JP6204349B2 - Injectable composition - Google Patents
Injectable composition Download PDFInfo
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- JP6204349B2 JP6204349B2 JP2014510147A JP2014510147A JP6204349B2 JP 6204349 B2 JP6204349 B2 JP 6204349B2 JP 2014510147 A JP2014510147 A JP 2014510147A JP 2014510147 A JP2014510147 A JP 2014510147A JP 6204349 B2 JP6204349 B2 JP 6204349B2
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- pirarubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
本発明はアントラサイクリン系制癌剤の注射剤用組成物に関し、より具体的には、該制癌剤としてのピラルビシンの溶解性の改善された注射剤を提供するための組成物に関する。 The present invention relates to a composition for injection of an anthracycline anticancer agent, and more specifically relates to a composition for providing an injection with improved solubility of pirarubicin as the anticancer agent.
現在販売されているピラルビシン製剤（賦形剤：乳糖）は、アントラサイクリン系制癌剤の注射剤であり、生理食塩水に対する溶解性がよくない。そのため注射用蒸留水に溶解した上で投与されているが、生理食塩水に比べて疼痛、膀胱への刺激が強いというマイナス面がある。このマイナス面を改善する目的で、生理食塩水への溶解性を高める工夫が試みられている（特許文献１、特許文献２、参照）。具体的には、前者は、製剤の溶解性を改善するために製剤の製造に際し、活性薬剤の塩の水溶液に水溶性有機溶媒を添加した後に凍結乾燥することを提案し、後者は、アントラサイクリン系抗悪性腫瘍抗生物質に対して配合禁忌でないとされるニコチン酸アミド、イソニコチン酸アミドまたはゲンチジン酸アミドを溶解補助剤として使用することを提案している。 The currently sold pirarubicin preparation (excipient: lactose) is an injection of an anthracycline anticancer agent and has poor solubility in physiological saline. Therefore, it is administered after being dissolved in distilled water for injection, but it has the downside that pain and irritation to the bladder are stronger than physiological saline. In order to improve this minus aspect, attempts have been made to improve the solubility in physiological saline (see Patent Document 1 and Patent Document 2). Specifically, the former proposes to add a water-soluble organic solvent to an aqueous solution of an active agent salt and then freeze-dry in order to improve the solubility of the formulation, while the latter is an anthracycline. It has been proposed to use nicotinamide, isonicotinic acid amide or gentisic acid amide, which are not contraindicated for systemic antineoplastic antibiotics, as a solubilizing agent.
先行技術によると、アントラサイクリン系抗悪性腫瘍抗生物質を含有する注射剤の溶解性を改善するとの所定の目的は達成されている。しかし、特許文献２によると、特許文献１（特開平７−７６５１５号に相当する）に記載の発明はハンドリングの問題から実施されていない状況にあると述べられている。一方、特許文献２の発明では、アントラサイクリン系抗悪性腫瘍抗生物質に対して配合禁忌でないというものの、いずれも一定の生理活性を有する化合物を溶解補助剤として使用するものである。仮に、このような化合物を用いることなく所期の目的が達成できるなら、それに勝るものはない。したがって、本発明の目的はアントラサイクリン系制癌剤の中でも特に生理食塩水に対する溶解性の劣るピラルビシンを含有する注射剤において、特定の生理活性を示す化合物を使用することなくピラルビシンの溶解性が向上した注射剤を提供することにある。 According to the prior art, the predetermined objective of improving the solubility of injections containing anthracycline antineoplastic antibiotics has been achieved. However, according to Patent Document 2, it is stated that the invention described in Patent Document 1 (corresponding to Japanese Patent Application Laid-Open No. 7-76515) is not implemented due to handling problems. On the other hand, in the invention of Patent Document 2, although it is not contraindicated for anthracycline antineoplastic antibiotics, all use a compound having a certain physiological activity as a solubilizing agent. If the intended purpose can be achieved without using such a compound, there is nothing better than that. Therefore, an object of the present invention is to provide an injection in which the solubility of pirarubicin is improved without using a compound exhibiting a specific physiological activity in an anthracycline-based anticancer agent, particularly an injection containing pirarubicin having poor solubility in physiological saline. It is to provide an agent.
