties to regenerate bortezomib by hydrolysis in an aqueous solution. Is a derivative. That is, a polyol compound containing 1,2-diol, an α-hydroxy-β-carboxylic acid compound, a reaction product of a dicarboxylic acid compound and bortezomib can be mentioned. For example, boronate ester derivatives of bortezomib and glycerin, mannitol, sorbitol, xylitol, glucose, maltose, sucrose, trehalose, lactose, fructose, meglumine, inositol, sodium gluconate, cyclodextrin and the like. Citric acid, tartaric acid, malic acid, salicylic acid, mandelic acid, acid anhydride-ester mixed derivatives of α-hydroxy-β-carboxylic acid and bortezomib such as 3-hydroxybutyric acid, dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, etc. An acid anhydride with an acid, etc. are mentioned.
In the present invention, bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib (A) may be any one chemical species of bortezomib, a salt of bortezomib, or a derivative of bortezomib. A mixture of the above may also be used. Further, a part may contain a self-dehydrating condensate such as a trimer of bortezomib. However, since the trimer is hardly soluble and becomes an insoluble foreign substance when administered as an aqueous solution, it is preferable not to contain a self-dehydrating condensate such as the trimer. The component (A) is preferably a quality level that can be used as an active ingredient for pharmaceuticals.
本発明における（Ａ）ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体とは、少なくともボルテゾミブを含有していることが好ましく、ボルテゾミブの含有量が５０質量％以上であることがより好ましい。（Ａ）成分がボルテゾミブであることが殊更好ましい。 In the present invention, (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib preferably contains at least bortezomib, and the content of bortezomib is more preferably 50% by mass or more. . It is particularly preferable that the component (A) is bortezomib.
本発明の医薬製剤は（Ｂ）グリセリンを含有する。グリセリンは有効成分である（Ａ）ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体の溶解性を向上させることができる。例えば、本発明の医薬製剤が凍結乾燥製剤の態様であって、投与時に例えば生理食塩水を用いて水溶液を再構成する場合、該グリセリン（Ｂ）を含む製剤は水溶性が向上しているため、凍結乾燥製剤の濡れ性が向上し速やかに溶解して投与用の水溶液を容易に調製することができる。
本発明の医薬製剤にグリセリン（Ｂ）を用いる場合、有効成分である（Ａ）ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体が１質量部に対し、（Ｂ）グリセリンが０．０１〜１０質量部を含有することが好ましい。好ましくは、（Ａ）成分が１質量部に対して、（Ｂ）グリセリンは０．１〜２質量部である。
The pharmaceutical preparation of the present invention contains (B) glycerin. Glycerin can improve the solubility of the active ingredient (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib. For example, when the pharmaceutical preparation of the present invention is in the form of a lyophilized preparation and the aqueous solution is reconstituted using, for example, physiological saline at the time of administration, the preparation containing the glycerin (B) has improved water solubility. The wettability of the lyophilized preparation is improved, and the aqueous solution for administration can be easily prepared by dissolving quickly.
When glycerin (B) is used in the pharmaceutical preparation of the present invention, the active ingredient (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib is 1 part by mass, and (B) glycerin is 0. It is preferable to contain 01-10 mass parts. Preferably, (B) glycerin is 0.1-2 mass parts with respect to 1 mass part of (A) component.
本明細書における濡れ性とは、固体表面に対する液体の親和性のことを示す。固体表面とは例えば凍結乾燥ケーキの表面であり、液体とは凍結乾燥製剤を再溶解する際に用いる液体であり例えば生理食塩水等が挙げられる。この液体が生理食塩水である場合、凍結乾燥ケーキの親水性が向上することで濡れ性が向上することが考えられる。 As used herein, wettability refers to the affinity of a liquid for a solid surface. The solid surface is, for example, the surface of a freeze-dried cake, and the liquid is a liquid used for re-dissolving the freeze-dried preparation, and examples thereof include physiological saline. When this liquid is physiological saline, it is considered that the wettability is improved by improving the hydrophilicity of the freeze-dried cake.
