JP4598484B2 - Ritodrine hydrochloride injection solution - Google Patents
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- JP4598484B2 JP4598484B2 JP2004328272A JP2004328272A JP4598484B2 JP 4598484 B2 JP4598484 B2 JP 4598484B2 JP 2004328272 A JP2004328272 A JP 2004328272A JP 2004328272 A JP2004328272 A JP 2004328272A JP 4598484 B2 JP4598484 B2 JP 4598484B2
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本発明は、塩酸リトドリンが溶解された液状の薬剤に関する。 The present invention relates to a liquid drug in which ritodrine hydrochloride is dissolved.
塩酸リトドリン注射液は、切迫流産・早産治療剤として使用されている医薬品であり、ブドウ糖またはマルトース注射液に希釈したかたちで点滴静注することにより投与されるものである。塩酸リトドリン注射液の市販品の仕様はガラスアンプル充填品であり、貯法については抗酸化剤として添加されている亜硫酸塩と塩酸リトドリンとの反応生成物が生じないよう、５℃以下の冷蔵保存となっている。さらに、ガラスアンプル製剤であるので容器が割れやすく、さらに混注時にはアンプルカット時に生じるガラス片混入のおそれや、菌による汚染の可能性もある。
このようなガラスアンプル製剤の問題を解決するものとして、塩酸リトドリン０．０５〜２ｍｇ／ｍＬ、亜硫酸塩類０．０２〜０．３ｍｇ／ｍＬと等張ないし高張濃度のブドウ糖もしくはマルトースを溶解した水溶液のｐＨを３．０〜４．０に調整し、加熱滅菌した注射剤が提案されている（特許文献１）。この注射剤は、希釈液であるブドウ糖又はマルトース水溶液に予め溶解したプレミックス製剤であり、用事希釈の必要がないが、一方でプレミックス製剤であるが故、製造時に投与時の濃度が予め規定されてしまうことになり、医療現場における使用時に濃度が調整できないために、却って使いづらいものとなっている。また、投与時のｐHが３．０〜４．０と、生理的ｐHと比較して相当低いため、血管痛が起きやすく、患者のQOLの点からも好ましい製剤とはいい難いものであった。
Ritodrine hydrochloride injection is a pharmaceutical used as a treatment for imminent abortion / premature labor, and is administered by intravenous infusion in the form of diluted glucose or maltose injection. The specification of the commercial product of ritodrine hydrochloride injection is a glass ampoule-filled product, and the storage method is refrigerated at 5 ° C or less so that the reaction product of sulfite added as an antioxidant and ritodrine hydrochloride does not occur. It has become. Furthermore, since it is a glass ampoule preparation, the container is easily broken, and there is a possibility of mixing glass pieces that occur during ampoule cutting and contamination by bacteria.
In order to solve the problem of such glass ampoule preparation, ritodrine hydrochloride 0.05-2 mg / mL, sulfites 0.02-0.3 mg / mL and an aqueous solution in which glucose or maltose having an isotonic or hypertonic concentration is dissolved An injection prepared by adjusting the pH to 3.0 to 4.0 and sterilizing by heating has been proposed (Patent Document 1). This injection is a premix preparation pre-dissolved in dilute glucose or maltose aqueous solution, and there is no need to dilute it on the other hand. On the other hand, since it is a premix preparation, the concentration at the time of administration is specified in advance at the time of manufacture. Since the concentration cannot be adjusted at the time of use in the medical field, it is difficult to use. In addition, since the pH at the time of administration is 3.0 to 4.0, which is considerably lower than the physiological pH, vascular pain is likely to occur, and it is difficult to say that the preparation is preferable from the viewpoint of patient QOL. .
