JP2012031151A - Gemcitabine lyophilized preparation containing nicotinamide - Google Patents
Gemcitabine lyophilized preparation containing nicotinamide Download PDFInfo
- Publication number
- JP2012031151A JP2012031151A JP2011141594A JP2011141594A JP2012031151A JP 2012031151 A JP2012031151 A JP 2012031151A JP 2011141594 A JP2011141594 A JP 2011141594A JP 2011141594 A JP2011141594 A JP 2011141594A JP 2012031151 A JP2012031151 A JP 2012031151A
- Authority
- JP
- Japan
- Prior art keywords
- gemcitabine
- freeze
- mass
- nicotinamide
- 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
Links
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 title claims abstract description 116
- 238000002360 preparation method Methods 0.000 title claims abstract description 114
- 229960005277 gemcitabine Drugs 0.000 title claims abstract description 92
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 title claims abstract description 84
- 235000005152 nicotinamide Nutrition 0.000 title claims abstract description 41
- 239000011570 nicotinamide Substances 0.000 title claims abstract description 41
- 229960003966 nicotinamide Drugs 0.000 title claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- -1 organic acid salt Chemical class 0.000 claims abstract description 21
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 11
- 235000000346 sugar Nutrition 0.000 claims abstract description 6
- 150000008163 sugars Chemical class 0.000 claims abstract description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 27
- 239000007864 aqueous solution Substances 0.000 claims description 25
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 24
- 229960005144 gemcitabine hydrochloride Drugs 0.000 claims description 21
- 235000010355 mannitol Nutrition 0.000 claims description 13
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 11
- 238000004108 freeze drying Methods 0.000 claims description 8
- 239000012931 lyophilized formulation Substances 0.000 claims description 8
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 35
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- 208000008443 pancreatic carcinoma Diseases 0.000 abstract description 3
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 5
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- 229910052782 aluminium Inorganic materials 0.000 description 5
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Landscapes
- Medicinal Preparation (AREA)
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Abstract
Description
本発明は、ゲムシタビン又はその薬理学的に許容される塩（以下、単に「ゲムシタビン又はその塩」と記載する。）を有効成分とし、更にニコチン酸アミドを含有するゲムシタビン凍結乾燥製剤に関する。 The present invention relates to a freeze-dried gemcitabine preparation containing gemcitabine or a pharmacologically acceptable salt thereof (hereinafter simply referred to as “gemcitabine or a salt thereof”) as an active ingredient and further containing nicotinamide.
ゲムシタビンは、抗腫瘍活性を有するヌクレオシド系の代謝拮抗剤に分類されるデオキシシチリジン誘導体であり、強力で特異性の高い代謝拮抗作用を有していることが知られている。ゲムシタビンは、４−アミノ−１−（２−デオキシ−２，２−ジフルオロ−β−Ｄ−リボフラノシル）−ピリミジン−２（１Ｈ）−オンまたは２’−デオキシ−２’，２’−ジフルオロシチジン（β異性体）と記述され、下記の構造を有する。 Gemcitabine is a deoxycytiridine derivative classified as a nucleoside antimetabolite having antitumor activity, and is known to have a powerful and highly specific antimetabolite action. Gemcitabine is composed of 4-amino-1- (2-deoxy-2,2-difluoro-β-D-ribofuranosyl) -pyrimidin-2 (1H) -one or 2′-deoxy-2 ′, 2′-difluorocytidine ( β isomer) and has the following structure:
ゲムシタビンは、核酸の合成を妨げることによって細胞のＤＮＡおよびＲＮＡ合成を阻止し、これにより、癌細胞の増殖を停止させ、その死滅を引き起こす。わが国においては、非小細胞肺癌、膵癌、胆道癌を適応として既に上市されている。重篤な副作用が少ないことも特徴とされる。 Gemcitabine blocks cellular DNA and RNA synthesis by interfering with nucleic acid synthesis, thereby stopping the growth of cancer cells and causing their death. In Japan, non-small cell lung cancer, pancreatic cancer and biliary tract cancer are already marketed. It is also characterized by few serious side effects.
ゲムシタビンは凍結乾燥製剤として市販されている。溶液の場合、それらは長時間にわたって非常に安定というわけではないため、凍結乾燥製剤が用いられている。市販品に用いられている添加物には、Ｄ−マンニトール、無水酢酸ナトリウム、ｐＨ調節剤が用いられている。ゲムシタビンは、滅菌形態の塩酸塩としてバイアルで、静脈注射用にのみ提供され、ゲムシタビンを含有し、マンニトールおよび酢酸ナトリウムと共に滅菌凍結乾燥粉末として処方されている。 Gemcitabine is commercially available as a lyophilized formulation. In the case of solutions, lyophilized formulations are used because they are not very stable over time. As additives used in commercial products, D-mannitol, anhydrous sodium acetate, and a pH adjuster are used. Gemcitabine is provided in a vial as a sterile form of the hydrochloride, only for intravenous injection, contains gemcitabine and is formulated as a sterile lyophilized powder with mannitol and sodium acetate.
ゲムシタビンの塩は、水系溶媒に対してやや溶けやすい程度の溶解性を示す。例えばゲムシタビン塩酸塩１ｇを水に溶解するには、１４．７ｍＬの水が必要であることが知られている（非特許文献１）。
上記の市販されている凍結乾燥製剤は水にやや溶けやすいものの、薬剤の投与の際に完全に溶解するまでには時間がかかっていた。このように溶解に長時間を要する場合、患者への注射投与に時間を要するため、医療上問題であり、溶解時間を短縮できる凍結乾燥製剤が望まれていた。さらに、注射剤とする場合に残渣が存在することは、薬剤の有効利用の観点からみると致命的な欠点となる。したがって、凍結乾燥製剤における添加物を含めたすべての成分が、短時間で溶解することが必要である。
The salt of gemcitabine exhibits a solubility that is slightly soluble in an aqueous solvent. For example, it is known that 14.7 mL of water is required to dissolve 1 g of gemcitabine hydrochloride in water (Non-patent Document 1).
Although the above-mentioned commercially available lyophilized preparations are slightly soluble in water, it took time until they were completely dissolved at the time of drug administration. When dissolution takes a long time in this way, it takes time to administer the injection to a patient, which is a medical problem, and a freeze-dried preparation that can shorten the dissolution time has been desired. Furthermore, the presence of residues in the case of injections is a fatal defect from the viewpoint of effective use of drugs. Therefore, it is necessary that all components including additives in the lyophilized preparation dissolve in a short time.
また、凍結乾燥製剤について、製造中或いは保存中における有効成分の安定性も、確保されていなければならない。しかし、従来の凍結乾燥製剤については、加熱等の苛酷条件等において経時的にゲムシタビンの類縁物質が増加する傾向にあるという問題点があった（非特許文献１）。この類縁物質は、主に５’−Ｏ−アセチル体とβ−ウリジンであると考えられているが、これら類縁物質の保存中の増加は、長期間保存する可能性がある医薬品としては、好ましいものではない。
以上より、ゲムシタビンを有効成分とする凍結乾燥製剤であって、注射用水等に短時間で溶解しやすく、さらに、安定性に優れた凍結乾燥製剤が望まれていた。
In addition, for freeze-dried preparations, the stability of active ingredients during production or storage must be ensured. However, the conventional freeze-dried preparation has a problem that the amount of gemcitabine-related substances tends to increase with time under severe conditions such as heating (Non-patent Document 1). This related substance is considered to be mainly 5'-O-acetyl and β-uridine, but the increase during storage of these related substances is preferable as a pharmaceutical that may be stored for a long period of time. It is not a thing.
Based on the above, a lyophilized preparation containing gemcitabine as an active ingredient, which can be easily dissolved in water for injection in a short time, and further has excellent stability.