本発明の医薬製剤はニコチン酸アミド（Ｃ）を含有することが好ましい。ニコチン酸アミドは有効成分である（Ａ）ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体の溶解性を向上させることができる。例えば、本発明の医薬製剤が凍結乾燥製剤の態様であって、投与時に例えば生理食塩水を用いて水溶液を再構成する場合、該ニコチン酸アミド（Ｃ）を含む製剤は水溶性が向上しているため、速やかに溶解して投与用の水溶液を容易に調製することができる。
本発明の医薬製剤にニコチン酸アミド（Ｃ）を用いる場合、有効成分である（Ａ）ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体が１質量部に対し、（Ｃ）ニコチン酸アミドが０．１〜３０質量部を含有することが好ましい。好ましくは、（Ａ）成分が１質量部に対して、（Ｃ）ニコチン酸アミドは１〜１５質量部である。
The pharmaceutical preparation of the present invention preferably contains nicotinamide (C). Nicotinamide can improve the solubility of the active ingredient (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib. For example, when the pharmaceutical preparation of the present invention is in the form of a lyophilized preparation and an aqueous solution is reconstituted using, for example, physiological saline at the time of administration, the preparation containing the nicotinamide (C) has improved water solubility. Therefore, it can be dissolved quickly and an aqueous solution for administration can be easily prepared.
When nicotinamide (C) is used in the pharmaceutical preparation of the present invention, the active ingredient (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib is used in an amount of (C) nicotinic acid. It is preferable that the amide contains 0.1 to 30 parts by mass. Preferably, (A) component is 1 part by mass, and (C) nicotinamide is 1 to 15 parts by mass.
本発明の医薬製剤は、（Ｄ）ｐＨ調整剤を含み、そのｐＨ調整剤が塩基性化合物と酸性化合物からなることが好ましい。
該（Ｄ）ｐＨ調整剤に使用される塩基性化合物及び酸性化合物は、医薬製剤において一般的に使用されているものであり、本発明の医薬製剤に悪影響を及ぼさないものであれば特に限定されない。塩基性化合物としては水酸化ナトリウム、水酸化カリウム、水酸化リチウム等のアルカリ金属又はアルカリ土類金属の水酸化物、リン酸二水素ナトリウム、リン酸一水素二ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム等の無機酸のアルカリ土類金属塩等を挙げることができる。また塩基性化合物として添加剤を使用してもよく、その添加剤としてはグアニジノ基を有する化合物、例えばグアニジン又はその塩、クレアチン、クレアチニン、アルギニン等を挙げることができる。酸性化合物としては、塩酸、リン酸、ホウ酸、炭酸等の無機酸、クエン酸、酒石酸、アスコルビン酸、乳酸及び酢酸等の有機酸が挙げられる。また、前記塩基性化合物と酸性化合物を混合してｐＨ調整した緩衝剤を用いても良い。緩衝剤としては、リン酸緩衝剤、酢酸緩衝剤、クエン酸緩衝剤、酒石酸緩衝剤、乳酸緩衝剤、コハク酸緩衝剤、ＴＲＩＳ緩衝剤、グリシン緩衝剤及びヒスチジン緩衝剤等が挙げられる。これらのｐＨ調整剤は単独で用いても良く、また二種以上を組み合わせて用いても良い。
本発明における（Ｄ）ｐＨ調整剤としては、好ましくは水酸化ナトリウム、アルギニン、塩酸、リン酸又はその塩（リン酸二水素ナトリウム、リン酸一水素二ナトリウム等）である。
（Ｄ）ｐＨ調整剤は、医薬製剤を製造する際に、溶液のｐＨを目的のｐＨに調整することができればよく、適量で使用される。本発明の医薬製剤の製造に使用されるｐＨ調整剤の配合量は、ｐＨを上記の範囲に調整できれば特に限定されない。通常、ｐＨ調整剤はｐＨを目的の範囲に調整できるように適量使用される。
The pharmaceutical preparation of the present invention preferably comprises (D) a pH adjuster, and the pH adjuster comprises a basic compound and an acidic compound.
The basic compound and acidic compound used in the (D) pH adjuster are generally used in pharmaceutical preparations and are not particularly limited as long as they do not adversely affect the pharmaceutical preparation of the present invention. . Basic compounds include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium dihydrogen phosphate, disodium monohydrogen phosphate, sodium carbonate, sodium hydrogen carbonate, etc. And alkaline earth metal salts of inorganic acids. An additive may be used as the basic compound, and examples of the additive include a compound having a guanidino group, such as guanidine or a salt thereof, creatine, creatinine, and arginine. Examples of the acidic compound include inorganic acids such as hydrochloric acid, phosphoric acid, boric acid, and carbonic acid, and organic acids such as citric acid, tartaric acid, ascorbic acid, lactic acid, and acetic acid. Moreover, you may use the buffer which mixed the said basic compound and the acidic compound and adjusted pH. Examples of the buffer include a phosphate buffer, an acetate buffer, a citrate buffer, a tartaric acid buffer, a lactic acid buffer, a succinic acid buffer, a TRIS buffer, a glycine buffer, and a histidine buffer. These pH adjusters may be used alone or in combination of two or more.