塩酸リトドリン注射液は、上述したように抗酸化剤との付加反応による反応生成物が問題となっており、冷蔵下にて保管されてきた。より安全に医療現場に提供していくためには、ガラスアンプルではなく、シリンジ、特にプラスチック性のシリンジに充填したプレフィルドシリンジ製剤が求められている。しかし、プレフィルドシリンジ化すると、一般に冷蔵保存下ではアンプル・バイアル形態の品目が主として構成されているため想定外の形状となってしまうシリンジ形態の製剤では保管が煩雑になるので、室温下にて保存可能なプラスチック製のプレフィルドシリンジ製剤が提供されることが医療現場では望まれている。ところが、抗酸化剤との反応生成物が問題となる塩酸リトドリン注射液製剤にとって、より酸素コントロールのしにくいプラスチック容器に充填することは未だ実現されていなかった。従って本発明は、安定で長期間にわたって室温保管可能な塩酸リトドリン注射液製剤を提供することを目的とするものである。 As described above, the ritodrine hydrochloride injection solution has a problem of a reaction product due to an addition reaction with an antioxidant, and has been stored under refrigeration. In order to provide a safer medical site, a prefilled syringe preparation filled with a syringe, particularly a plastic syringe, is required instead of a glass ampoule. However, when prefilled syringes are used, ampules and vials are generally composed mainly under refrigerated storage, so storage of syringes that have unexpected shapes becomes complicated, so store at room temperature. It is desirable in the medical field to provide a possible plastic prefilled syringe formulation. However, it has not been realized yet to fill a plastic container in which oxygen control is difficult for the ritodrine hydrochloride injection preparation in which a reaction product with an antioxidant is a problem. Accordingly, an object of the present invention is to provide a ritodrine hydrochloride injection solution preparation that is stable and can be stored at room temperature for a long period of time.
上記課題に鑑み、塩酸リトドリン自体の分解を抑制するとともに、塩酸リトドリンと他の成分との付加反応生成物の生成を抑制すべく、鋭意検討した結果、本発明者らは、亜硫酸塩類等の抗酸化剤を処方から抜くことで塩酸リトドリン注射液の安定性を保つとともに、抗酸化剤で酸素吸収する役割を脱酸素剤にて担うことを試み本発明を完成するに至った。
即ち、上記課題は、以下の（１）〜（７）によって解決される。
（１） 塩酸リトドリンを含有し、亜硫酸塩類からなる抗酸化剤を含有しない、ｐＨ４．７〜５．５の注射液が充填されたプラスチック製容器と脱酸素剤とが酸素難透過性包材に封入されてなることを特徴とする塩酸リトドリン注射液製剤。
（２） 前記プラスチック製容器が注射器である上記（１）に記載の塩酸リトドリン注射液製剤。
（３） 前記酸素難透過性包材は遮光性を有するものである上記（１）または（２）に記載の塩酸リトドリン注射液製剤。
（４） 室温で保存するための塩酸リトドリン注射液製剤である上記（１）〜（３）のいずれかに記載の塩酸リトドリン注射液製剤。
（５） 注射液が高圧蒸気滅菌されている上記（１）〜（４）のいずれかに記載の塩酸リトドリン注射液製剤。
（６） 注射液中の塩酸リトドリンの濃度が１０〜５０ｍｇ／ｍＬである上記（１）〜（５）のいずれかに記載の塩酸リトドリン注射液製剤。
（７） 注射液が窒素バブリングによって窒素置換されている上記（１）〜（６）のいずれかに記載の塩酸リトドリン注射液製剤。
In view of the above problems, as a result of intensive studies to suppress the decomposition of ritodrine hydrochloride itself and to suppress the formation of addition reaction products between ritodrine hydrochloride and other components, the present inventors have found that anti-sulfite salts and other anti-sulfur salts are resistant to the above-mentioned problems. By removing the oxidizing agent from the formulation, the stability of the ritodrine hydrochloride injection solution was maintained, and the oxygen scavenging role of the antioxidant was tried by the oxygen scavenger to complete the present invention.
That is, the said subject is solved by the following (1)-( 7 ).
(1) A plastic container filled with an injection solution having a pH of 4.7 to 5.5, which contains ritodrine hydrochloride and does not contain an antioxidant composed of sulfites, and an oxygen-deficient packaging material. A ritodrine hydrochloride injection preparation characterized by being encapsulated.