本発明は、安全で、なおかつ、使用しやすいゲムシタビン凍結乾燥製剤を提供することにある。
医療現場では、即時使用可能な注射溶液が迅速に調製されることが望ましいことは明らかであり、注射投与処置をする者の負担をできるだけ少なくするためにも、できるだけ短時間かつ少ない操作で、使用可能な注射溶液を調製できる凍結乾燥製剤が望まれている。また、長期間の保存においても類縁物質が増加することの無い、安定性に優れた凍結乾燥製剤が望まれていた。
すなわち、本発明の具体的な課題は、注射用水等に短時間で溶解しやすく、さらに、長期保存安定性に優れたゲムシタビン凍結乾燥製剤を提供することにより、安全で、なおかつ、使用しやすいゲムシタビン凍結乾燥製剤を提供することにある。
An object of the present invention is to provide a gemcitabine lyophilized preparation that is safe and easy to use.
In the medical field, it is clear that a ready-to-use injection solution should be prepared quickly, so that it can be used in the shortest time and with few operations as much as possible in order to minimize the burden on the person performing the injection treatment. There is a need for lyophilized formulations that can prepare possible injection solutions. In addition, a freeze-dried preparation excellent in stability that does not increase related substances even after long-term storage has been desired.
That is, a specific problem of the present invention is to provide a gemcitabine lyophilized preparation that is easily dissolved in water for injection in a short time and has excellent long-term storage stability, so that it is safe and easy to use. It is to provide a lyophilized formulation.
かかる課題を解決するために、本発明者は鋭意検討した結果、ゲムシタビン又はその塩と共に、ニコチン酸アミドを含有するゲムシタビン凍結乾燥製剤は注射用水に短時間で溶解し、かつ、溶解状態が安定した均一な注射溶液が得られることを見出した。これは、ゲムシタビン塩酸塩の注射用溶液への溶解性がニコチン酸アミドにより高められると共に、凍結乾燥製剤の溶解後の溶液粘度が低められるためと思われる。また、該凍結乾燥製剤はニコチン酸アミドを含有することにより、加熱等の苛酷条件下においても、経時的にゲムシタビンの類縁物質が増加せず、該凍結乾燥製剤の長期保存安定性が向上することを見出し、本発明を完成するに至った。 In order to solve such problems, the present inventor has diligently studied. As a result, gemcitabine lyophilized preparation containing nicotinamide together with gemcitabine or a salt thereof was dissolved in water for injection in a short time, and the dissolved state was stable. It has been found that a uniform injection solution can be obtained. This seems to be because the solubility of gemcitabine hydrochloride in an injectable solution is enhanced by nicotinamide and the solution viscosity after dissolution of the lyophilized formulation is lowered. In addition, the freeze-dried preparation contains nicotinamide, so that even under severe conditions such as heating, the related substances of gemcitabine do not increase over time, and the long-term storage stability of the freeze-dried preparation is improved. As a result, the present invention has been completed.
即ち、本発明は下記（１）〜（９）の発明に関する。
（１）ゲムシタビン又はその薬理学的に許容される塩及びニコチン酸アミドを含有するゲムシタビン凍結乾燥製剤。
（２）ニコチン酸アミドをゲムシタビン又はその薬理学的に許容される塩に対して１質量％〜２０質量％含有する上記（１）に記載のゲムシタビン凍結乾燥製剤。
（３）ゲムシタビン又はその薬理学的に許容される塩及びニコチン酸アミドを含有し、ｐＨが２〜４である水溶液を凍結乾燥して得られる上記（１）又は（２）に記載のゲムシタビン凍結乾燥製剤。
（４）ゲムシタビン又はその薬理学的に許容される塩がゲムシタビン塩酸塩である上記（１）〜（３）のいずれか一に記載のゲムシタビン凍結乾燥製剤。
（５）さらにＣ２〜Ｃ６有機酸塩を含有する上記（１）〜（４）のいずれか一に記載のゲムシタビン凍結乾燥製剤。
（６）該有機酸塩として少なくとも酢酸ナトリウムを含む上記（５）に記載のゲムシタビン凍結乾燥製剤。
（７）さらに糖類及び糖アルコール類から選択される少なくとも１種の賦形剤を含有する上記（１）〜（６）のいずれか一に記載のゲムシタビン凍結乾燥製剤。
（８）該賦形剤がＤ−マンニトールである上記（７）に記載のゲムシタビン凍結乾燥製剤。
（９）ゲムシタビン又はその薬理学的に許容される塩を、製剤総量に対して、３０〜７０質量％、ニコチン酸アミドを２〜１４質量％の割合で含み、残部に医薬用添加剤を含有する上記（１）〜（８）のいずれか一に記載のゲムシタビン凍結乾燥製剤。
That is, the present invention relates to the following inventions (1) to (9).
(1) Gemcitabine lyophilized preparation containing gemcitabine or a pharmacologically acceptable salt thereof and nicotinamide.
(2) The gemcitabine lyophilized preparation according to (1) above, containing 1% by mass to 20% by mass of nicotinic acid amide with respect to gemcitabine or a pharmacologically acceptable salt thereof.
(3) Gemcitabine freezing according to the above (1) or (2) obtained by freeze-drying an aqueous solution containing gemcitabine or a pharmacologically acceptable salt thereof and nicotinamide and having a pH of 2 to 4 Dry formulation.
(4) The gemcitabine lyophilized preparation according to any one of (1) to (3) above, wherein gemcitabine or a pharmacologically acceptable salt thereof is gemcitabine hydrochloride.
(5) The gemcitabine freeze-dried preparation according to any one of (1) to (4), further containing a C2 to C6 organic acid salt.
(6) The gemcitabine lyophilized preparation according to the above (5), which contains at least sodium acetate as the organic acid salt.
(7) The gemcitabine freeze-dried preparation according to any one of (1) to (6), further containing at least one excipient selected from sugars and sugar alcohols.
(8) The gemcitabine lyophilized preparation according to the above (7), wherein the excipient is D-mannitol.
(9) Gemcitabine or a pharmacologically acceptable salt thereof is contained in a proportion of 30 to 70% by mass and nicotinamide in a ratio of 2 to 14% by mass with respect to the total preparation amount, and the remainder contains a pharmaceutical additive The gemcitabine lyophilized preparation according to any one of (1) to (8) above.
本発明のゲムシタビン凍結乾燥製剤は、再溶解時の溶解性に優れ、注射用水に短時間で溶解し、安定な均一の溶液を形成する。さらに、該凍結乾燥製剤では苛酷試験でのゲムシタビン類縁物質の増加が抑えられ、製剤中におけるゲムシタビン又はその塩が安定に保持される結果、該凍結乾燥製剤は経時的な安定性に優れている。 The gemcitabine lyophilized preparation of the present invention is excellent in solubility upon re-dissolution and dissolves in water for injection in a short time to form a stable uniform solution. Furthermore, in the freeze-dried preparation, an increase in gemcitabine-related substances in a severe test is suppressed, and gemcitabine or a salt thereof in the preparation is stably maintained. As a result, the freeze-dried preparation is excellent in stability over time.
本発明は、上記した如く、その基本的態様として、ゲムシタビン又はその薬理学的に許容される塩、好ましくはゲムシタビン塩酸塩を活性成分として含有する凍結乾燥製剤であって、ニコチン酸アミドを含有することを特徴とする凍結乾燥製剤である。通常、上記活性成分およびニコチン酸アミド以外に、残部として任意の医薬用添加剤を含むことができる。
本発明の凍結乾燥製剤中におけるゲムシタビン又はその塩の含量は、有効投与量であれば良いが、通常は凍結乾燥製剤の総量に対して、３０〜７０質量％、好ましくは、４０〜６０質量％であり、より好ましくは４５〜５５質量％である。
任意の医薬用添加剤として好ましいものとしては、後記する有機酸塩、賦形剤、ｐＨ調整剤などを挙げることができる。
As described above, the basic aspect of the present invention is a lyophilized preparation containing gemcitabine or a pharmacologically acceptable salt thereof, preferably gemcitabine hydrochloride as an active ingredient, which contains nicotinamide. This is a freeze-dried preparation characterized by the above. Usually, in addition to the above active ingredient and nicotinamide, any pharmaceutical additive can be included as the balance.