本発明者等は、当該技術分野で、通常、賦形剤として使用されることの多いマルトースまたは白糖を、ピラルビシン塩酸塩に対して一定割合以上配合すると、こうして調製される組成物は急激に生理食塩水への溶解性が向上することを、今ここに、見出した。マルトースまたは白糖は特許文献１及び２のいずれにも賦形剤として使用することすら記載も示唆もされていないことから、上記の知見は驚くべきことである。 When the present inventors blend maltose or sucrose, which is often used as an excipient in the art, with a certain ratio or more with respect to pirarubicin hydrochloride, the composition prepared in this manner is rapidly physiological. It has now been found here that the solubility in saline is improved. The above findings are surprising because maltose or sucrose is neither described nor suggested to be used as an excipient in either of Patent Documents 1 and 2.
したがって、上記課題を解決する手段として、活性薬剤としてのピラルビシン及び添加剤を含有する注射剤用組成物であって、活性薬剤としてのピラルビシンがピラルビシン塩酸塩であり、添加剤がマルトース及び白糖から選ばれるいずれか１種もしくは２種である注射剤用組成物が提供され、当該組成物は、以下のａ）からｃ）までのいずれかの条件を満たすことを特徴とする。
ａ）ピラルビシン塩酸塩対マルトースの重量比が１：少なくとも２２であること。
ｂ）ピラルビシン塩酸塩対白糖の重量比が１：少なくとも２２であること。
ｃ）ピラルビシン塩酸塩対白糖とマルトースの合計の重量比が１：少なくとも２２であること。Therefore, as a means for solving the above-mentioned problems, an injectable composition containing pirarubicin as an active agent and an additive, wherein pirarubicin as an active agent is pirarubicin hydrochloride, and the additive is selected from maltose and sucrose. The composition for injections which is any 1 type or 2 types provided is provided, The said composition satisfy | fills one of the conditions from the following a) to c).
a) The weight ratio of pirarubicin hydrochloride to maltose is 1: at least 22.
b) The weight ratio of pirarubicin hydrochloride to sucrose is 1: at least 22.
c) The total weight ratio of pirarubicin hydrochloride to sucrose and maltose is 1: at least 22.
このような組成物は、２５℃において、生理食塩水に対して３０秒以内に溶解し、かつ、凍結乾燥品の貯蔵安定性は、賦形剤として乳糖を含有する現在臨床使用されているピラルビシンの注射剤用凍結乾燥品のそれに優るとも劣らない。 Such a composition dissolves in physiological saline at 25 ° C. within 30 seconds, and the storage stability of the lyophilized product is pirarubicin currently used clinically containing lactose as an excipient. It is not inferior to that of the freeze-dried product for injection.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
注射剤用組成物にいう、注射剤は、患者の体内に注入される製剤であれば、その投与経路、投与部位、投与様式等により何ら制限されないが、就中、静脈内、動脈内、膀胱内へ投与される製剤を意図している。 As long as the injection is a preparation to be injected into the patient's body, the injection is not limited at all by the administration route, administration site, administration mode, etc. In particular, intravenous, intraarterial, bladder Contemplates formulations that are administered internally.
組成物は当該技術分野で常用される意味で使用されており、２種以上の物質の混合物を意味する。したがって、組成物には、上記の活性薬剤と添加剤に加え、本発明の目的に沿うものであるなら、当該技術分野で常用されている、他の賦形剤、緩衝剤またはｐＨ調節剤、浸透圧調節剤、防腐剤、抗酸化剤等を含むことができる。 The composition is used in the meaning commonly used in the technical field, and means a mixture of two or more substances. Therefore, in addition to the active agents and additives described above, the composition includes other excipients, buffers or pH adjusters that are commonly used in the art as long as they meet the objectives of the present invention, An osmotic pressure regulator, preservative, antioxidant and the like can be included.
ピラルビシンまたはピラルビシン塩酸塩は、特開昭５４−３０１４６号公報、特開昭６０−１６９９８号公報、特開昭６２−１１６５９１号公報または特開平１−１９０９１号公報に記載の方法により調製することができる。 Pirarubicin or pirarubicin hydrochloride can be prepared by the method described in JP-A-54-30146, JP-A-60-16998, JP-A-62-116591 or JP-A-1-19091. it can.