(2) The ritodrine hydrochloride injection solution preparation according to (1), wherein the plastic container is a syringe.
(3) The ritodrine hydrochloride injection liquid preparation according to the above (1) or (2), wherein the oxygen poorly permeable packaging material has light shielding properties.
(4) The ritodrine hydrochloride injection liquid preparation according to any one of the above (1) to (3), which is a ritodrine hydrochloride injection liquid preparation for storage at room temperature.
(5) The ritodrine hydrochloride injection liquid preparation according to any one of (1) to (4) above, wherein the injection liquid is autoclaved.
(6) The ritodrine hydrochloride injection solution formulation according to any one of (1) to (5) above, wherein the concentration of ritodrine hydrochloride in the injection solution is 10 to 50 mg / mL.
(7) The ritodrine hydrochloride injection solution preparation according to any one of (1) to (6), wherein the injection solution is nitrogen-substituted by nitrogen bubbling.
本発明は、亜硫酸塩類からなる抗酸化剤を不含とし、塩酸リトドリン等との付加反応生成物の生成を抑制するとともに、酸化反応の抑制が、室温下において長期間維持されることを可能とし、室温保存可能な塩酸リトドリン注射液製剤を提供するものである。
また、容器がプラスチック製であるので、破損のおそれもなく、ガラスフレークが注射液に混入するおそれもなくなった。
また、容器をシリンジ等の注射器とすることによって、ブドウ糖注射液やマルトース注射液等の希釈液に短時間で容易かつ確実に混注することができるようになったため、医療現場に更なる安全と安心を提供するものである。
The present invention does not contain an antioxidant composed of sulfites , suppresses the formation of an addition reaction product with ritodrine hydrochloride and the like, and enables the suppression of the oxidation reaction to be maintained at room temperature for a long period of time. The present invention provides a ritodrine hydrochloride injection solution that can be stored at room temperature.
Further, since the container is made of plastic, there is no risk of breakage, and there is no possibility of glass flakes being mixed into the injection solution.
In addition, since the container is a syringe or other syringe, it can be easily and reliably mixed in a diluted solution such as glucose injection solution or maltose injection solution in a short time. Is to provide.
本発明の塩酸リトドリン注射液製剤は、亜硫酸塩類からなる抗酸化剤を含有しない塩酸リトドリン水溶液からなる注射液をプラスチック製容器に充填し、密封したものを高圧蒸気滅菌したのち、脱酸素剤とともに酸素難透過性材に封入したもので、塩酸リトドリンの分解物や付加反応生成物の生成が抑制された安定な注射液製剤である。 The ritodrine hydrochloride injection liquid preparation of the present invention is prepared by filling a plastic container with an injection liquid consisting of an aqueous ritodrine hydrochloride solution containing no antioxidants consisting of sulfites , and sterilizing the sealed one with high-pressure steam, It is a stable injection preparation that is encapsulated in a poorly permeable material and suppresses the formation of degradation products and addition reaction products of ritodrine hydrochloride.
上記注射液中の塩酸リトドリンの濃度は、塩酸リトドリンとして１ｍｇ／ｍＬ〜５０ｍｇ／ｍＬとすることが望ましい。
注射液には、塩化ナトリウム、ブドウ糖、マルトース、マンニトール、ソルビトール、マンノース、クエン酸ナトリウム、酢酸ナトリウム、リン酸二水素ナトリウム、または乳酸ナトリウム等の等張化剤を適宜配合することができる。
また、注射液のｐＨは、投与時の低ｐＨに起因する血管痛発生を防止するため、できるかぎりｐＨを中性域に近づけ、ｐH４．５〜７．４とすることが望ましいが、本発明では、処方上の他の要因などを考慮して、ｐＨ４．７〜５．５に設定している。
また、この注射剤は、酢酸、氷酢酸、塩酸、クエン酸、乳酸、硫酸、コハク酸、Ｌ−アスパラギン酸、Ｌ−グルタミン酸、安息香酸、リン酸、リンゴ酸、アスコルビン酸、グルコン酸、またはニコチン酸等の酸性物質、水酸化ナトリウム、酢酸ナトリウム、クエン酸ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム、乳酸ナトリウム、リン酸ニカリウム、リン酸三ナトリウム、リン酸水素ニナトリウム、または酢酸アンモニウム等の塩基性物質を添加することができる。なお、必要であればこれらの酸性物質や塩基性物質を用いてさらにｐＨを調整することも可能であるが、特にｐＨ調整を行わなくとも概ね良好なｐＨを示す。
なお、本発明に係る注射液中には、ピロ亜硫酸ナトリウムや亜硫酸水素ナトリウムに代表される亜硫酸塩類からなる抗酸化剤を含有していない。
このため、本発明の製剤を常温にて保存しても塩酸リトドリンやその分解物と抗酸化剤との付加反応生成物の発生が抑制される。
The concentration of ritodrine hydrochloride in the injection solution is desirably 1 mg / mL to 50 mg / mL as ritodrine hydrochloride.