(D) The pH adjuster in the present invention is preferably sodium hydroxide, arginine, hydrochloric acid, phosphoric acid or a salt thereof (sodium dihydrogen phosphate, disodium monohydrogen phosphate, etc.).
(D) When manufacturing a pharmaceutical formulation, (D) pH adjuster should just adjust the pH of a solution to the target pH, and is used in an appropriate quantity. The blending amount of the pH adjuster used for producing the pharmaceutical preparation of the present invention is not particularly limited as long as the pH can be adjusted to the above range. Usually, the pH adjuster is used in an appropriate amount so that the pH can be adjusted to the target range.
前記塩基性化合物と酸性化合物からなるｐＨ調整剤は、塩基性化合物が１当量のとき酸性化合物の当量が１〜４当量であることが好ましく、塩基性化合物が１当量のとき酸性化合物の当量が１〜３．５当量であることがより好ましい。 The pH adjuster comprising the basic compound and the acidic compound preferably has an acidic compound equivalent of 1 to 4 equivalents when the basic compound is 1 equivalent, and the acidic compound equivalent when the basic compound is 1 equivalent. It is more preferably 1 to 3.5 equivalents.
当量とは、ある物質が過不足なく反応する時の物質量であり、化学当量、電気化学当量、熱の仕事当量がある。通常化学当量を意味する。化学当量には、元素の当量、酸−塩基の当量、酸化−還元の当量がある。本明細書における当量とは、酸−塩基の当量のことである。すなわち、塩基性化合物が１当量で酸性化合物が１当量のときそれぞれのＨ＋及びＯＨ−の数が等しいことを意味し、塩基性化合物が１当量で酸性化合物が２当量のときＨ＋の数がＯＨ−の数の２倍であることを意味する。 The equivalent is the amount of a substance when a certain substance reacts without excess or deficiency, and includes a chemical equivalent, an electrochemical equivalent, and a work equivalent of heat. Usually means chemical equivalent. Chemical equivalents include elemental equivalents, acid-base equivalents, and oxidation-reduction equivalents. In this specification, the equivalent means an acid-base equivalent. That is, when the basic compound is 1 equivalent and the acidic compound is 1 equivalent, the number of H + and OH − is equal, and when the basic compound is 1 equivalent and the acidic compound is 2 equivalents, the number of H + Is twice the number of OH − .
本発明の医薬製剤は、ｐＨ調整剤を含み、有効成分であるボルテゾミブ又はボルテゾミブの誘導体の（Ａ）濃度として１．０〜２．５ｍｇ／ｍＬとした本発明の医薬製剤水溶液において、ｐＨが４．０〜７．０である、医薬製剤であることが好ましい。該ボルテゾミブの誘導体は、水溶液中にてボルテゾミブが再生される物性であることから、有効成分であるボルテゾミブの濃度として１．０〜２．５ｍｇ／ｍＬの水溶液において、ｐＨが４．０〜７．０である、医薬製剤であることが好ましい。好ましくは、前記水溶液としてｐＨ４．５〜６．５である医薬製剤である。更に好ましく、ｐＨ５．０〜６．０の範囲に調整するのが特に好ましい。 The pharmaceutical preparation of the present invention contains a pH adjuster, and the aqueous pharmaceutical preparation aqueous solution of the present invention has a pH of 4 to 4 as the concentration (A) of bortezomib or a derivative of bortezomib as an active ingredient. It is preferably a pharmaceutical preparation that is 0.0 to 7.0. Since the bortezomib derivative has physical properties such that bortezomib is regenerated in an aqueous solution, the pH of the bortezomib is 4.0 to 7.7 in an aqueous solution having a concentration of bortezomib as an active ingredient of 1.0 to 2.5 mg / mL. It is preferably a pharmaceutical preparation that is zero. Preferably, it is a pharmaceutical preparation having a pH of 4.5 to 6.5 as the aqueous solution. More preferably, the pH is particularly preferably adjusted within the range of 5.0 to 6.0.