本発明に必須の成分であるピラルビシン塩酸塩は疎水性が高いため、従来の乳糖を添加剤または賦形剤に用いて調製した製剤を生理食塩水に溶解しようとすると、相当量の乳糖を用いても原薬が溶解不良を起こす場合がしばしばであった。ところが、理論に拘束されるものでないが、賦形剤として例えば、マルトースを用いると、原薬の疎水性がマルトースにより打ち消されるため、例えば、原薬１に対してマルトースを２２以上添加したところで溶解性に劇的な変化が起こり、原薬が生理食塩水へもスムーズに溶解するようになったものと理解できる。また、白糖もマルトースと同様な挙動を示す。したがって、ピラルビシン塩酸塩と添加剤としてのマルトースまたは白糖は、上述した重量比で含まれておれば、理論上添加剤の含有量に上限はない。しかし、かような組成物は、通常、凍結乾燥された形態で提供されることを考慮すると、以下の１）および２）の効果を奏するため、添加剤の濃度が１３５ｍｇ／ｍＬを越えないようにすることが好ましい。
１）凍結乾燥処理が円滑に実施できる。
２）処理後に取得できる凍結乾燥ケーキがバイアル中で２層になったり、下部がやせたりした外観にならない。Since pirarubicin hydrochloride, which is an essential component of the present invention, has high hydrophobicity, when a preparation prepared using conventional lactose as an additive or excipient is dissolved in physiological saline, a considerable amount of lactose is used. However, the drug substance often caused poor dissolution. However, although not bound by theory, for example, when maltose is used as an excipient, the hydrophobicity of the drug substance is counteracted by maltose. For example, dissolution occurs when 22 or more maltose is added to drug substance 1. It can be understood that there was a dramatic change in sex, and the drug substance dissolved smoothly in physiological saline. Sucrose also behaves similarly to maltose. Therefore, as long as pirarubicin hydrochloride and maltose or sucrose as an additive are contained in the above-described weight ratio, there is no theoretical upper limit on the content of the additive. However, considering that such a composition is usually provided in a lyophilized form, the following effects 1) and 2) are exerted, so that the additive concentration does not exceed 135 mg / mL. It is preferable to make it.
1) The freeze-drying process can be carried out smoothly.
2) The freeze-dried cake that can be obtained after processing does not have the appearance of two layers in the vial or the lower part is thin.
したがって、限定されるものではないが、本発明の組成物の好ましい態様として、活性薬剤としてのピラルビシン及び添加剤を含有する注射剤用組成物であって、活性薬剤としてのピラルビシンがピラルビシン塩酸塩であり、添加剤がマルトース及び白糖から選ばれるいずれか１種もしくは２種であり、かつ、以下のａ）からｃ）までのいずれかの条件を満たすことを特徴とする組成物を挙げることができる。
ａ）ピラルビシン塩酸塩対マルトースの重量比が１：２２〜４１であること。
ｂ）ピラルビシン塩酸塩対白糖が１：２２〜４１の重量比であること。
ｃ）ピラルビシン塩酸塩対白糖とマルトースの合計の重量比が１：２２〜４１であること。Accordingly, although not limited thereto, a preferred embodiment of the composition of the present invention is a composition for injection containing pirarubicin as an active agent and an additive, wherein pirarubicin as an active agent is pirarubicin hydrochloride. And a composition characterized in that the additive is any one or two selected from maltose and sucrose, and satisfies any of the following conditions a) to c): .
a) The weight ratio of pirarubicin hydrochloride to maltose is 1: 22-41.
b) The weight ratio of pirarubicin hydrochloride to sucrose is 1: 22-41.
c) The total weight ratio of pirarubicin hydrochloride to sucrose and maltose is 1: 22-41.
さらに、好ましい態様としては、ａ）では、ピラルビシン塩酸塩対マルトースの重量比が１：２５〜３８であり、ｂ）では、ピラルビシン塩酸塩対白糖の重量比が１：２５〜３８であり、ｃ）では、ピラルビシン塩酸塩対マルトースと白糖の合計の重量比が１：２５〜３８である。 Furthermore, in a preferred embodiment, in a) the weight ratio of pirarubicin hydrochloride to maltose is 1:25 to 38, in b) the weight ratio of pirarubicin hydrochloride to sucrose is 1:25 to 38, c ), The total weight ratio of pirarubicin hydrochloride to maltose and sucrose is 1: 25-38.