An isotonic agent such as sodium chloride, glucose, maltose, mannitol, sorbitol, mannose, sodium citrate, sodium acetate, sodium dihydrogen phosphate, or sodium lactate can be appropriately added to the injection solution.
Further, the pH of injection solutions are, for preventing vascular pain occurs due to the low pH at the time of administration, pH closer to a neutral range as far as possible, Shi desirable to pH4.5~7.4 Iga, In the present invention , the pH is set to 4.7 to 5.5 in consideration of other prescription factors.
In addition, this injection is composed of acetic acid, glacial acetic acid, hydrochloric acid, citric acid, lactic acid, sulfuric acid, succinic acid, L-aspartic acid, L-glutamic acid, benzoic acid, phosphoric acid, malic acid, ascorbic acid, gluconic acid, or nicotine. Acidic substances such as acids, sodium hydroxide, sodium acetate, sodium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium lactate, dipotassium phosphate, trisodium phosphate, disodium hydrogen phosphate, or ammonium acetate Basic substances can be added. If necessary, it is possible to further adjust the pH by using these acidic substances and basic substances, but the pH is generally good without particularly adjusting the pH.
Incidentally, the injection solution according to the present invention does not contain an antioxidant consisting of sulfite typified by sodium metabisulfite or sodium bisulfite.
For this reason, even if the preparation of the present invention is stored at room temperature, the generation of addition reaction products of ritodrine hydrochloride and its decomposition products and antioxidants is suppressed.
本発明におけるプラスチック製容器としては、ポリプロピレン、環状オレフィンホモポリマー、環状オレフィンコポリマー等の酸素透過性プラスチックを用いることができる。また、容器は、プラスチックアンプル、プラスチックバイアル等の形態とすることができるが、注射器の形態であることが好ましい。注射器としては、先端に注射針が取り付けられているか、注射針の取付部を有する外筒、該外筒の内側面と密接し外筒内部空間の後端開口側を密封するとともに外筒内を摺動可能なガスケット、該ガスケット後端に取り付けられるプランジャー、とで構成されるシリンジ形態のものが好ましい。この場合、注射液は上記内部空間に密封されている。ガスケットとしては上記した機能を有するものであれば良いが、ブチルゴム、イソプレンゴム等の合成ゴムや、スチレン系エラストマーやオレフィン系エラストマーを主成分としたエラストマー組成物などが形成材料として例示される。なお、注射器としては、容器自体を外部から押圧することにより充填された注射液が取り付けられた注射針から吐出するよう構成されているスポイト形状など、公知の種々の注射器の形状を採用することができる。 As the plastic container in the present invention, oxygen permeable plastics such as polypropylene, cyclic olefin homopolymer, and cyclic olefin copolymer can be used. The container may be in the form of a plastic ampule, a plastic vial or the like, but is preferably in the form of a syringe. The syringe has an injection needle attached to the tip, or an outer cylinder having an attachment part for the injection needle, is in close contact with the inner surface of the outer cylinder, seals the rear end opening side of the outer cylinder inner space, and the inside of the outer cylinder. A syringe in the form of a slidable gasket and a plunger attached to the rear end of the gasket is preferred. In this case, the injection solution is sealed in the internal space. The gasket is not particularly limited as long as it has the above-described functions, but examples of the forming material include synthetic rubbers such as butyl rubber and isoprene rubber, and elastomer compositions mainly composed of styrene elastomers and olefin elastomers. In addition, as a syringe, it is possible to adopt various known syringe shapes such as a syringe shape configured to discharge from a syringe needle to which an injection solution filled by pressing the container itself from the outside is attached. it can.