本発明の（Ａ）ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体を有効成分とする医薬製剤は、（Ｂ）グリセリン、並びに任意の添加成分である（Ｃ）ニコチン酸アミド、（Ｄ）ｐＨ調整剤以外に、通常の医薬製剤に用いられる他の添加剤を含有していても良い。他の添加剤としては、ボルテゾミブの安定性を維持する範囲において通常の医薬製剤に用いられる等張化剤、賦形剤、溶解補助剤、抗酸化剤等を添加しても良い。
等張化剤としては塩化ナトリウム等の塩類、マンニトール、ラクトース、スクロース、マルトース、トレハロース、キシリトール、ソルビトール、イノシトール、グルコン酸ナトリウム、メグルミン、シクロデキストリン等の糖又は糖アルコール及び尿素等が挙げられる。
また、賦形剤としても、塩化ナトリウム等の塩類、マンニトール、ラクトース、スクロース、マルトース、トレハロース、キシリトール、ソルビトール、イノシトール、グルコン酸ナトリウム、メグルミン、シクロデキストリン等の糖又は糖アルコールを用いることができる。
溶解補助剤としては、チオグリセリン、プロピレングリコール等のポリオール類、ポリソルベート、ポリエチレングリコール、ポリプロピレングリコール、ポリオキシエチレンヒマシ油等のポリエーテル系化合物等を挙げることができる。
抗酸化剤としては、没食子酸プロピル、アスコルビン酸、トコフェロールポリエチレングリコールスクシナート、Ｌ‐システイン等が挙げられる。
他の添加剤の含有量は、ボルテゾミブの安定性を考慮して適切な量を適宜設定して用いられるが、有効成分であるボルテゾミブ又はその誘導体（Ａ）１質量部に対し、それぞれ３０質量部以下で添加して用いることが好ましい。より好ましくは、ボルテゾミブ１質量部に対し、それぞれ１５質量部以下の適用量である。
The pharmaceutical preparation comprising as an active ingredient (A) bortezomib or a pharmaceutically acceptable salt thereof or a derivative of bortezomib of the present invention is (B) glycerin, as well as (C) nicotinamide, D) In addition to the pH adjuster, other additives used in normal pharmaceutical preparations may be contained. As other additives, isotonic agents, excipients, solubilizers, antioxidants and the like used in ordinary pharmaceutical preparations may be added as long as the stability of bortezomib is maintained.
Examples of tonicity agents include salts such as sodium chloride, sugars such as mannitol, lactose, sucrose, maltose, trehalose, xylitol, sorbitol, inositol, sodium gluconate, meglumine, cyclodextrin, and sugar alcohols and urea.
Further, as the excipient, salts such as sodium chloride, saccharides such as mannitol, lactose, sucrose, maltose, trehalose, xylitol, sorbitol, inositol, sodium gluconate, meglumine, cyclodextrin, or sugar alcohol can be used.
Examples of the solubilizer include polyols such as thioglycerin and propylene glycol, polyether compounds such as polysorbate, polyethylene glycol, polypropylene glycol, and polyoxyethylene castor oil.
Antioxidants include propyl gallate, ascorbic acid, tocopherol polyethylene glycol succinate, L-cysteine, and the like.
The content of the other additives is appropriately set in consideration of the stability of bortezomib, and is used in an appropriate amount, but 30 parts by mass with respect to 1 part by mass of bortezomib or its derivative (A) as an active ingredient It is preferable to add and use in the following. More preferably, the application amount is 15 parts by mass or less per 1 part by mass of bortezomib.
本発明は、医薬製剤に関する。ボルテゾミブを有効成分とする医薬品は、注射剤の製剤形で静脈内投与又は皮下投与にて抗腫瘍剤として提供されていることから、本発明の医薬製剤も注射用製剤であることが好ましい。すなわち凍結乾燥製剤若しくは注射液製剤等の製剤型であることが好ましい。 The present invention relates to pharmaceutical formulations. Since pharmaceuticals containing bortezomib as an active ingredient are provided as antitumor agents by intravenous or subcutaneous administration in the form of injections, the pharmaceutical preparations of the present invention are also preferably injectable preparations. That is, it is preferable that it is a formulation type such as a lyophilized formulation or an injection solution formulation.
本発明の医薬製剤は、所定量の（Ａ）ボルテゾミブ又はその医薬的に許容される塩、若しくはボルテゾミブの誘導体、（Ｂ）グリセリン、並びに任意の添加成分である（Ｃ）ニコチン酸アミド、（Ｄ）ｐＨ調整剤、その他の添加剤を含有する溶液を調製し、これをメンブランフィルターにて濾過し、ガラス製バイアルに分注することで調製できる。注射液製剤の場合は、これを無菌的に封止することで調製することができ、凍結乾燥製剤の場合は、溶液を分注したバイアルを凍結乾燥して無菌的に封止すれば良い。
前記成分（Ａ）及び（Ｂ）、並びに任意の成分（Ｃ）、（Ｄ）及びその他の添加剤を含有する溶液を調製するための溶剤は、これらの成分を溶解できて、医薬的に許容される溶剤であれば特に限定されるものではなく、適宜選択して適当な溶剤を用いて良い。例えば、水、エタノール、イソプロパノール、ｔｅｒｔ−ブタノール、グリセリン、プロピレングリコール、Ｎ−メチルピロリドン、ジメチルスルホキシド、ポリエチレングリコール（マクロゴール）、ポリソルベート（Ｔｗｅｅｎ）、クレモホール等が挙げられ、これらの単独使用若しくは、２種以上の混合溶剤として用いても良い。
The pharmaceutical preparation of the present invention comprises a predetermined amount of (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib, (B) glycerin, and optional additives (C) nicotinamide, (D ) A solution containing a pH adjusting agent and other additives can be prepared, filtered through a membrane filter, and dispensed into a glass vial. In the case of an injection solution formulation, it can be prepared by aseptically sealing it, and in the case of a lyophilized formulation, the vial into which the solution has been dispensed may be lyophilized and aseptically sealed.