The content of gemcitabine or a salt thereof in the freeze-dried preparation of the present invention may be an effective dose, but is usually 30 to 70% by weight, preferably 40 to 60% by weight, based on the total amount of the freeze-dried preparation. More preferably, it is 45-55 mass%.
Preferable examples of optional pharmaceutical additives include organic acid salts, excipients, pH adjusters and the like described later.
本発明のゲムシタビン凍結乾燥製剤に用いられるゲムシタビンは、例えば特公平５−４２４３８号に記載の方法等により、製造することができる。
ゲムシタビンの薬理学的に許容される塩は、ゲムシタビンと無機酸または有機酸とを適当な溶媒中で処理することにより、調製することができる。そのような無機酸としては、塩酸、臭化水素酸、硫酸、硝酸、リン酸、過ヨウ素酸等が挙げられる。また有機酸としては、ギ酸、酢酸、酪酸、シュウ酸、マロン酸、プロピオン酸、吉草酸、コハク酸、フマル酸、マレイン酸、酒石酸、クエン酸、リンゴ酸、安息香酸、ｐ−トルエンスルホン酸、メタンスルホン酸、エタンスルホン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸等を挙げることができる。ゲムシタビンの薬理学的に許容される塩としては、ゲムシタビン塩酸塩が特に好ましい。
Gemcitabine used in the gemcitabine lyophilized preparation of the present invention can be produced, for example, by the method described in JP-B-5-42438.
The pharmacologically acceptable salt of gemcitabine can be prepared by treating gemcitabine and an inorganic acid or an organic acid in a suitable solvent. Examples of such inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, periodic acid and the like. Examples of organic acids include formic acid, acetic acid, butyric acid, oxalic acid, malonic acid, propionic acid, valeric acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-toluenesulfonic acid, Examples thereof include methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, and benzenesulfonic acid. As a pharmacologically acceptable salt of gemcitabine, gemcitabine hydrochloride is particularly preferable.
本発明に用いられるニコチン酸アミドは、ナイアシンアミド（ｎｉａｃｉｎｅ ａｍｉｄｅ）ともいわれ、分子式Ｃ６Ｈ６Ｎ２Ｏ、分子量１２２．１３である。ニコチン酸アミドは、植物界ではニコチン酸と共存して広く分布し、哺乳類では肝臓に多く存在する。ニコチン酸アミドは、ニコチン酸と同様に水溶性のビタミンＢ複合体の一つであって、ヒトの抗ペラグラ因子である。本発明に用いられるニコチン酸アミドは、医療用に用いることができるニコチン酸アミドであれば良いが、注射剤に用いられるグレードのものがより好ましい。
本発明の凍結乾燥製剤に含有されるニコチン酸アミドの含量割合は本発明製剤の特徴が発揮される限り、特に制限はないが、ゲムシタビン又はその塩に対して、通常１〜２０質量％であり、５〜２０質量％が好ましく、５〜１５質量％がより好ましく、１０〜１５質量％がさらに好ましい。本発明の凍結乾燥製剤の総量に対するニコチン酸アミド含量割合は、通常２〜１４質量％程度であり、好ましくは３〜１４質量％程度であり、より好ましくは３〜１２質量％程度であり、更に好ましくは４〜１０質量％程度である。
The nicotinic acid amide used in the present invention is also referred to as niacinamide and has a molecular formula of C 6 H 6 N 2 O and a molecular weight of 122.13. Nicotinamide is widely distributed along with nicotinic acid in the plant kingdom, and abundant in the liver in mammals. Nicotinamide is a water-soluble vitamin B complex similar to nicotinic acid, and is a human anti-pellagra factor. The nicotinic acid amide used in the present invention may be nicotinic acid amide that can be used for medical purposes, but is preferably a grade used for injections.
The content ratio of nicotinic acid amide contained in the lyophilized preparation of the present invention is not particularly limited as long as the characteristics of the preparation of the present invention are exhibited, but is usually 1 to 20% by mass with respect to gemcitabine or a salt thereof. 5-20 mass% is preferable, 5-15 mass% is more preferable, 10-15 mass% is further more preferable. The content ratio of nicotinamide to the total amount of the lyophilized preparation of the present invention is usually about 2 to 14% by mass, preferably about 3 to 14% by mass, more preferably about 3 to 12% by mass, Preferably it is about 4-10 mass%.
また、本発明の凍結乾燥製剤は、必要に応じて、医薬用添加剤の一つとして、酢酸ナトリウム等の有機酸塩、好ましくはＣ２〜Ｃ６有機酸塩（好ましくはアルカリ金属塩）を含有しても良い。Ｃ２〜Ｃ６有機酸塩としてはクエン酸ナトリウム、酒石酸ナトリウム、乳酸ナトリウム又は酢酸ナトリウム等を挙げることができる。より好ましいものは酢酸のアルカリ金属塩であり、酢酸ナトリウムが更に好ましく、その無水物が通常使用される。これは、製剤中のｐＨを安定に保持し、ゲムシタビン又はその塩、好ましくはゲムシタビン塩酸塩の安定性に寄与するものと思われ、通常含むのが好ましい。該有機酸塩の含量割合は、ゲムシタビン又はその塩１００質量部に対して、通常０〜２０質量部程度、好ましくは２〜１０質量部程度、更に、好ましくは３〜８質量部程度の割合である。
また、本発明の凍結乾燥製剤の総量に対する、該有機酸塩の含量割合は、０．５〜１０質量％、好ましくは１〜５質量％程度である。
In addition, the lyophilized preparation of the present invention contains an organic acid salt such as sodium acetate, preferably a C2 to C6 organic acid salt (preferably an alkali metal salt) as one of pharmaceutical additives, if necessary. May be. Examples of the C2 to C6 organic acid salt include sodium citrate, sodium tartrate, sodium lactate and sodium acetate. More preferred is an alkali metal salt of acetic acid, sodium acetate is more preferred, and its anhydride is usually used. This is believed to contribute to the stability of gemcitabine or a salt thereof, preferably gemcitabine hydrochloride, which is kept stable at the pH in the preparation, and is preferably included. The content ratio of the organic acid salt is usually about 0 to 20 parts by mass, preferably about 2 to 10 parts by mass, and more preferably about 3 to 8 parts by mass with respect to 100 parts by mass of gemcitabine or a salt thereof. is there.
Moreover, the content rate of this organic acid salt with respect to the total amount of the freeze-dried formulation of this invention is 0.5-10 mass%, Preferably it is about 1-5 mass%.
本発明の凍結乾燥製剤の製造には、必要に応じてｐＨ調整剤を用いることができる。
ｐＨ調整剤としては、医薬製剤において一般的に使用されているものであり、本発明の凍結乾燥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。例えば、塩酸及びリン酸等の無機酸；クエン酸、酒石酸、炭酸、乳酸及び酢酸等の有機酸；水酸化ナトリウム、水酸化カリウム及び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２水素ナトリウム、リン酸１水素ナトリウム、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金属塩；等を挙げることができる。
本発明の凍結乾燥製剤に使用するｐＨ調整剤として好ましくは、塩酸、リン酸もしくはその塩（リン酸２水素ナトリウム、リン酸１水素ナトリウム等）及び水酸化ナトリウムが挙げられる。より好ましくは、塩酸及び水酸化ナトリウムである。ｐＨ調整剤は、凍結乾燥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。
In the production of the freeze-dried preparation of the present invention, a pH adjuster can be used as necessary.
The pH adjuster is not particularly limited as long as it is generally used in pharmaceutical preparations and does not adversely affect the lyophilized preparation of the present invention. For example, inorganic acids such as hydrochloric acid and phosphoric acid; organic acids such as citric acid, tartaric acid, carbonic acid, lactic acid and acetic acid; hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide and lithium hydroxide And alkali metal salts of inorganic acids such as sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium carbonate, sodium hydrogen carbonate, and the like.
Preferably, the pH adjuster used in the lyophilized preparation of the present invention includes hydrochloric acid, phosphoric acid or a salt thereof (sodium dihydrogen phosphate, sodium monohydrogen phosphate, etc.) and sodium hydroxide. More preferred are hydrochloric acid and sodium hydroxide. The pH adjuster may be used in an appropriate amount as long as the pH of the solution can be adjusted to the target pH when the freeze-dried preparation is produced.