本発明において使用される包材は酸素難透過性を有するものであり、該包材を形成する材料は、酸素透過性が無いか、あっても極めて低いものであり、例えば、アルミニウム箔、アルミ蒸着フィルム、酸化アルミ蒸着フィルム、酸化珪素蒸着フィルム、ポリビニルアルコール、エチレンビニルアルコール共重合体、ポリエチレンテレフタレート、ポリエチレンナフタレート、ポリ塩化ビニリデン、等をガスバリア層として有するラミネートフィルムが挙げられ、包装体としたとき包材の外から内部を視認する必要がある場合は、酸化アルミ蒸着フィルム、酸化珪素蒸着フィルム、ポリビニルアルコール、エチレンビニルアルコール共重合体、ポリエチレンテレフタレート、ポリエチレンナフタレート、ポリ塩化ビニリデン、等の透明性の高いガスバリア層を採用することが好ましいが、必要に応じアルミニウム箔やアルミ蒸着フィルム等を採用して遮光包材とすることもできる。
脱酸素剤としては、水酸化鉄、酸化鉄、炭化鉄などの鉄化合物を有効成分とするもの等を利用できる。その市販品としては、エージレス（三菱ガス化学（株）製）、モジュラン（日本化薬（株）製）およびセキュール（日本曹達（株）製）等が挙げられる。
The packaging material used in the present invention has poor oxygen permeability, and the material forming the packaging material has no or even very low oxygen permeability. For example, aluminum foil, aluminum A laminate film having a vapor barrier film, an aluminum oxide vapor deposition film, a silicon oxide vapor deposition film, polyvinyl alcohol, ethylene vinyl alcohol copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride, etc. as a gas barrier layer is used as a package. When it is necessary to visually recognize the inside from the outside of the packaging material, transparent such as aluminum oxide vapor deposition film, silicon oxide vapor deposition film, polyvinyl alcohol, ethylene vinyl alcohol copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride, etc. High quality It is preferable to employ a gas barrier layer, but may also be a light shielding packaging material adopts aluminum foil or aluminum deposition film or the like as needed.
As the oxygen scavenger, those containing iron compounds such as iron hydroxide, iron oxide and iron carbide as active ingredients can be used. The commercial products include AGELESS (Mitsubishi Gas Chemical Co., Ltd.), Modulan (Nippon Kayaku Co., Ltd.), Secur (Nippon Soda Co., Ltd.) and the like.
本発明では、上記した脱酸素剤と共に、亜硫酸塩類からなる抗酸化剤を含有しない塩酸リトドリン注射液を充填したプラスチック容器を酸素難透過性包材で密封することで、該注射液内の溶存酸素等の酸素を徐々に除去することで塩酸リトドリンの酸化分解を抑制し、上述したように抗酸化剤を含んでいないので塩酸リトドリン等との付加反応生成物の生成も起こらず、室温下であっても長期にわたる保存安定化を可能としている。
注射液中や容器内の空間部に存在する酸素による酸化を防ぐために、容器空間部および薬液中のガスを窒素などの不活性ガスで置換することが望ましい。例えば、注射液を窒素バブリングし、容器への充填を窒素雰囲気下行うことなどによって行われる。
In the present invention, a plastic container filled with ritodrine hydrochloride injection solution containing no oxidant consisting of sulfites together with the oxygen scavenger described above is sealed with a poorly oxygen permeable packaging material, so that dissolved oxygen in the injection solution is sealed. The oxidative degradation of ritodrine hydrochloride is suppressed by gradually removing oxygen such as the above, and since no antioxidant is contained as described above, no addition reaction product with ritodrine hydrochloride or the like occurs, and at room temperature. Even long-term storage stability is possible.