これらの組成物は、上記活性薬剤の粉末と添加剤の粉末（特に、日局マルトースまたは日局白糖（スクロース）のいずれか１種または２種）を機械的に混合することによって調製することができる。しかし、一般に、注射剤として用時溶解して用いることが望ましいことを考慮すると、活性薬剤及び添加剤をそれぞれ個別に水に溶解させた後、両者を混合するか、また、いずれか一方の水溶液に他方の固形物を添加溶解した溶液を凍結乾燥させて調製してもよい。以上の溶解処理は０℃〜室温（例えば、２０℃〜３０℃）で行うことができる。 These compositions may be prepared by mechanically mixing the active agent powder and the additive powder (especially, either one or two of JP JP maltose or JP sucrose). it can. However, in general, considering that it is desirable to dissolve and use it as an injection at the time of use, the active agent and the additive are individually dissolved in water and then mixed together, or either aqueous solution Alternatively, a solution in which the other solid is added and dissolved may be prepared by lyophilization. The above dissolution treatment can be performed at 0 ° C. to room temperature (for example, 20 ° C. to 30 ° C.).
凍結乾燥は薬液を−４０℃〜−８０℃に冷却して完全に凍結させた後、減圧下乾燥を行うことで実施することができる。 Freeze-drying can be performed by cooling the drug solution to −40 ° C. to −80 ° C. to completely freeze it, and then drying under reduced pressure.
こうして得られる組成物は、活性薬剤１０ｍｇ含有組成物として調製し、凍結乾燥後のケーキを２５℃において１０ｍＬの生理食塩水（例えば、日局生理食塩液）に振とう溶解させたとき３０秒以内に溶解し、しかも凍結乾燥後のケーキは均質の外観を呈し、あたかも局所的に圧縮粘着したような外観や２層になったり、下部がやせたりした外観は呈さない。さらに、このような凍結乾燥品は、４０℃や６０℃の苛酷貯蔵環境下においたとき、乳糖を用いた製剤に匹敵する活性薬剤の貯蔵安定性を示す。本明細書において「溶解する」とは、一定期間振とうし、静置したときの目視により内容物が完全に溶解し終わることを意味する。 The composition thus obtained is prepared as a composition containing 10 mg of the active agent, and when the cake after lyophilization is dissolved in 10 mL of physiological saline (for example, JP saline) at 25 ° C. within 30 seconds In addition, the cake after lyophilization exhibits a homogeneous appearance, and does not appear as if it was locally compressed and adhered, or formed into two layers, or the lower part was thin. Furthermore, such freeze-dried products exhibit storage stability of active agents comparable to formulations using lactose when placed in a severe storage environment at 40 ° C. or 60 ° C. In the present specification, “dissolve” means that the contents are completely dissolved by shaking for a certain period of time and visually observed when left standing.
一方、現在市販されているピラルビシンの注射用製剤の賦形剤として用いられている乳糖を上記添加剤に代えて調製した、ピラルビシン塩酸塩対乳糖の重量比が１：１５〜３１である凍結乾燥製品は、最も早く溶解するものにあっては、溶解するまでに約１分にまで短縮できるが、マルトースや白糖と比較して格段に多くの乳糖を必要とする。また、当該技術分野で賦形剤として常用されているＤ−マンニトール、Ｄ−ソルビトール、グルコース、フルクトースを上記添加剤に代えて使用すると、Ｄ−マンニトール、Ｄ−ソルビトールは、活性薬剤の溶解性をある程度向上させるものの、貯蔵安定性に劣り、また、グルコース、フルクトースは凍結乾燥製品の調製自体が困難である。 On the other hand, lyophilization with a weight ratio of pirarubicin hydrochloride to lactose of 1:15 to 31 was prepared by replacing lactose used as an excipient for an injectable formulation of pirarubicin currently marketed with the above additive The product that dissolves the fastest can be shortened to about 1 minute by dissolution, but requires much more lactose than maltose or sucrose. In addition, when D-mannitol, D-sorbitol, glucose, and fructose, which are commonly used as excipients in the technical field, are used in place of the above additives, D-mannitol and D-sorbitol improve the solubility of the active agent. Although it improves to some extent, it is inferior in storage stability, and glucose and fructose are difficult to prepare lyophilized products.
本発明の組成物は、生理食塩水（例えば、日局生理食塩液）液に溶解することにより、注射剤とすることができるが、注射用水（例えば、日局注射用水）または５％ブドウ糖注射液（例えば、日局ブドウ糖注射液）に溶解して注射液とすることもできる。 The composition of the present invention can be made into an injection by dissolving in a physiological saline (for example, JP saline) solution, but water for injection (for example, JP water for injection) or 5% glucose injection It can also be dissolved in a solution (for example, a JP glucose injection solution) to give an injection solution.
