JP2013056875A - Pharmaceutical preparation including bisphosphonate - Google Patents
Pharmaceutical preparation including bisphosphonate Download PDFInfo
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- JP2013056875A JP2013056875A JP2011213392A JP2011213392A JP2013056875A JP 2013056875 A JP2013056875 A JP 2013056875A JP 2011213392 A JP2011213392 A JP 2011213392A JP 2011213392 A JP2011213392 A JP 2011213392A JP 2013056875 A JP2013056875 A JP 2013056875A
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- bisphosphonate
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Abstract
Description
ビスホスホネート溶液を含むガラス材の容器からなる医薬製剤であって、注射溶液を提供する。 A pharmaceutical formulation comprising a glass container containing a bisphosphonate solution, which provides an injection solution.
ビスホスホネートは破骨細胞性骨吸収阻害作用を有していることが知られており、種々の骨吸収異常を伴う疾患の治療に用いられている。 Bisphosphonates are known to have an osteoclast bone resorption inhibitory effect and are used for the treatment of various diseases associated with abnormal bone resorption.
例えば、ビスホスホネートが悪性腫瘍による高カルシウム血症および多発性骨髄腫の処置のために採られる投与形態は、静脈注射溶液である。
しかしながら、ビスホスホネート溶液は、化学的に安定であるが、二価および多価陽イオンと反応し、またガラス中のシリコンと反応し不溶性の沈殿を形成することが知られている。さらに、標準的なガラス容器ではかなりの量の二価および多価イオンが浸出されることが示されていることから、ビスホスホネート溶液製剤のガラス容器での長期保存は不可能とされている。従って、当該製剤はプラスチック材からなる容器中で保存されているのが現状である。また、プラスチック材からなる容器は発熱性物質除去および滅菌に広く汎用される高温の加熱処理が困難なため容易に加熱処理が出来るガラス容器が求められる。For example, the dosage form in which bisphosphonates are taken for the treatment of hypercalcemia and multiple myeloma due to malignant tumors is an intravenous solution.
However, bisphosphonate solutions are chemically stable, but are known to react with divalent and polyvalent cations and with silicon in glass to form insoluble precipitates. In addition, the long-term storage of bisphosphonate solution formulations in glass containers is not possible, since standard glass containers have been shown to leach significant amounts of divalent and multivalent ions. Therefore, the present condition is that the said formulation is preserve | saved in the container which consists of a plastic material. In addition, since a container made of a plastic material is difficult to perform a high-temperature heat treatment widely used for exothermic substance removal and sterilization, a glass container that can be easily heat-treated is required.
本発明は、溶液注射剤の形態で提供される、少なくとも１つのビスホスホネート成分および溶解補助剤を含有し、ビスホスホネート溶液注射剤を発熱性物質を除去したガラス容器で安定に長期貯蔵することに成功した。 The present invention succeeded in stable and long-term storage of a bisphosphonate solution injection in a glass container that contains at least one bisphosphonate component and a solubilizing agent provided in the form of a solution injection and from which pyrogens have been removed. .
本発明は、ビスホスホネート溶液製剤に少量の非イオン性界面活性剤を添加することによりガラス容器中で微粒子生成を抑制することを可能にした。
非イオン性界面活性剤は、好ましくはポリソルベート８０である。The present invention makes it possible to suppress the formation of fine particles in a glass container by adding a small amount of a nonionic surfactant to a bisphosphonate solution formulation.
The nonionic surfactant is preferably polysorbate 80.
本発明の使用に最も好ましいビスホスホネートは、２−（イミダゾール−１−イル）−１−ヒドロキシエタン−１，１−ジホスホン酸（ゾレドロン酸）又はその塩である。 The most preferred bisphosphonate for use in the present invention is 2- (imidazol-1-yl) -1-hydroxyethane-1,1-diphosphonic acid (zoledronic acid) or a salt thereof.
ビスホスホネート溶液注射剤が、汎用されているガラスバイアル中で安定に長期貯蔵することが可能となる。 The bisphosphonate solution injection can be stably stored for a long time in a commonly used glass vial.