これらのｐＨ調整剤は単独で用いてもよく、また二種以上を組み合わせて用いてもよい。
本発明においては、必要に応じて上記ｐＨ調整剤を使用することにより、凍結乾燥に供する溶液のｐＨを２〜４の範囲に調整するのが好ましく、ｐＨ２．０〜３．５の範囲に調整するのがより好ましく、ｐＨ２．５〜３．５の範囲に調整するのが更に好ましく、ｐＨ２．９〜３．１の範囲に調整するのが特に好ましい。
本発明の凍結乾燥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。
These pH adjusters may be used alone or in combination of two or more.
In the present invention, it is preferable to adjust the pH of the solution to be lyophilized to a range of 2 to 4 by using the above pH adjuster as necessary, and to a pH of 2.0 to 3.5. It is more preferable to adjust the pH to 2.5 to 3.5, and it is particularly preferable to adjust the pH to 2.9 to 3.1.
The blending amount of the pH adjuster used for producing the freeze-dried 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.
本発明の凍結乾燥製剤には、必要に応じて、糖類及び糖アルコール類から選択される少なくとも１種類以上の賦形剤を用いることができる。
糖類としては、凍結乾燥製剤の賦形剤として使用されている糖であれば特に限定されないが、例えば、グルコース、フルクトース等の単糖類、及び、マルトース、ラクトース、スクロース、トレハロース等の二糖類等を挙げることができる。糖アルコール類としては、凍結乾燥製剤の賦形剤として使用されている糖アルコールであれば特に限定されないが、例えば、マンニトール、エリスリトール、イノシトール及びソルビトール等を挙げることができる。本発明の凍結乾燥製剤に使用する糖類及び糖アルコール類から選択される賦形剤としては、グルコース及びＤ−マンニトールが好ましく、Ｄ−マンニトールがより好ましい。
本発明の凍結乾燥製剤中の、糖類及び糖アルコール類から選択される１種以上の賦形剤の配合量は、ゲムシタビン又はその塩１質量部に対して、通常０．０１〜１００質量部であり、好ましくは０．１〜１０質量部であり、より好ましくは０．５〜５質量部である。本発明の凍結乾燥製剤の総量に対する該賦形剤の含量割合は、１０〜７０質量％程度、好ましくは２０〜６０質量％程度、より好ましくは３０〜５５質量％程度、最も好ましくは３５〜５０質量％程度である。
In the freeze-dried preparation of the present invention, at least one kind of excipient selected from saccharides and sugar alcohols can be used as necessary.
The sugar is not particularly limited as long as it is a sugar used as an excipient for a freeze-dried preparation, and examples thereof include monosaccharides such as glucose and fructose, and disaccharides such as maltose, lactose, sucrose, and trehalose. Can be mentioned. The sugar alcohol is not particularly limited as long as it is a sugar alcohol used as an excipient for a lyophilized preparation, and examples thereof include mannitol, erythritol, inositol, and sorbitol. As the excipient selected from the saccharides and sugar alcohols used in the freeze-dried preparation of the present invention, glucose and D-mannitol are preferable, and D-mannitol is more preferable.
The compounding quantity of the 1 or more types of excipient | filler selected from saccharides and sugar alcohols in the lyophilized formulation of this invention is 0.01-100 mass parts normally with respect to 1 mass part of gemcitabine or its salt. Yes, preferably 0.1 to 10 parts by mass, more preferably 0.5 to 5 parts by mass. The content ratio of the excipient to the total amount of the lyophilized preparation of the present invention is about 10 to 70% by mass, preferably about 20 to 60% by mass, more preferably about 30 to 55% by mass, and most preferably 35 to 50%. It is about mass%.
本発明の好ましい凍結乾燥製剤は、１）ゲムシタビン又はその塩、２）ニコチン酸アミド、及び、必要に応じて、医薬用添加剤として、３）有機酸塩、４）ｐＨ調整剤及び５）糖類及び糖アルコール類から選択される少なくとも一種の賦形剤からなる群から選択される少なくとも一種を含有する。
本発明の好ましい凍結乾燥製剤として、例えば、１）ゲムシタビン又はその塩、好ましくはゲムシタビン塩酸塩を、製剤の総量に対して３０〜７０質量％、好ましくは４０〜６０質量％、２）ニコチン酸アミドを、製剤の総量に対して２〜１４質量％含有し、残部が賦形剤等の任意の医薬添加剤である凍結乾燥製剤を挙げることができる。
本発明のゲムシタビン凍結乾燥製剤における上記成分の配合比を、好ましい場合も含めて例示すれば、下記の通りである。但し、ｐＨ調整剤は必要に応じて使用される。
ゲムシタビン又はその塩（好ましくはゲムシタビン塩酸塩）１００質量部に対して、
ニコチン酸アミド：１〜２０質量部、好ましくは５〜２０質量部、より好ましくは５〜１５質量部、さらに好ましくは１０〜１５質量部、
有機酸塩：０〜２０質量部、好ましくは２〜１０質量部、更に好ましくは３〜８質量部、
ｐＨ調整剤：適量（例えば０〜２０質量部）
糖類及び糖アルコール類から選択される１種以上の賦形剤：１〜１００００質量部、好ましくは１０〜１０００質量部、より好ましくは５０〜５００質量部。
Preferred lyophilized preparations of the present invention are 1) gemcitabine or a salt thereof, 2) nicotinamide, and, if necessary, as a pharmaceutical additive, 3) an organic acid salt, 4) a pH adjuster, and 5) a saccharide. And at least one selected from the group consisting of at least one excipient selected from sugar alcohols.
Preferred lyophilized preparations of the present invention include, for example, 1) gemcitabine or a salt thereof, preferably gemcitabine hydrochloride, in an amount of 30 to 70% by mass, preferably 40 to 60% by mass, and 2) nicotinamide. Can be mentioned as a lyophilized preparation containing 2 to 14% by mass with respect to the total amount of the preparation and the balance being any pharmaceutical additive such as an excipient.
Examples of the mixing ratio of the above components in the gemcitabine lyophilized preparation of the present invention, including preferred cases, are as follows. However, the pH adjuster is used as necessary.
For 100 parts by mass of gemcitabine or a salt thereof (preferably gemcitabine hydrochloride)
Nicotinamide: 1 to 20 parts by weight, preferably 5 to 20 parts by weight, more preferably 5 to 15 parts by weight, still more preferably 10 to 15 parts by weight,
Organic acid salt: 0 to 20 parts by mass, preferably 2 to 10 parts by mass, more preferably 3 to 8 parts by mass,
pH adjuster: appropriate amount (for example, 0 to 20 parts by mass)
One or more excipients selected from saccharides and sugar alcohols: 1 to 10000 parts by mass, preferably 10 to 1000 parts by mass, more preferably 50 to 500 parts by mass.
本発明の凍結乾燥製剤は、さらに、医薬用添加剤の一つとして、界面活性剤、浸透圧調整剤、防腐剤、安定化剤及び抗酸化剤等の、その他の添加物を含有していてもよい。
上記界面活性剤としては、ポリソルベート、ポリオキシエチレンポリオキシプロピレングリコール、ポリエチレン硬化ヒマシ油及びセスキオレイン酸ソルビタンなどが挙げられ、上記浸透圧調整剤としては、ブドウ糖、キシリトール及びソルビトールなどが挙げられ、防腐剤としては、安息香酸及びアスコルビン酸などが挙げられる。しかし、これらに限定されるわけではない。
上記のその他の添加物を本発明の凍結乾燥製剤に使用する場合、その配合量は、ゲムシタビン又はその塩１質量部に対して、０．００１〜１質量部である。
なお、上記浸透圧調整剤のうち賦形剤としても使用可能なものについては、浸透圧調整剤と賦形剤の区別無く本発明の凍結乾燥製剤に使用することができ、その配合量も上記のその他の添加物の配合量に限定されない。
The freeze-dried preparation of the present invention further contains other additives such as surfactants, osmotic pressure regulators, preservatives, stabilizers and antioxidants as one of the pharmaceutical additives. Also good.