In order to prevent oxidation due to oxygen present in the injection solution or in the space in the container, it is desirable to replace the gas in the container space and the chemical with an inert gas such as nitrogen. For example, it is performed by bubbling the injection solution with nitrogen and filling the container under a nitrogen atmosphere.
以下に実施例などにより本発明について具体的に説明するが、本発明は以下の例により何ら限定されない。
（実施例1） 注射用水４５０ｍＬに塩酸リトドリン５．０ｇ及び塩化ナトリウム１．４５ｇを入れ、攪拌溶解させた。塩酸リトドリン及び塩化ナトリウムが完全に溶解した後、氷酢酸２．２ｇを加え撹拌し、水酸化ナトリウム１．２ｇを加えて撹拌した。注射用水を加えて全量を５００ｍＬとし、塩酸リトドリン注射液（１０ｍｇ／ｍＬ）を製した。この液を０．２μｍの酢酸セルロースフィルターにより無菌ろ過後、溶存酸素を窒素バブリングによって窒素置換してから、容器として先端ノズル部を封止してなる容量５ｍＬのポリプロピレン製シリンジ外筒に５ｍＬ充填し、空間部を窒素置換した後、注射液の充填口として用いたシリンジ後端開口からスチレン系エラストマー組成物製のガスケットを挿入し、空間部が極力小さくなるようにして該ガスケットによる施栓を行い、塩酸リトドリン注射液充填プレフィルドシリンジを製造した。
ついで、該塩酸リトドリン注射液充填プレフィルドシリンジを１１５℃１５分間高圧蒸気滅菌し、脱酸素剤（商品名：エージレス、三菱瓦斯化学社製）と共にアルミ蒸着フィルム製ガスバリア層を有するラミネートフィルムからなる酸素難透過性包材に開口をヒートシールすることにより密封包装して、塩酸リトドリン注射液充填プレフィルドシリンジ包装体とした。
Hereinafter, the present invention will be specifically described with reference to examples and the like, but the present invention is not limited to the following examples.
(Example 1) 5.0 g of ritodrine hydrochloride and 1.45 g of sodium chloride were added to 450 mL of water for injection and dissolved by stirring. After ritodrine hydrochloride and sodium chloride were completely dissolved, 2.2 g of glacial acetic acid was added and stirred, and 1.2 g of sodium hydroxide was added and stirred. Water for injection was added to make a total volume of 500 mL, and a ritodrine hydrochloride injection solution (10 mg / mL) was produced. This solution is aseptically filtered through a 0.2 μm cellulose acetate filter, and then dissolved oxygen is replaced with nitrogen by nitrogen bubbling, and then 5 mL is filled into a 5 mL polypropylene syringe outer cylinder with the tip nozzle portion sealed as a container. After replacing the space with nitrogen, insert a gasket made of a styrene elastomer composition from the back end opening of the syringe used as a filling port for the injection solution, and plugging with the gasket so that the space becomes as small as possible, A prefilled syringe filled with ritodrine hydrochloride injection was prepared.
Subsequently, the prefilled syringe filled with the ritodrine hydrochloride injection solution was sterilized by high-pressure steam at 115 ° C. for 15 minutes, and an oxygen barrier comprising a laminate film having a gas barrier layer made of an aluminum vapor deposition film together with an oxygen scavenger (trade name: Ageless, manufactured by Mitsubishi Gas Chemical Co., Ltd.). The permeable packaging material was hermetically packaged by heat-sealing the opening to obtain a prefilled syringe package filled with ritodrine hydrochloride injection solution.
（比較例１） 実施例１において、注射用水に塩酸リトドリンと塩化ナトリウムを入れた際に、ピロ亜硫酸ナトリウム０．５ｇを同時に加えた以外は、実施例１と同様にして製造し、塩酸リトドリン注射液充填プレフィルドシリンジ包装体とした。 (Comparative Example 1) In Example 1, when ritodrine hydrochloride and sodium chloride were added to water for injection, it was prepared in the same manner as in Example 1 except that 0.5 g of sodium pyrosulfite was added at the same time. A liquid-filled prefilled syringe package was obtained.