以下、具体例を挙げながら本発明をさらに具体的に説明するが、本発明をこれらの例に限定することを意図するものではない。 Hereinafter, the present invention will be described more specifically with specific examples. However, the present invention is not intended to be limited to these examples.
例１：ピラルビシン製剤の製造例
使用原料
・ピラルビシン塩酸塩（ＴＨＰともいう）は、ピラルビシン（日本マイクロバイオファーマ社製）に塩酸を添加して調製した。
・マルトース、白糖及び乳糖は、それぞれ、日局品として市販されているものをそのまま使用した。
・トレハロースは（株）林原生物化学研究所製をそのまま使用した。Example 1: Production Example of Pirarubicin Formulation The raw material used, pirarubicin hydrochloride (also referred to as THP), was prepared by adding hydrochloric acid to pirarubicin (manufactured by Nippon Microbiopharma).
-As maltose, sucrose, and lactose, those commercially available as JP products were used as they were.
-Trehalose was directly used by Hayashibara Biochemical Laboratories.
１−１：乳糖 ２５０ｍｇ ＴＨＰ１０ｍｇ力価 凍結乾燥時の薬液量（薬液充填量ともいう）３ｍＬ製剤の製法
ピラルビシン塩酸塩１００ｍｇ（力価）および乳糖２．５ｇを水に溶解し、水酸化ナトリウムでｐＨ６に調整し、全量３０ｍＬにした後に無菌ろ過をおこない、３ｍＬずつ１５ｍＬ容量のガラスバイアルに充填後凍結乾燥をして凍結乾燥製品を得た。1-1: Lactose 250 mg THP 10 mg titer Preparation of 3 mL drug solution at freeze-drying (also referred to as drug solution filling amount) 100 mg (titer) of pirarubicin hydrochloride and 2.5 g of lactose were dissolved in water, and the pH was adjusted to 6 with sodium hydroxide. The total volume was adjusted to 30 mL, and aseptic filtration was performed, and 3 mL each was filled into a 15 mL capacity glass vial and freeze-dried to obtain a freeze-dried product.
１−２：マルトース ２９０ｍｇ ＴＨＰ１０ｍｇ力価 薬液充填量３ｍＬ製剤の製法
ピラルビシン塩酸塩８４０ｍｇ（力価）およびマルトース２４．４ｇを水に溶解し、水酸化ナトリウムでｐＨ６に調整し、全量２５２ｍＬにした後に無菌ろ過をおこない、３ｍＬずつ１５ｍＬ容量のガラスバイアルに充填後凍結乾燥をして凍結乾燥製品を得た。1-2: Maltose 290 mg THP 10 mg titer Preparation of 3 mL drug solution Pilarubicin hydrochloride 840 mg (titer) and maltose 24.4 g are dissolved in water, adjusted to pH 6 with sodium hydroxide, and sterilized after total volume of 252 mL Filtration was performed, and 3 mL each was filled into a 15 mL capacity glass vial and then freeze-dried to obtain a freeze-dried product.
１−３：白糖 ２５０ｍｇ ＴＨＰ１０ｍｇ力価 薬液充填量３ｍＬ製剤の製法
ピラルビシン塩酸塩１００ｍｇ（力価）および白糖２．５ｇを水に溶解し、水酸化ナトリウムでｐＨ６に調整し、全量３０ｍＬにした後に無菌ろ過をおこない、３ｍＬずつ１５ｍＬ容量のガラスバイアルに充填後凍結乾燥をして凍結乾燥製品を得た。1-3: Sucrose 250 mg THP 10 mg titer Preparation of 3 mL drug solution formulation Pilarubicin hydrochloride 100 mg (titer) and sucrose 2.5 g are dissolved in water, adjusted to pH 6 with sodium hydroxide, and sterilized after total volume of 30 mL Filtration was performed, and 3 mL each was filled into a 15 mL capacity glass vial and then freeze-dried to obtain a freeze-dried product.