Examples of the surfactant include polysorbate, polyoxyethylene polyoxypropylene glycol, polyethylene hydrogenated castor oil, and sorbitan sesquioleate. Examples of the osmotic pressure adjusting agent include glucose, xylitol, and sorbitol. Examples of the agent include benzoic acid and ascorbic acid. However, the present invention is not limited to these.
When said other additive is used for the lyophilized formulation of this invention, the compounding quantity is 0.001-1 mass part with respect to 1 mass part of gemcitabine or its salt.
The osmotic pressure adjusting agent that can also be used as an excipient can be used for the lyophilized preparation of the present invention without distinction between the osmotic pressure adjusting agent and the excipient, and the blending amount thereof is also described above. It is not limited to the compounding quantity of other additives.
本発明の凍結乾燥製剤の製造方法としては、特に限定されないが、たとえば、以下の方法により製造することができる。
まずは、１）ゲムシタビン又はその塩、２）ニコチン酸アミド、及び必要に応じて、医薬用添加剤、例えば、３）有機酸塩、４）ｐＨ調整剤、５）糖類及び糖アルコール類から選択される１種以上の賦形剤、さらに、必要に応じて、安定化剤及び抗酸化剤等のその他の添加物を、水又は適当な水性溶媒（水及び水と混和可能な有機溶媒の混合物、たとえば、水とアルコールの混合物）に溶解させる。上記各成分を水又は水性溶媒に溶解させる順序は、成分の種類に特に依存することなく、任意の順序で溶解させることができる。上記各成分を溶解させる水又は水性溶媒としては、注射用蒸留水を使用するのが好ましい。
このときの水性溶液中のゲムシタビン又はその塩の濃度（ゲムシタビン相当量）は、通常０．１ｍｇ／ｍＬ〜１０ｍｇ／ｍＬであり、好ましくは０．５ｍｇ／ｍＬ〜５ｍｇ／ｍＬであり、より好ましくは０．５ｍｇ／ｍＬ〜２ｍｇ／ｍＬである。
得られた水性溶液につき、所望により、メンブレンフィルタなどを用いて濾過滅菌を行う。次いで、得られた無菌溶液をバイアル又はトレーなどの容器に分注し、通常の凍結乾燥方法により、本発明の凍結乾燥製剤とすることができる。
Although it does not specifically limit as a manufacturing method of the lyophilized formulation of this invention, For example, it can manufacture by the following method.
First, it is selected from 1) gemcitabine or a salt thereof, 2) nicotinamide, and optionally a pharmaceutical additive such as 3) an organic acid salt, 4) a pH adjuster, 5) sugars and sugar alcohols. One or more excipients, and optionally other additives such as stabilizers and antioxidants, water or a suitable aqueous solvent (water and a mixture of water miscible organic solvents, For example, it is dissolved in a mixture of water and alcohol). The order of dissolving each of the above components in water or an aqueous solvent can be dissolved in any order without depending on the type of the component. As water or an aqueous solvent for dissolving each of the above components, it is preferable to use distilled water for injection.
At this time, the concentration of gemcitabine or a salt thereof in the aqueous solution (equivalent to gemcitabine) is usually 0.1 mg / mL to 10 mg / mL, preferably 0.5 mg / mL to 5 mg / mL, more preferably 0.5 mg / mL to 2 mg / mL.
The obtained aqueous solution is sterilized by filtration using a membrane filter or the like, if desired. Subsequently, the obtained aseptic solution can be dispensed into a container such as a vial or a tray, and the lyophilized preparation of the present invention can be obtained by a normal lyophilization method.
凍結乾燥方法としては、通常の凍結乾燥方法であれば、いずれも支障は無い。
本発明の凍結乾燥製剤は、凍結乾燥工程の乾燥時間及び乾燥温度を調節することにより、その製造初期水分量をコントロールすることが可能である。本凍結乾燥製剤の製造初期水分量は、通常０．５質量％以下であり、好ましくは０．２質量％以下である。
As the freeze-drying method, any ordinary freeze-drying method can be used.
The lyophilized preparation of the present invention can control the initial water content of production by adjusting the drying time and drying temperature in the lyophilization process. The initial production moisture content of the freeze-dried preparation is usually 0.5% by mass or less, preferably 0.2% by mass or less.
上記で得られた凍結乾燥製剤が充填した容器、又は必要に応じて、上記で得られた凍結乾燥製剤を別の容器に移した後、容器内のヘッドスペースを窒素等の不活性ガスで置換し、次いで通常の打栓又は熔閉等の方法で密封することにより、本発明の保存用凍結乾燥製剤が得られる。凍結乾燥製剤を封入する容器としては、打栓又は熔閉等により密封することができるものであれば特に限定されないが、外部からの水分を完全に遮断できるとの観点から、バイアルやアンプルが好ましい。
このようにして得られる本凍結乾燥製剤は、賦形剤が非晶質粉体として存在するため、長期間に渡る経時的安定性を保つことができる。本発明の凍結乾燥製剤は、固体粉末状であるものが好ましい。
A container filled with the lyophilized preparation obtained above or, if necessary, the lyophilized preparation obtained above is transferred to another container, and then the head space in the container is replaced with an inert gas such as nitrogen. Then, the lyophilized preparation for storage of the present invention is obtained by sealing with a usual method such as plugging or fusing. The container for lyophilized preparation is not particularly limited as long as it can be sealed by stoppering or fusing, but a vial or an ampoule is preferable from the viewpoint that moisture from the outside can be completely blocked. .
The freeze-dried preparation thus obtained can maintain stability over time over a long period of time because the excipient is present as an amorphous powder. The lyophilized preparation of the present invention is preferably a solid powder.
本発明の凍結乾燥製剤の再溶解液の調製に使用する溶媒としては、通常、注射剤に使用される溶剤であれば、いずれも使用でき、具体例として、用時注射用蒸留水、生理食塩水、及び、その他一般的輸液（たとえば、５％ブドウ糖輸液、アミノ酸輸液など）が挙げられる。本発明の凍結乾燥製剤を上記溶媒に溶解させて得られる再溶解液は、静脈注射剤、皮下注射剤、筋肉注射剤又は点滴注射剤などの注射剤（注射液）として、非経口投与することができる。本発明の凍結乾燥製剤を、上記の注射用蒸留水、生理食塩水、又は輸液等の溶媒で溶解した液は、十分に安定である。
本発明の凍結乾燥製剤の復水・希釈時におけるゲムシタビンの濃度（ゲムシタビン相当量）は、通常、０．００１ｍｇ／ｍＬ〜１００ｍｇ／ｍＬであり、好ましくは、０．００５ｍｇ／ｍＬ〜５０ｍｇ／ｍＬである。
As the solvent used for the preparation of the redissolved solution of the lyophilized preparation of the present invention, any solvent can be used as long as it is usually used for injections. Specific examples include distilled water for injection, physiological saline Water and other common infusions (for example, 5% glucose infusion, amino acid infusion, etc.) can be mentioned. The redissolved solution obtained by dissolving the lyophilized preparation of the present invention in the above solvent is administered parenterally as an injection (injection solution) such as intravenous injection, subcutaneous injection, intramuscular injection or infusion injection. Can do. A solution obtained by dissolving the freeze-dried preparation of the present invention with a solvent such as the above-mentioned distilled water for injection, physiological saline, or infusion is sufficiently stable.
The concentration of gemcitabine (the amount equivalent to gemcitabine) at the time of condensing and dilution of the freeze-dried preparation of the present invention is usually 0.001 mg / mL to 100 mg / mL, preferably 0.005 mg / mL to 50 mg / mL. is there.
以下に本発明の実施例及び比較例を挙げて、本発明をさらに詳細に説明するが、これらは例示的なものであり、本発明は以下の実施例等に制限されるものではない。当業者は、以下に示す実施例に様々な変更を加えて本発明を実施することができ、かかる変更は本願特許請求の範囲に包含される。 EXAMPLES The present invention will be described in more detail below with reference to examples and comparative examples of the present invention, but these are illustrative, and the present invention is not limited to the following examples. Those skilled in the art can implement the present invention by making various modifications to the embodiments shown below, and such modifications are included in the scope of the claims of the present application.