ビスホスホネート注射溶液製剤 Bisphosphonate injection solution formulation
実施例１：ゾレドロン酸 ４ｍｇ／４ｍＬ
注射用水の全量の約９０％を、ステンレススチール配合容器に充填する。緩衝剤であるクエン酸及びクエン酸ナトリウムを撹拌下で加え、溶解する。更に溶解剤であるポリソルベート８０水溶液を別途調製し混和する。製剤原料であるゾレドロン酸を撹拌下で加え、溶解する。その液をｐＨ調整剤であるクエン酸ナトリウム水溶液にて、ｐＨ６．３に調整する。調製液を注射用水で最終容量に調整する。バルク溶液を、０．２μｍ孔サイズのフィルターを通し充填する。洗浄および乾燥したガラスバイアルにバルク溶液を充填する。滅菌したＨｅｌｖｏｅｔ社のＦＭ２５９／オムニフレックスプラスでコートした栓をバイアルにはめこみ、その栓をしたガラスバイアルをアルミニウムキャップでシールする。
前記生成物は、４０℃／７５％ＲＨ（相対湿度）の条件下で安定である。About 90% of the total amount of water for injection is filled into a stainless steel compounding container. Buffers citric acid and sodium citrate are added under stirring and dissolved. Further, a polysorbate 80 aqueous solution as a dissolving agent is separately prepared and mixed. Zoledronic acid, which is a raw material for the preparation, is added with stirring and dissolved. The solution is adjusted to pH 6.3 with a sodium citrate aqueous solution as a pH adjuster. Adjust the preparation to final volume with water for injection. The bulk solution is filled through a 0.2 μm pore size filter. Fill washed and dried glass vials with bulk solution. A stopper coated with sterile Helvoet FM259 / Omniflex Plus is fitted into the vial and the stoppered glass vial is sealed with an aluminum cap.
The product is stable under conditions of 40 ° C./75% RH (relative humidity).
実施例２：ゾレドロン酸 ４ｍｇ／４ｍＬ
注射用水の全量の約９０％を、ステンレススチール配合容器に充填する。緩衝剤であるクエン酸及びクエン酸ナトリウムを撹拌下で加え、溶解する。更に溶解剤であるポリソルベート８０水溶液を別途調製し混和する。製剤原料であるゾレドロン酸を撹拌下で加え、溶解する。その液をｐＨ調整剤であるクエン酸ナトリウム水溶液にて、ｐＨ６．３に調整する。調製液を注射用水で最終容量に調整する。バルク溶液を、０．２μｍ孔サイズのフィルターを通し充填する。洗浄および乾燥したガラスバイアルにバルク溶液を充填する。滅菌したゴム栓をバイアルにはめこみ、その栓をしたガラスバイアルをアルミニウムキャップでシールする。
前記生成物は、５０℃の苛酷条件下で安定である。About 90% of the total amount of water for injection is filled into a stainless steel compounding container. Buffers citric acid and sodium citrate are added under stirring and dissolved. Further, a polysorbate 80 aqueous solution as a dissolving agent is separately prepared and mixed. Zoledronic acid, which is a raw material for the preparation, is added with stirring and dissolved. The solution is adjusted to pH 6.3 with a sodium citrate aqueous solution as a pH adjuster. Adjust the preparation to final volume with water for injection. The bulk solution is filled through a 0.2 μm pore size filter. Fill washed and dried glass vials with bulk solution. A sterile rubber stopper is fitted into the vial, and the stoppered glass vial is sealed with an aluminum cap.
The product is stable under severe conditions of 50 ° C.
種々の骨吸収異常を伴う疾患の治療に用いられるビスホスホネートを長期保存安定な注射液として提供することができる。 Bisphosphonates used for treatment of various diseases associated with abnormal bone resorption can be provided as injection solutions that are stable for long-term storage.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2011213392A JP2013056875A (en) | 2011-09-09 | 2011-09-09 | Pharmaceutical preparation including bisphosphonate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2011213392A JP2013056875A (en) | 2011-09-09 | 2011-09-09 | Pharmaceutical preparation including bisphosphonate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2013056875A true JP2013056875A (en) | 2013-03-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2011213392A Withdrawn JP2013056875A (en) | 2011-09-09 | 2011-09-09 | Pharmaceutical preparation including bisphosphonate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721132A (en) * | 2013-12-21 | 2015-06-24 | 石药集团恩必普药业有限公司 | Zoledronic acid injection and preparation method thereof |
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2011
- 2011-09-09 JP JP2011213392A patent/JP2013056875A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721132A (en) * | 2013-12-21 | 2015-06-24 | 石药集团恩必普药业有限公司 | Zoledronic acid injection and preparation method thereof |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A300 | Withdrawal of application because of no request for examination |
Free format text: JAPANESE INTERMEDIATE CODE: A300 Effective date: 20141202 |