１−４：マルトース ２５０ｍｇ ＴＨＰ１０ｍｇ力価 薬液充填量２ｍＬ製剤の製法
ピラルビシン塩酸塩１００ｍｇ（力価）およびマルトース２．５ｇを水に溶解し、水酸化ナトリウムでｐＨ６に調整し、全量２０ｍＬにした後に無菌ろ過をおこない、２ｍＬずつ１５ｍＬ容量のガラスバイアルに充填後凍結乾燥をして凍結乾燥製品を得た。1-4: Maltose 250 mg THP 10 mg titer Preparation of 2 mL drug liquid formulation Pilarubicin hydrochloride 100 mg (titer) and maltose 2.5 g are dissolved in water, adjusted to pH 6 with sodium hydroxide, and sterilized after total volume of 20 mL Filtration was performed, and 2 mL each was filled into a 15 mL capacity glass vial and freeze-dried to obtain a freeze-dried product.
１−５：トレハロース ２５０ｍｇ ＴＨＰ１０ｍｇ力価 薬液充填量３ｍＬ製剤の製法
ピラルビシン塩酸塩１００ｍｇ（力価）およびトレハロース２．５ｇを水に溶解し、水酸化ナトリウムでｐＨ６に調整し、全量３０ｍＬにした後に無菌ろ過をおこない、３ｍＬずつ１５ｍＬ容量のガラスバイアルに充填後凍結乾燥をして凍結乾燥製品を得た。1-5: Trehalose 250 mg THP 10 mg titer Preparation of 3 mL drug solution: Pilarubicin hydrochloride 100 mg (titer) and trehalose 2.5 g are dissolved in water, adjusted to pH 6 with sodium hydroxide, and sterilized after total volume of 30 mL Filtration was performed, and 3 mL each was filled into a 15 mL capacity glass vial and then freeze-dried to obtain a freeze-dried product.
１−６：マルトースと白糖の混合物を含むＴＨＰ１０ｍｇ力価 薬液充填量３ｍＬ製剤の製法
ピラルビシン塩酸塩１００ｍｇ（力価）とマルトースおよび白糖を水に溶解し、水酸化ナトリウムでｐＨ６に調整し、全量３０ｍＬにした後に無菌ろ過をおこない、３ｍＬずつ１５ｍＬ容量のガラスバイアルに充填後凍結乾燥をして凍結乾燥製品を得た。1-6: THP containing a mixture of maltose and sucrose 10 mg titer Preparation of 3 mL drug solution Preparation of pirarubicin hydrochloride 100 mg (titer), maltose and sucrose dissolved in water, adjusted to pH 6 with sodium hydroxide, total volume 30 mL Then, aseptic filtration was performed, and 3 mL each was filled into a 15 mL capacity glass vial and lyophilized to obtain a lyophilized product.
例２：凍結乾燥製品の生理食塩水への溶解試験
例１のようにして得られた凍結乾燥製品に生理食塩水１０ｍＬを添加して振とうし、バイアル内の固形物が完全に溶解するまでの時間を計測した。その結果を下記表１〜５に示す。凍結乾燥製品を構成するピラルビシン塩酸塩１０ｍｇに対して含めた添加剤の種類及び量は、それぞれ表に示した量で使用した。Example 2: Lyophilized product dissolution test in physiological saline 10 mL of physiological saline was added to the lyophilized product obtained as in Example 1 and shaken until the solid in the vial was completely dissolved. Was measured. The results are shown in Tables 1 to 5 below. The types and amounts of additives included in 10 mg of pirarubicin hydrochloride constituting the lyophilized product were used in the amounts shown in the table.
上記表１〜表５の各条件で調製した試験品は、すべて問題なく凍結乾燥製品を得ることができた。 All of the test products prepared under the conditions in Tables 1 to 5 were able to obtain freeze-dried products without any problem.
例３：凍結乾燥製品の苛酷条件下での安定性試験
例１に記載にしたがって製造した凍結乾燥製品の中で製造した注射剤（マルトース２７０ｍｇ含有）を６０℃及び４０℃環境下で保管し、表に示す保管期間におけるピラルビシンの残存率を測定した。なお対照品にはＴＨＰ１０ｍｇにつき乳糖９０ｍｇを含有する従来の製剤品を用いて同様に残存率を測定した。結果を表６に示す。Example 3: Stability test of lyophilized product under severe conditions The injection (contained 270 mg of maltose) produced in the lyophilized product produced according to Example 1 was stored in an environment of 60 ° C and 40 ° C. The residual rate of pirarubicin during the storage period shown in the table was measured. For the control product, the residual rate was measured in the same manner using a conventional preparation containing 90 mg of lactose per 10 mg of THP. The results are shown in Table 6.