実施例１
注射用蒸留水に、ゲムシタビン塩酸塩２２８ｍｇ、Ｄ−マンニトール２００ｍｇ、無水酢酸ナトリウム１２．５ｍｇ及びニコチン酸アミド２９ｍｇを溶解し、１０％塩酸を用いて、ｐＨを３．０±０．１に調整し、全量を５ｇとなるように調製した。次に、得られた水性溶液をフィルター（日本ポール株式会社製、商品名フロロダイン、孔径０．２μｍ）を用いてろ過し、得られたろ液の全量をバイアル（容量１５ｍｌ）に充填した。
得られたバイアルを凍結乾燥装置により、通常の方法で凍結乾燥した。凍結乾燥時間は約７１時間であった。得られた凍結乾燥製剤の水分量は、０．１９質量％であった。
上記の凍結乾燥工程により得られた凍結乾燥製剤入りバイアルのヘッドスペースを窒素置換し、次いで、バイアル内圧を約７０ｋＰａとしてゴム栓で減圧打栓した後、アルミキャップで巻き締め、本発明のゲムシタビン凍結乾燥製剤を得た。
Example 1
In distilled water for injection, 228 mg of gemcitabine hydrochloride, 200 mg of D-mannitol, 12.5 mg of anhydrous sodium acetate and 29 mg of nicotinamide are dissolved, and the pH is adjusted to 3.0 ± 0.1 using 10% hydrochloric acid. The total amount was adjusted to 5 g. Next, the obtained aqueous solution was filtered using a filter (trade name Fluorodyne, manufactured by Nippon Pole Co., Ltd., pore size 0.2 μm), and the whole amount of the obtained filtrate was filled in a vial (capacity 15 ml).
The obtained vial was freeze-dried by a usual method using a freeze-drying apparatus. The lyophilization time was about 71 hours. The water content of the obtained freeze-dried preparation was 0.19% by mass.
The head space of the vial containing the freeze-dried preparation obtained by the above-mentioned freeze-drying process was replaced with nitrogen, and then the vial internal pressure was reduced to about 70 kPa, and the vial was stoppered with a rubber stopper, and then wrapped with an aluminum cap to freeze the gemcitabine of the present invention. A dry formulation was obtained.
実施例２
実施例１と同様に、注射用蒸留水、ゲムシタビン塩酸塩１１４０ｍｇ、Ｄ−マンニトール１０００ｍｇ、無水酢酸ナトリウム６２．５ｍｇ、ニコチン酸アミド１４５ｍｇを用いて、全量を２５ｇとした水性溶液を調製した。得られた水性溶液のｐＨは３．０±０．１であった。次いで実施例１と同様の手順で、この水性溶液をろ過してバイアル（容量５０ｍｌ）に充填した後、実施例１と同じ凍結乾燥工程により、本発明のゲムシタビン凍結乾燥製剤を得た。
Example 2
In the same manner as in Example 1, an aqueous solution having a total amount of 25 g was prepared using distilled water for injection, 1140 mg of gemcitabine hydrochloride, 1000 mg of D-mannitol, 62.5 mg of anhydrous sodium acetate, and 145 mg of nicotinamide. The pH of the obtained aqueous solution was 3.0 ± 0.1. Next, this aqueous solution was filtered and filled in a vial (capacity: 50 ml) in the same procedure as in Example 1, and then the gemcitabine lyophilized preparation of the present invention was obtained by the same lyophilization process as in Example 1.
比較例１
実施例１と同様に、注射用蒸留水、ゲムシタビン塩酸塩２２８ｍｇ、Ｄ−マンニトール２００ｍｇ、無水酢酸ナトリウム１２．５ｍｇを用いて、全量を５ｇとした水性溶液を調製した。得られた水性溶液のｐＨは３．０±０．１であった。次いで実施例１と同様の手順で、この水性溶液をろ過してバイアル（容量１５ｍｌ）に充填した後、実施例１と同じ凍結乾燥工程により、ニコチン酸アミドを含有しない、比較用凍結乾燥製剤を得た。
Comparative Example 1
In the same manner as in Example 1, an aqueous solution having a total amount of 5 g was prepared using distilled water for injection, 228 mg of gemcitabine hydrochloride, 200 mg of D-mannitol, and 12.5 mg of anhydrous sodium acetate. The pH of the obtained aqueous solution was 3.0 ± 0.1. Next, this aqueous solution was filtered and filled in a vial (capacity 15 ml) in the same procedure as in Example 1, and then a comparative lyophilized preparation containing no nicotinamide was prepared by the same lyophilization process as in Example 1. Obtained.
比較例２
実施例１と同様に、注射用蒸留水、ゲムシタビン塩酸塩１１４０ｍｇ、Ｄ−マンニトール１０００ｍｇ、無水酢酸ナトリウム６２．５ｍｇを用いて、全量を２５ｇとした水性溶液を調製した。得られた水性溶液のｐＨは３．０±０．１であった。次いで実施例１と同様の手順で、この水性溶液をろ過してバイアル（容量５０ｍｌ）に充填した後、実施例１と同じ凍結乾燥工程により、ニコチン酸アミドを含有しない、比較用凍結乾燥製剤を得た。
Comparative Example 2
In the same manner as in Example 1, an aqueous solution having a total amount of 25 g was prepared using distilled water for injection, 1140 mg of gemcitabine hydrochloride, 1000 mg of D-mannitol, and 62.5 mg of anhydrous sodium acetate. The pH of the obtained aqueous solution was 3.0 ± 0.1. Next, this aqueous solution was filtered and filled in a vial (volume 50 ml) in the same procedure as in Example 1, and then a comparative lyophilized preparation containing no nicotinamide was prepared by the same lyophilization process as in Example 1. Obtained.
試験例１（溶解性試験）
実施例１、実施例２、比較例１及び比較例２で得られた凍結乾燥製剤を用いて、溶解性試験を行った。
実施例１および比較例１については、生理食塩水５ｍＬをバイアルに加え、激しく振り混ぜ、完全に溶解するまでの時間を測定した。実施例２および比較例２については、生理食塩水２５ｍＬを用いて同様に試験を行った。
溶解性試験の結果を下記表１に示す。
Test Example 1 (Solubility test)
Using the freeze-dried preparations obtained in Example 1, Example 2, Comparative Example 1 and Comparative Example 2, a solubility test was performed.
For Example 1 and Comparative Example 1, 5 mL of physiological saline was added to the vial, shaken vigorously, and the time until complete dissolution was measured. Example 2 and Comparative Example 2 were similarly tested using 25 mL of physiological saline.
The results of the solubility test are shown in Table 1 below.
ゲムシタビン塩酸塩２２８ｍｇ及びニコチン酸アミド２９ｍｇを含有する実施例１の凍結乾燥製剤は、ニコチン酸アミドを含有しない比較例１の凍結乾燥製剤と比べて、溶解時間が２５秒短縮した。また、ゲムシタビン塩酸塩１１４０ｍｇ及びニコチン酸アミド１４５ｍｇを含有する実施例２の凍結乾燥製剤は、ニコチン酸アミドを含有しない比較例２の凍結乾燥製剤と比べて、溶解時間が５０秒短縮した。
この試験結果より、ニコチン酸アミドの添加による、ゲムシタビン凍結乾燥製剤の再溶解時間の短縮が認められた。
The lyophilized preparation of Example 1 containing 228 mg of gemcitabine hydrochloride and 29 mg of nicotinamide had a dissolution time reduced by 25 seconds compared to the lyophilized preparation of Comparative Example 1 containing no nicotinamide. In addition, the freeze-dried preparation of Example 2 containing 1140 mg of gemcitabine hydrochloride and 145 mg of nicotinamide had a dissolution time reduced by 50 seconds compared to the freeze-dried preparation of Comparative Example 2 containing no nicotinamide.
From this test result, shortening of the redissolution time of the gemcitabine lyophilized preparation was recognized by the addition of nicotinamide.