（試験例１） 実施例１および比較例１で得られた塩酸リトドリン注射液充填プレフィルドシリンジ包装体をそれぞれ、４０℃７５％Ｒ．Ｈ．にて保存し、製造直後の試験開始時、試験開始より１週間経過後、２週間経過後、３週間経過後、３箇月経過後、６箇月経過後の各時点でのリトドリン含量をＨＰＬＣにて測定し、その結果を表１に示した（表中、値はｎ＝３の平均値，単位は％）。また、含量測定と同時に各時点での不純物量を測定し、表２に示した（表中、値はｎ＝３の平均値，単位は％）。
測定にあたっては局外規塩酸リトドリン純度試験を準用し、内標準法にて試験を実施した。リトドリン含量および不純物量は、標準溶液中の内標準物質の面積に対するリトドリンの面積を100として、試料溶液中の内標準物質の面積に対するリトドリンピークの面積あるいは出現した未確認ピークの面積からその割合をそれぞれ、リトドリン含量、不純物量として算出した。
なお、それぞれのｐHは次の通りである。実施例１では、高圧蒸気滅菌前が５．２５、滅菌後が５．２４で、これ以降保存期間中、ｐHの変動は認められなかった。また、実施例２では、高圧蒸気滅菌前後、保存期間中にわたって５．２７であった。
測定の結果、実施例１、比較例１の製剤は、ともに保存条件下６箇月間にわたって有意な含量低下は認められなかった。しかし、比較例１においては３ヶ月経過後および６箇月経過後の不純物の発生が認められ、リトドリン分解物あるいは付加反応生成物の生成が示唆された。
(Test Example 1) The ritodrine hydrochloride injection-filled prefilled syringe packages obtained in Example 1 and Comparative Example 1 were each 40 ° C. and 75% R.D. H. The ritodrine content at each time point after the start of the test immediately after production, 1 week, 2 weeks, 3 weeks, 3 months, and 6 months after the start of the test was determined by HPLC. The results were measured and the results are shown in Table 1 (in the table, the value is an average value of n = 3, and the unit is%). Simultaneously with the content measurement, the amount of impurities at each time point was measured and shown in Table 2 (in the table, the value is an average value of n = 3, and the unit is%).
In the measurement, an external standard ritodrine hydrochloride purity test was applied mutatis mutandis and the test was carried out by the internal standard method. The ritodrine content and the amount of impurities are calculated based on the area of the ritodrine peak relative to the area of the internal standard substance in the sample solution or the area of the unidentified peak that appeared, where the area of ritodrine relative to the area of the internal standard substance in the standard solution is 100. , Ritodrine content, impurity amount.
Each pH is as follows. In Example 1, it was 5.25 before autoclave sterilization and 5.24 after sterilization, and thereafter no change in pH was observed during the storage period. In Example 2, it was 5.27 before and after autoclaving and during the storage period.
As a result of the measurement, no significant decrease in the content of the preparations of Example 1 and Comparative Example 1 was observed over 6 months under storage conditions. However, in Comparative Example 1, generation of impurities was observed after 3 months and after 6 months, suggesting the formation of ritodrine degradation products or addition reaction products.
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| JP5351480B2 (en) * | 2008-09-26 | 2013-11-27 | テルモ株式会社 | Water filled prefilled syringe for injection |
| JP2012001493A (en) * | 2010-06-17 | 2012-01-05 | Terumo Corp | Ritodrine hydrochloride injection formulation |
| CN111918645A (en) * | 2018-11-14 | 2020-11-10 | Avm生物技术有限责任公司 | Stable glucocorticoid formulations |
| CN115181030A (en) * | 2022-05-14 | 2022-10-14 | 海南久常制药有限公司 | Ritodrine hydrochloride raw material medicine and preparation method of injection thereof |
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