The solvent for preparing a solution containing the components (A) and (B) and the optional components (C), (D) and other additives can dissolve these components and is pharmaceutically acceptable. The solvent is not particularly limited, and an appropriate solvent may be used by appropriately selecting. For example, water, ethanol, isopropanol, tert-butanol, glycerin, propylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, polyethylene glycol (macrogol), polysorbate (Tween), cremophor and the like can be mentioned. You may use as a mixed solvent of a seed or more.
本発明の医薬製剤は、凍結乾燥製剤であることを含む。
凍結乾燥製剤を調製する場合、本発明の医薬製剤を含む溶液を調製するための前記溶剤は、製剤調製工程を考慮すると融点−４０℃以上であることが好ましい。例えば、水、ｔｅｒｔ−ブタノール、グリセリン、Ｎ−メチルピロリドン、ジメチルスルホキシド等を用いることが好ましい。水又は水と有機溶剤の水系混合溶剤を用いることがより好ましい。この溶剤を用いた当該溶液を凍結乾燥し、無菌的に封止することで凍結乾燥製剤を調製することができる。
The pharmaceutical preparation of the present invention includes a lyophilized preparation.
When preparing a freeze-dried preparation, the solvent for preparing the solution containing the pharmaceutical preparation of the present invention preferably has a melting point of −40 ° C. or higher in consideration of the preparation process. For example, it is preferable to use water, tert-butanol, glycerin, N-methylpyrrolidone, dimethyl sulfoxide, or the like. It is more preferable to use water or an aqueous mixed solvent of water and an organic solvent. A freeze-dried preparation can be prepared by freeze-drying the solution using this solvent and sealing aseptically.
本発明の医薬製剤は、ボルテゾミブの自己縮合による多量体形成が抑制されている。したがって、当該医薬製剤を投与のために溶液調製しても、ボルテゾミブ三量体といった不溶性成分の生成の問題を解決できている。したがって、投与時の溶液調製の課題を解決した安全な医薬製剤を提供することができる。 In the pharmaceutical preparation of the present invention, multimer formation due to self-condensation of bortezomib is suppressed. Therefore, even if the pharmaceutical preparation is prepared as a solution for administration, the problem of generation of insoluble components such as bortezomib trimer can be solved. Therefore, it is possible to provide a safe pharmaceutical preparation that solves the problem of solution preparation at the time of administration.
本発明の医薬製剤は、ボルテゾミブを有効成分とする医薬として使用することができる。ボルテゾミブ製剤は、プロテアソーム阻害作用に基づく多発性骨髄腫やマントル細胞リンパ腫といった悪性腫瘍治療剤として用いられていることから、同様に抗腫瘍剤として適用することができる。 The pharmaceutical preparation of the present invention can be used as a medicine containing bortezomib as an active ingredient. Since bortezomib preparations are used as therapeutic agents for malignant tumors such as multiple myeloma and mantle cell lymphoma based on proteasome inhibitory action, they can be similarly applied as antitumor agents.
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。 In the following, the present invention will be further illustrated by examples. However, the present invention is not limited to these examples.
［実施例１］
グリセリン１８ｍｇ、ニコチン酸アミド４６０ｍｇを２４ｍＬの注射用水に溶解し、アルギニン４０ｍｇを加えて溶解し、水溶液のｐＨを約１０．５としたものにボルテゾミブ６０ｍｇを加えて溶解した。０．５Ｍのリン酸溶液を４８０μＬ加えてｐＨ５．６に調整し、注射用水を加えて全量を６０ｍＬとした。その溶液はｐＨ５．６であった。
この溶液を孔径０．２２μｍのメンブレンフィルターを用いて無菌ろ過を行い、バイアルにろ過した液を３ｍＬ充填し、凍結乾燥を行い、実施例１に係る凍結乾燥製剤を調製した。
[Example 1]
18 mg of glycerin and 460 mg of nicotinamide were dissolved in 24 mL of water for injection, 40 mg of arginine was added and dissolved, and 60 mg of bortezomib was added and dissolved in an aqueous solution having a pH of about 10.5. 480 μL of 0.5 M phosphoric acid solution was added to adjust the pH to 5.6, and water for injection was added to make the total volume 60 mL. The solution was pH 5.6.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Example 1 was prepared.