試験例２（安定性試験）
実施例１、実施例２、比較例１及び比較例２について苛酷試験を行い、苛酷試験後の各凍結乾燥製剤について純度試験を行った。
実施例１、実施例２、比較例１及び比較例２で得られた凍結乾燥製剤のバイアルを恒温槽に入れ、７０℃の条件下で１週間及び２週間保存した。製造直後（イニシャル）、７０℃１週間放置後、７０℃２週間放置後の各サンプルについて、下記の純度試験を行った。
各凍結乾燥製剤につき、製剤時の組成に従いゲムシタビンとして０．２ｇに相当する量をとり、これを精製水５ｍＬに溶かした。この溶液１ｍＬに精製水を加えて２０ｍＬとし、試料溶液とした。試料溶液とは別に、ゲムシタビン塩酸塩標準品２３ｍｇ及びシトシン２０ｍｇを正確に量り、精製水に溶かして１０ｍＬの溶液とした。この溶液１ｍＬを量り、精製水を加えて１００ｍＬとした。この液１ｍＬを量り、精製水を加えて１０ｍＬとし、標準溶液とした。各試料溶液及び標準溶液２０μＬにつき、下記の条件で高速液体クロマトグラフィーにより定量分析を行った。それぞれの試料溶液及び標準溶液につき、ゲムシタビン由来のピーク面積、及び、各類縁物質由来のピーク面積を、自動積分法により測定した。
Test Example 2 (Stability test)
A severe test was conducted on Example 1, Example 2, Comparative Example 1 and Comparative Example 2, and a purity test was conducted on each lyophilized preparation after the severe test.
The vials of freeze-dried preparations obtained in Example 1, Example 2, Comparative Example 1 and Comparative Example 2 were placed in a thermostatic bath and stored at 70 ° C. for 1 week and 2 weeks. Immediately after production (initial), each sample after being allowed to stand at 70 ° C. for 1 week and then left at 70 ° C. for 2 weeks was subjected to the following purity test.
For each freeze-dried preparation, an amount corresponding to 0.2 g as gemcitabine was taken according to the composition at the time of preparation, and this was dissolved in 5 mL of purified water. Purified water was added to 1 mL of this solution to make 20 mL, which was used as a sample solution. Separately from the sample solution, 23 mg of gemcitabine hydrochloride standard and 20 mg of cytosine were accurately weighed and dissolved in purified water to give a 10 mL solution. 1 mL of this solution was weighed and purified water was added to make 100 mL. 1 mL of this solution was weighed and purified water was added to make 10 mL, which was used as a standard solution. Each sample solution and 20 μL of the standard solution were quantitatively analyzed by high performance liquid chromatography under the following conditions. For each sample solution and standard solution, the peak area derived from gemcitabine and the peak area derived from each related substance were measured by an automatic integration method.
高速液体クロマトグラフィーの測定条件：
検出器：紫外吸光光度計、波長２７５ｎｍ。
カラム：内径４．６ｍｍ、長さ２５ｃｍのステンレス管にオクチルシリル化シリカゲル（５μｍ）を充填したカラム。
カラム温度：２５℃。
移動相Ａ：リン酸二水素ナトリウム二水和物１５．６ｇを精製水に溶かし、さらにそこにリン酸を加えて、ｐＨが２．５で総量が１０００ｍＬとなるように調製した溶液。
移動相Ｂ：メタノール
移動相の送液：移動相Ａ及び移動相Ｂの混合比を下記表Ａのように変えて濃度勾配を制御した。
Measurement conditions for high performance liquid chromatography:
Detector: ultraviolet absorptiometer, wavelength 275 nm.
Column: A column in which a stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm is packed with octylsilylated silica gel (5 μm).
Column temperature: 25 ° C.
Mobile phase A: A solution prepared by dissolving 15.6 g of sodium dihydrogen phosphate dihydrate in purified water and further adding phosphoric acid thereto to a pH of 2.5 and a total volume of 1000 mL.
Mobile phase B: methanol Mobile phase feeding: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table A below.
表Ａ
注入後の時間 移動相Ａ 移動相Ｂ
（分） （ｖｏｌ％） （ｖｏｌ％）
０〜８ ９７ ３
８〜１３ ９７→５０ ３→５０
１３〜２０ ５０ ５０
２０〜２５ ５０→９７ ５０→３
流量：毎分１．２ｍＬ
面積測定範囲：ゲムシタビンの保持時間の４倍の範囲
純度試験の結果を下記表２に示した。下記表２の値は、各保存条件における、類縁物質由来の各ピーク面積の総和／ゲムシタビン由来のピーク面積×１００（％）を表す。
Table A
Time after injection Mobile phase A Mobile phase B
(Minutes) (vol%) (vol%)
0-8 97 3
8-13 97 → 50 3 → 50
13-20 50 50
20-25 50 → 97 50 → 3
Flow rate: 1.2 mL per minute
Area measurement range: 4 times the retention time of gemcitabine The results of the purity test are shown in Table 2 below. The values in Table 2 below represent the sum of the peak areas derived from related substances / the peak area derived from gemcitabine × 100 (%) under each storage condition.
この試験結果より、ニコチン酸アミドを添加していない比較例１及び比較例２の製剤では類縁物質の増加が認められたが、ニコチン酸アミドを添加した製剤では殆ど類縁物質は増加しなかった。イニシャルと７０℃２週間放置後を比較すると、比較例１及び比較例２の製剤ではそれぞれ、類縁物質が４倍及び９．５倍増加したのに対し、実施例１及び実施例２では１．５倍の増加にとどまった。これはニコチン酸アミドの添加により、類縁物質の中でもとくにゲムシタビンの５’−Ｏ−アセチル体の副生が抑制されたためと考えられる。 From this test result, an increase in the related substances was observed in the preparations of Comparative Examples 1 and 2 to which nicotinamide was not added, but the related substances were hardly increased in the preparation to which nicotinamide was added. Comparing the initial values with those after standing at 70 ° C. for 2 weeks, in the preparations of Comparative Example 1 and Comparative Example 2, the related substances increased 4 times and 9.5 times, respectively. Only a five-fold increase. This is thought to be due to the addition of nicotinic acid amide to suppress the by-product of the 5'-O-acetyl form of gemcitabine, among other related substances.
実施例３
ニコチン酸アミドを４０ｍｇ使用すること以外は実施例１と同様にして、ゲムシタビン塩酸塩を含有する全量５ｇの水性溶液を調製した。得られた水性溶液のｐＨは３．０±０．１であった。次に、実施例１と同様の方法により、得られた水性溶液をろ過し、得られたろ液の全量をバイアル（容量１５ｍｌ）に充填した後、実施例１と同じ凍結乾燥工程、減圧打栓工程及びアルミキャップの巻き締め工程を経て、本発明のゲムシタビン凍結乾燥製剤を得た。得られた凍結乾燥製剤の水分量は０．１９質量％であった。
Example 3
A total amount of 5 g of an aqueous solution containing gemcitabine hydrochloride was prepared in the same manner as in Example 1 except that 40 mg of nicotinamide was used. The pH of the obtained aqueous solution was 3.0 ± 0.1. Next, the obtained aqueous solution was filtered by the same method as in Example 1, and the entire amount of the obtained filtrate was filled in a vial (capacity: 15 ml). The gemcitabine lyophilized preparation of the present invention was obtained through the steps and the aluminum cap winding step. The water content of the obtained freeze-dried preparation was 0.19% by mass.