本発明の活性薬剤としてのピラルビシン及び添加剤を含有する注射剤用組成物は、注射剤調製に際し迅速に活性薬剤を生理食塩水に溶解できるうえに、貯蔵安定性に優れているため、ピラルビシン製剤の製薬産業で利用できる。 The composition for injections containing pirarubicin as an active agent and an additive of the present invention can rapidly dissolve an active agent in physiological saline for preparation of an injection, and is excellent in storage stability. Available in the pharmaceutical industry.
Claims (6)
活性薬剤としてのピラルビシンがピラルビシン塩酸塩であり、添加剤がマルトース及び白糖から選ばれるいずれか１種もしくは２種であり、かつ、以下のａ）からｃ）までの条件のいずれかの条件を満たすことを特徴とする組成物。
ａ）ピラルビシン塩酸塩対マルトースの重量比が１：少なくとも２２であること。
ｂ）ピラルビシン塩酸塩対白糖の重量比が１：少なくとも２２であること。
ｃ）ピラルビシン塩酸塩対白糖とマルトースの合計の重量比が１：少なくとも２２であること。 An injectable composition comprising a lyophilized product comprising only pirarubicin and an additive as an active agent, or comprising only pirarubicin and an additive and a pH adjusting agent as an active agent ,
Pirarubicin as the active agent is pirarubicin hydrochloride, is any one or two or the additive is selected from maltose and saccharose, and one of the conditions of conditions from the following a) c) until A composition characterized by satisfying.
a) The weight ratio of pirarubicin hydrochloride to maltose is 1: at least 22.
b) The weight ratio of pirarubicin hydrochloride to sucrose is 1: at least 22.
c) The total weight ratio of pirarubicin hydrochloride to sucrose and maltose is 1: at least 22.
ａ）ピラルビシン塩酸塩対マルトースの重量比が１：２２〜４１であること。
ｂ）ピラルビシン塩酸塩対白糖の重量比が１：２２〜４１であること。
ｃ）ピラルビシン塩酸塩対白糖とマルトースの合計の重量比が１：２２〜４１であること。 The composition for injection according to claim 1, which satisfies any one of the following conditions a) to c).
a) The weight ratio of pirarubicin hydrochloride to maltose is 1: 22-41.
b) The weight ratio of pirarubicin hydrochloride to sucrose is 1: 22-41.
c) The total weight ratio of pirarubicin hydrochloride to sucrose and maltose is 1: 22-41.
活性薬剤としてのピラルビシンがピラルビシン塩酸塩であり、添加剤がマルトース及び白糖から選ばれるいずれか１種もしくは２種であり、かつ、以下のａ）からｃ）までの条件のいずれかの条件を満たすことを特徴とする凍結乾燥品。
ａ）ピラルビシン塩酸塩対マルトースの重量比が１：少なくとも２２であること。
ｂ）ピラルビシン塩酸塩対白糖の重量比が１：少なくとも２２であること。
ｃ）ピラルビシン塩酸塩対白糖とマルトースの合計の重量比が１：少なくとも２２であること。 A freeze-dried product consisting only of pirarubicin as an active agent and an additive,
Pirarubicin as the active agent is pirarubicin hydrochloride, the additive is any one or two selected from maltose and sucrose, and any of the following conditions from a) to c) is satisfied A freeze-dried product characterized by that.
a) The weight ratio of pirarubicin hydrochloride to maltose is 1: at least 22.
b) The weight ratio of pirarubicin hydrochloride to sucrose is 1: at least 22.
c) The total weight ratio of pirarubicin hydrochloride to sucrose and maltose is 1: at least 22.
ａ）ピラルビシン塩酸塩対マルトースの重量比が１：２２〜４１であること。
ｂ）ピラルビシン塩酸塩対白糖の重量比が１：２２〜４１であること。
ｃ）ピラルビシン塩酸塩対白糖とマルトースの合計の重量比が１：２２〜４１であること。 A lyophilized product according to claim 5 , wherein the composition satisfies any one of the following conditions a) to c).
a) The weight ratio of pirarubicin hydrochloride to maltose is 1: 22-41.
b) The weight ratio of pirarubicin hydrochloride to sucrose is 1: 22-41.
c) The total weight ratio of pirarubicin hydrochloride to sucrose and maltose is 1: 22-41.
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