［実施例２］
グリセリン１８ｍｇ、尿素１０００ｍｇを２４ｍＬの注射用水に溶解し、５Ｍの水酸化ナトリウムを１００μＬ加えて水溶液のｐＨを１１．０とした液にボルテゾミブ６０ｍｇを加えて溶解した。この水溶液を０．５Ｍのリン酸溶液を４００μＬ加えてｐＨ５．３に調整し、注射用水を加えて全量を６０ｍＬとした。その溶液はｐＨ５．３であった。
この溶液を孔径０．２２μｍのメンブレンフィルターを用いて無菌ろ過を行い、バイアルにろ過した液を３ｍＬ充填し、凍結乾燥を行い、実施例２に係る凍結乾燥製剤を調製した。
[Example 2]
18 mg of glycerin and 1000 mg of urea were dissolved in 24 mL of water for injection, and 100 mg of 5M sodium hydroxide was added to adjust the pH of the aqueous solution to 11.0, and 60 mg of bortezomib was added and dissolved. 400 μL of 0.5 M phosphoric acid solution was added to this aqueous solution to adjust the pH to 5.3, and water for injection was added to make the total volume 60 mL. The solution had a pH of 5.3.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Example 2 was prepared.
［比較例１］
ニコチン酸アミド５００ｍｇを２４ｍＬの注射用水に溶かし、アルギニン４０ｍｇを加えて溶解し、水溶液のｐＨを１０．５とした液にボルテゾミブ６０ｍｇを加えて溶解した。この水溶液を０．５Ｍのリン酸溶液を４８０μＬ加えてｐＨ５．５に調整し、注射用水を加えて全量を６０ｍＬとした。その溶液はｐＨ５．５であった。
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、バイアルにろ過した液を３ｍＬ充填し、凍結乾燥を行い、比較例１に係る凍結乾燥製剤を調製した。
[Comparative Example 1]
Nicotinamide 500 mg was dissolved in 24 mL of water for injection, 40 mg of arginine was added and dissolved, and 60 mg of bortezomib was dissolved in a solution with a pH of the aqueous solution of 10.5. The aqueous solution was adjusted to pH 5.5 by adding 480 μL of a 0.5 M phosphoric acid solution, and water for injection was added to make a total volume of 60 mL. The solution had a pH of 5.5.
The solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Comparative Example 1 was prepared.
［比較例２］
ＰＥＧ４０００ ８００ｍｇとニコチン酸アミド４２０ｍｇを２４ｍＬの注射用水に溶解し、アルギニン４０ｍｇを加えて溶解し、水溶液のｐＨを約１０．５とした液にボルテゾミブ６０ｍｇを加え溶解した。この水溶液を０．５Ｍのリン酸溶液を４５０μＬ加えてｐＨ５．６に調整し、注射用水を加えて全量を６０ｍＬとした。その溶液はｐＨ５．６であった。
この溶液を孔径０．２２μｍのメンブレンフィルターを用いて無菌ろ過を行い、バイアルにろ過した液を３ｍＬ充填し、凍結乾燥を行い、比較例２に係る凍結乾燥製剤を調製した。
[Comparative Example 2]
800 mg of PEG 4000 and 420 mg of nicotinamide were dissolved in 24 mL of water for injection, 40 mg of arginine was added and dissolved, and 60 mg of bortezomib was added and dissolved in a solution having a pH of about 10.5. 450 μL of 0.5 M phosphoric acid solution was added to this aqueous solution to adjust the pH to 5.6, and water for injection was added to make a total volume of 60 mL. The solution was pH 5.6.
This solution was aseptically filtered using a membrane filter having a pore diameter of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Comparative Example 2 was prepared.