実施例４
ニコチン酸アミドを２５ｍｇ使用すること、及び、１０％塩酸を用いて溶液のｐＨを２．０±０．１に調整すること以外は実施例１と同様にして、ゲムシタビン塩酸塩を含有する全量５ｇの水性溶液を調製した。次に、実施例１と同様の方法により、得られた水性溶液をろ過し、得られたろ液の全量をバイアル（容量１５ｍｌ）に充填した後、実施例１と同じ凍結乾燥工程、減圧打栓工程及びアルミキャップの巻き締め工程を経て、本発明のゲムシタビン凍結乾燥製剤を得た。得られた凍結乾燥製剤の水分量は０．１９質量％であった。
Example 4
5 g total amount containing gemcitabine hydrochloride in the same manner as in Example 1 except that 25 mg of nicotinamide was used and the pH of the solution was adjusted to 2.0 ± 0.1 using 10% hydrochloric acid. An aqueous solution of was prepared. Next, the obtained aqueous solution was filtered by the same method as in Example 1, and the entire amount of the obtained filtrate was filled in a vial (capacity: 15 ml). The gemcitabine lyophilized preparation of the present invention was obtained through the steps and the aluminum cap winding step. The water content of the obtained freeze-dried preparation was 0.19% by mass.
実施例５
ゲムシタビン塩酸塩を１３９．６５ｍｇ、Ｄ−マンニトールを２８８．３５ｍｇ、ニコチン酸アミドを２５ｍｇ使用すること以外は実施例１と同様にして、ゲムシタビン塩酸塩を含有する全量５ｇの水性溶液を調製した。得られた水性溶液のｐＨは３．０±０．１であった。次に、実施例１と同様の方法により、得られた水性溶液をろ過し、得られたろ液の全量をバイアル（容量１５ｍｌ）に充填した後、実施例１と同じ凍結乾燥工程、減圧打栓工程及びアルミキャップの巻き締め工程を経て、本発明のゲムシタビン凍結乾燥製剤を得た。得られた凍結乾燥製剤の水分量は０．１９質量％であった。
Example 5
A total amount of 5 g of an aqueous solution containing gemcitabine hydrochloride was prepared in the same manner as in Example 1 except that 139.65 mg of gemcitabine hydrochloride, 288.35 mg of D-mannitol and 25 mg of nicotinamide were used. The pH of the obtained aqueous solution was 3.0 ± 0.1. Next, the obtained aqueous solution was filtered by the same method as in Example 1, and the entire amount of the obtained filtrate was filled in a vial (capacity: 15 ml). The gemcitabine lyophilized preparation of the present invention was obtained through the steps and the aluminum cap winding step. The water content of the obtained freeze-dried preparation was 0.19% by mass.
実施例６
Ｄ−マンニトール２００ｍｇの代わりにブドウ糖（グルコース）水和物２００ｍｇを使用すること、及び、ニコチン酸アミドを２５ｍｇ使用すること以外は実施例１と同様にして、ゲムシタビン塩酸塩を含有する全量５ｇの水性溶液を調製した。得られた水性溶液のｐＨは３．０±０．１であった。次に、実施例１と同様の方法により、得られた水性溶液をろ過し、得られたろ液の全量をバイアル（容量１５ｍｌ）に充填した後、実施例１と同じ凍結乾燥工程、減圧打栓工程及びアルミキャップの巻き締め工程を経て、本発明のゲムシタビン凍結乾燥製剤を得た。得られた凍結乾燥製剤の水分量は０．１９質量％であった。
Example 6
A total amount of 5 g of aqueous solution containing gemcitabine hydrochloride was obtained in the same manner as in Example 1 except that 200 mg of glucose (glucose) hydrate was used instead of 200 mg of D-mannitol and 25 mg of nicotinamide was used. A solution was prepared. The pH of the obtained aqueous solution was 3.0 ± 0.1. Next, the obtained aqueous solution was filtered by the same method as in Example 1, and the entire amount of the obtained filtrate was filled in a vial (capacity: 15 ml). The gemcitabine lyophilized preparation of the present invention was obtained through the steps and the aluminum cap winding step. The water content of the obtained freeze-dried preparation was 0.19% by mass.
試験例３（溶解性試験）
実施例３〜６で得られた凍結乾燥製剤を用いて、生理食塩水５ｍＬを４秒でバイアルに注入し、バイアルを１秒間に３〜４回横回転させて撹拌し、完全に溶解するまでの時間を測定した。生理食塩水の注入には容量５０ｍＬのシリンジ及び２１ゲージの注射針を使用した。
実施例３〜６の凍結乾燥製剤における溶解性試験の結果を下記表３に示す。
Test Example 3 (Solubility test)
Using the lyophilized preparations obtained in Examples 3-6, 5 mL of physiological saline was injected into the vial in 4 seconds, and the vial was swirled 3-4 times per second until stirred until completely dissolved. Was measured. For injection of physiological saline, a syringe with a capacity of 50 mL and a 21 gauge needle were used.
The results of the solubility test in the freeze-dried preparations of Examples 3 to 6 are shown in Table 3 below.
試験例４（安定性試験）
実施例４及び５で得られた凍結乾燥製剤について苛酷試験を行い、苛酷試験後の各凍結乾燥製剤について純度試験を行った。
実施例４及び５で得られた凍結乾燥製剤のバイアルを恒温槽に入れ、７０℃の条件下で１週間保存した。熱処理前（イニシャル）及び７０℃１週間放置後の各サンプルについて、試験例２と同様に純度試験を行った。
純度試験の結果を下記表４に示した。下記表４の値は、熱処理前及び熱処理後の凍結乾燥製剤における、類縁物質由来の各ピーク面積の総和／ゲムシタビン由来のピーク面積×１００（％）を表す。
Test Example 4 (Stability test)
The lyophilized preparations obtained in Examples 4 and 5 were subjected to a severe test, and each lyophilized preparation after the severe test was subjected to a purity test.
The freeze-dried vials obtained in Examples 4 and 5 were placed in a thermostatic bath and stored at 70 ° C. for 1 week. The purity test was performed in the same manner as in Test Example 2 for each sample before heat treatment (initial) and after being left at 70 ° C. for 1 week.
The results of the purity test are shown in Table 4 below. The values in Table 4 below represent the sum of the peak areas derived from related substances / the peak area derived from gemcitabine × 100 (%) in the freeze-dried preparation before and after heat treatment.
ニコチン酸アミドを添加して得られる本発明の凍結乾燥製剤のうち、実施例４では過酷試験前後の類縁物質の増加がイニシャルの１．３３倍にとどまり、実施例５では類縁物質は３分の２に減少した。これはニコチン酸アミドの添加により、類縁物質の中でもとくにゲムシタビンの５’−Ｏ−アセチル体の副生が抑制されたためと考えられる。 Among the freeze-dried preparations of the present invention obtained by adding nicotinamide, in Example 4, the increase in the related substances before and after the severe test was 1.33 times the initial, and in Example 5, the related substances were 3 minutes. Decreased to 2. This is thought to be due to the addition of nicotinic acid amide to suppress the by-product of the 5'-O-acetyl form of gemcitabine, among other related substances.
本発明により、注射用水に短時間で溶解して安定な均一の溶液を形成するという再溶解時の溶解性に優れ、さらに、苛酷試験でのゲムシタビン類縁物質の増加が抑えられ、製剤中におけるゲムシタビン又はその塩が安定に保持される結果、経時的な安定性に優れたゲムシタビン凍結乾燥製剤が提供される。ゲムシタビンは良好な非小細胞肺癌、膵癌、胆道癌等に対する治療作用を有することから、本発明により、用時調製型の製剤として、これら疾患の治療に極めて有効な製剤を提供できるものである。 According to the present invention, it is excellent in solubility at the time of re-dissolution of dissolving in water for injection in a short time to form a stable uniform solution, and further, an increase in gemcitabine-related substances in severe tests can be suppressed, and gemcitabine in the preparation Alternatively, as a result of the stable retention of the salt thereof, a gemcitabine lyophilized preparation having excellent stability over time is provided. Gemcitabine has good therapeutic effects on non-small cell lung cancer, pancreatic cancer, biliary tract cancer, and the like, and therefore, according to the present invention, a preparation that is extremely effective for the treatment of these diseases can be provided as a ready-to-use preparation.
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| JP2013231029A (en) * | 2012-04-27 | 2013-11-14 | Sun Pharmaceutical Industries Ltd | Ready to be infused gemcitabine solution |
| JP2018012660A (en) * | 2016-07-20 | 2018-01-25 | 日本化薬株式会社 | Pharmaceutical composition comprising bortezomib |
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