［比較例３］
ＥＤＴＡ２Ｎａ１８０ｍｇ、ニコチン酸アミド４２０ｍｇを２４ｍＬの注射用水に溶解し、アルギニン４０ｍｇを加えて溶解し、５Ｍの水酸化ナトリウム溶液を２００μＬ加えてｐＨ１１．５とした液にボルテゾミブ６０ｍｇを加え溶解した。この溶液を０．５Ｍのリン酸溶液を１．５ｍＬ加えてｐＨ５．０に調整し、注射用水を加えて全量を６０ｍＬとした。その溶液はｐＨ５．０であった。
この溶液を孔径０．２２μｍのメンブレンフィルターを用いて無菌ろ過を行い、バイアルにろ過した液を３ｍＬ充填し、凍結乾燥を行い、比較例３に係る凍結乾燥製剤を調製した。
[Comparative Example 3]
180 mg of EDTA2Na and 420 mg of nicotinamide were dissolved in 24 mL of water for injection, 40 mg of arginine was added and dissolved, and 200 mg of 5M sodium hydroxide solution was added to adjust the pH to 11.5, and 60 mg of bortezomib was added and dissolved. This solution was adjusted to pH 5.0 by adding 1.5 mL of 0.5 M phosphoric acid solution, and water for injection was added to make the total volume 60 mL. The solution was pH 5.0.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Comparative Example 3 was prepared.
［比較例４］
安息香酸Ｎａ６ｍｇ、ニコチン酸アミド４２０ｍｇを２４ｍＬの注射用水に溶解し、アルギニン４０ｍｇを加えて溶解し、ｐＨ１０．５とした液にボルテゾミブ６０ｍｇを加え溶解した。この溶液を０．５Ｍのリン酸溶液を４８０μＬ加えてｐＨ５．２に調整し、注射用水を加えて全量を６０ｍＬとした。その溶液はｐＨ５．６であった。
この溶液を孔径０．２２μｍのメンブレンフィルターを用いて無菌ろ過を行い、バイアルにろ過した液を３ｍＬ充填し、凍結乾燥を行い、比較例４に係る凍結乾燥製剤を調製した。
[Comparative Example 4]
6 mg of sodium benzoate and 420 mg of nicotinamide were dissolved in 24 mL of water for injection, dissolved by adding 40 mg of arginine, and dissolved by adding 60 mg of bortezomib to a solution adjusted to pH 10.5. This solution was adjusted to pH 5.2 by adding 480 μL of 0.5 M phosphoric acid solution, and water for injection was added to make the total volume 60 mL. The solution was pH 5.6.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Comparative Example 4 was prepared.
［比較例５］
ポリソルベート８０ ６０ｍｇ、ニコチン酸アミド４２０ｍｇを２４ｍＬの注射用水に溶解し、アルギニン４０ｍｇを加えて溶解し、ｐＨ１０．５とした液にボルテゾミブ６０ｍｇを加え溶解した。この溶液を０．５Ｍのリン酸溶液を４８０μＬ加えてｐＨ５．６に調整し、注射用水を加えて全量を６０ｍＬとした。その溶液はｐＨ５．７であった。
この溶液を孔径０．２２μｍのメンブレンフィルターを用いて無菌ろ過を行い、バイアルにろ過した液を３ｍＬ充填し、凍結乾燥を行い、比較例５に係る凍結乾燥製剤を調製した。
[Comparative Example 5]
60 mg of polysorbate 80 and 420 mg of nicotinamide were dissolved in 24 mL of water for injection, dissolved by adding 40 mg of arginine, and dissolved by adding 60 mg of bortezomib to a solution adjusted to pH 10.5. This solution was adjusted to pH 5.6 by adding 480 μL of 0.5 M phosphoric acid solution, and water for injection was added to make the total volume 60 mL. The solution had a pH of 5.7.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Comparative Example 5 was prepared.
実施例１及び実施例２、比較例１〜５に係る医薬製剤１バイアル当たりの各成分組成を表１にまとめた。
［表１］
Table 1 shows the composition of each component per vial of pharmaceutical preparations according to Examples 1 and 2 and Comparative Examples 1 to 5.
[Table 1]
［試験例１］（溶解性試験）
実施例１、比較例１〜５で得られた凍結乾燥製剤を用いて溶解性試験を行った。
それぞれのサンプルに生理食塩水１．２ｍＬをバイアルに加え、凍結乾燥ケーキが液になじむように優しく振り混ぜ、静置し、完全に溶解するまでの時間を測定した。結果を表２に示す。
［表２］
A solubility test was performed using the freeze-dried preparations obtained in Example 1 and Comparative Examples 1 to 5.
To each sample, 1.2 mL of physiological saline was added to the vial, and the mixture was gently shaken so that the freeze-dried cake was familiar with the solution, allowed to stand, and the time until complete dissolution was measured. The results are shown in Table 2.
[Table 2]
グリセリンを含有する実施例１の凍結乾燥製剤は、グリセリンを含有しない比較例１、他の添加剤を含有する比較例２〜５の凍結乾燥製剤と比べて、濡れ性が良く、溶解時間が４分以上短縮した。この試験結果から、グリセリンの添加によりボルテゾミブを有効成分とする医薬製剤の再溶解性が良好になることが認められた。 The lyophilized preparation of Example 1 containing glycerin has better wettability and a dissolution time of 4 compared to Comparative Example 1 not containing glycerin and the lyophilized preparations of Comparative Examples 2 to 5 containing other additives. Shortened by more than a minute. From this test result, it was confirmed that the resolubility of the pharmaceutical preparation containing bortezomib as an active ingredient is improved by the addition of glycerin.
［試験例２］６０℃保存安定性試験
実施例１及び実施例２、比較例１〜５の注射用凍結乾燥製剤を、６０℃の条件下にて１週間保存した。各製剤について、ボルテゾミブ由来の類縁物質をＨＰＬＣにて分析した。ボルテゾミブ類縁物質のＨＰＬＣ分析条件を下に示した。
[Test Example 2] Storage stability test at 60 ° C. The freeze-dried preparations for injection of Examples 1 and 2 and Comparative Examples 1 to 5 were stored at 60 ° C. for 1 week. For each formulation, bortezomib-derived related substances were analyzed by HPLC. The HPLC analysis conditions for bortezomib-related substances are shown below.
［ボルテゾミブ由来の類縁物質の分析条件］
実施例及び比較例のボルテゾミブ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：Waters Symmetry Shield RP18 5μm，4.6mm×250mm
カラム温度：３５℃
移動相Ａ：水／アセトニトリル／ギ酸混液（７１５：２８５：１）
移動相Ｂ：メタノール／水／ギ酸混液（８００：２００：１）
送液量：１．０ｍＬ／ｍｉｎ．
波長：２７０ｎｍ
移動相の送液：表３に示す条件で送液した。
[Analysis conditions for related substances derived from bortezomib]
The related substances derived from the degradation of bortezomib in Examples and Comparative Examples were analyzed under the following liquid chromatography (HPLC) conditions.
Column: Waters Symmetry Shield RP18 5μm, 4.6mm x 250mm
Column temperature: 35 ° C
Mobile phase A: water / acetonitrile / formic acid mixture (715: 285: 1)
Mobile phase B: methanol / water / formic acid mixture (800: 200: 1)
Liquid feeding amount: 1.0 mL / min.
Wavelength: 270nm
Liquid feeding of mobile phase: Liquid feeding was carried out under the conditions shown in Table 3.
［表３］
実施例１〜２、及び比較例１〜５の凍結乾燥製剤の６０℃保存安定性試験における、各類縁物質含量を表４にまとめた。
［表４］
[Table 4]
実施例１及び実施例２は類縁物質Ａ及びＥの生成量が初期値でも少なく、製剤調製工程において類縁物質の生成が抑制されていた。更に、６０℃で１週間保存しても総類縁物質が０．５％（ｗ／ｗ）以下であり、保存条件下においても類縁物質の生成を抑制した。これに対し、比較例１も類縁物質の生成量が初期値でも、６０℃１週間保存しても総類縁物質が０．５％（ｗ／ｗ）以下であり、安定であることが分かった。しかしながら、再溶解に要する時間が５分以上のため、製剤としては適さないと考えられた。また、比較例２〜５は、初期においても総類縁物質が実施例１を超える量で含有しており、製剤製造工程中でも類縁物質の明らかな増加が認められた。更に６０℃で１週間保存すると、総類縁物質を１％以上含有し、保存条件下において類縁物質の生成を抑制することができなかった。以上の結果を比較すると、本発明の医薬製剤は、製剤製造工程中から製剤保存期間中に亘り、ボルテゾミブ類縁物質の生成を抑制することができることが明らかになった。 In Examples 1 and 2, the production amounts of related substances A and E were small even at the initial value, and the generation of related substances was suppressed in the preparation process. Furthermore, even if it preserve | saved for one week at 60 degreeC, a total related substance is 0.5% (w / w) or less, and the production | generation of the related substance was suppressed also on storage conditions. On the other hand, even in Comparative Example 1, even when the amount of related substances produced was the initial value, even when stored at 60 ° C. for 1 week, the total related substances were 0.5% (w / w) or less, indicating that they were stable. . However, since the time required for re-dissolution was 5 minutes or more, it was considered unsuitable as a preparation. In Comparative Examples 2 to 5, the total related substances were contained in an amount exceeding Example 1 even in the initial stage, and a clear increase in related substances was recognized even during the preparation manufacturing process. Furthermore, when stored at 60 ° C. for 1 week, it contained 1% or more of the total related substances, and the generation of related substances could not be suppressed under the storage conditions. Comparison of the above results revealed that the pharmaceutical preparation of the present invention can suppress the production of bortezomib related substances from the preparation manufacturing process to the preparation storage period.
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