JP2012001493A - Ritodrine hydrochloride injection formulation - Google Patents
Ritodrine hydrochloride injection formulation Download PDFInfo
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- JP2012001493A JP2012001493A JP2010138229A JP2010138229A JP2012001493A JP 2012001493 A JP2012001493 A JP 2012001493A JP 2010138229 A JP2010138229 A JP 2010138229A JP 2010138229 A JP2010138229 A JP 2010138229A JP 2012001493 A JP2012001493 A JP 2012001493A
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- JP
- Japan
- Prior art keywords
- ritodrine hydrochloride
- hydrochloride injection
- ritodrine
- injection
- sulfite
- 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.)
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- IOVGROKTTNBUGK-SJKOYZFVSA-N (1S,2R)-ritodrine Chemical compound N([C@H](C)[C@@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJKOYZFVSA-N 0.000 title claims abstract description 66
- 229960000720 ritodrine hydrochloride Drugs 0.000 title claims abstract description 64
- 238000002347 injection Methods 0.000 title claims abstract description 55
- 239000007924 injection Substances 0.000 title claims abstract description 55
- 239000000203 mixture Substances 0.000 title claims abstract description 7
- 238000009472 formulation Methods 0.000 title claims abstract 3
- 239000000243 solution Substances 0.000 claims abstract description 34
- 229920003023 plastic Polymers 0.000 claims abstract description 15
- 239000004033 plastic Substances 0.000 claims abstract description 15
- 239000005022 packaging material Substances 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 10
- 229940123973 Oxygen scavenger Drugs 0.000 claims description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 abstract description 18
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000007789 sealing Methods 0.000 abstract description 6
- 239000007788 liquid Substances 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000007972 injectable composition Substances 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 46
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- GIZSHQYTTBQKOQ-UHFFFAOYSA-N threo-Syringoylglycerol Chemical compound COC1=CC(C(O)C(O)CO)=CC(OC)=C1O GIZSHQYTTBQKOQ-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
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- 239000007789 gas Substances 0.000 description 10
- 238000003860 storage Methods 0.000 description 9
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 8
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 2
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- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000005033 polyvinylidene chloride Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000013094 purity test Methods 0.000 description 2
- 229960001634 ritodrine Drugs 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 229910052814 silicon oxide Inorganic materials 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 235000011083 sodium citrates Nutrition 0.000 description 2
- 239000001540 sodium lactate Substances 0.000 description 2
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- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
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。
一般的に、塩酸リトドリン注射液は、熱により酸化分解物や異性化物（トレオ体）の生成が起こるため、室温保存は困難である。そのため、市販の塩酸リトドリン注射液は、５℃以下の冷蔵保存を要するガラスアンプル充填製剤であり、酸化防止剤として亜硫酸塩類が配合されている。
しかし、亜硫酸塩類を配合すると、酸化分解物の生成が抑制される代わりに、塩酸リトドリンの亜硫酸付加物（S1：スレオ−１−（４−ヒドロキシフェニル）−２−〔２−（４−ヒドロキシフェニル）エチルアミノ〕−１−プロパンスルフォン酸、S2 ：エリスロ−１−（４−ヒドロキシフェニル）−２−〔２−（４−ヒドロキシフェニル）エチルアミノ〕−１−プロパンスルフォン酸）の生成が起こるという問題がある。特に、製造工程中に高圧蒸気滅菌を行った場合、トレオ体、亜硫酸付加物の生成が増加することが報告されている（非特許文献１）。
このように、塩酸リトドリンは、冷蔵保存であれば問題ないが、熱の影響により、トレオ体や亜硫酸付加物が生成するため、加熱滅菌を行ったり、室温保存に変更したりすることは非常に困難である。
Ritodrine hydrochloride 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.
In general, ritodrine hydrochloride injection solution is difficult to store at room temperature because oxidative degradation products and isomerized products (threo form) are generated by heat. Therefore, commercially available ritodrine hydrochloride injection is a glass ampoule filling preparation that requires refrigerated storage at 5 ° C. or less, and sulfites are blended as an antioxidant.
However, when sulfites are added, instead of inhibiting the formation of oxidative degradation products, the sulfido adduct of ritodrine hydrochloride (S1: threo-1- (4-hydroxyphenyl) -2- [2- (4-hydroxyphenyl) ) Ethylamino] -1-propanesulfonic acid, S2: erythro-1- (4-hydroxyphenyl) -2- [2- (4-hydroxyphenyl) ethylamino] -1-propanesulfonic acid) There's a problem. In particular, it has been reported that when high-pressure steam sterilization is performed during the production process, the production of threo bodies and sulfite adducts increases (Non-patent Document 1).
In this way, ritodrine hydrochloride has no problem if stored refrigerated, but threo and sulfite adducts are generated due to the effect of heat, so it is very easy to perform heat sterilization or change to room temperature storage. Have difficulty.
塩酸リトドリン注射液は、上述したように類縁物質の生成を抑えるために、５℃以下の冷蔵保存を要するガラスアンプル充填製剤であった。この注射液を医療現場により安全に提供していくためには、ガラスアンプルに充填されたものではなく、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、従来のアンプル・バイアルとは形状が異なるため、一般にアンプル・バイアルの保存に適したレイアウトがなされている冷蔵庫での保管が煩雑となることから、そのような制限のない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。
室温保存にするためには、トレオ体の生成を抑えることが重要となるが、そのために安定化剤として加える亜硫酸塩類が過剰であると、塩酸リトドリンの亜硫酸付加物が多量に生成する。従って本発明は、トレオ体の生成とともに亜硫酸付加物の生成も抑えることで、長期間にわたって室温保存可能で、安全な塩酸リトドリン注射製剤を提供することを目的とするものである。
The ritodrine hydrochloride injection solution was a glass ampoule-filled preparation that required refrigerated storage at 5 ° C. or lower in order to suppress the formation of related substances as described above. In order to provide this injection solution more safely in the medical field, a prefilled syringe preparation filled in a syringe, particularly a plastic syringe, is required instead of a glass ampule. However, when prefilled syringes are used, the shape is different from that of conventional ampules and vials, so storage in a refrigerator that is generally laid out suitable for storage of ampules and vials becomes complicated, so there is no such limitation. In the medical field, it is desired to provide a plastic prefilled syringe preparation that can be stored at room temperature.
In order to preserve at room temperature, it is important to suppress the formation of a threo form. For this reason, if an excessive amount of sulfite is added as a stabilizer, a large amount of sulfidoline adduct of ritodrine hydrochloride is produced. Accordingly, an object of the present invention is to provide a safe ritodrine hydrochloride injection preparation that can be stored at room temperature for a long period of time by suppressing the formation of a threo form as well as the formation of a sulfite adduct.
上記課題に鑑み、塩酸リトドリンを含有し、亜硫酸塩類を含有する注射液につき、鋭意検討を重ねた結果、亜硫酸塩類の配合量を特定の範囲に設定することにより上記問題を解決できることを究明し、本発明に到達した。 In view of the above-mentioned problems, as a result of intensive research on an injection solution containing ritodrine hydrochloride and containing sulfites, it was found that the above problem can be solved by setting the blending amount of sulfites to a specific range, The present invention has been reached.
上記課題は以下の本発明により解決される。 The above problems are solved by the present invention described below.
（１）塩酸リトドリン５〜１５ｍｇ／ｍＬおよび亜硫酸塩類０．３〜０．７ｍｇ／ｍＬを含有し、ｐＨが４．７〜５．５である塩酸リトドリン注射製剤。 (1) A ritodrine hydrochloride injection preparation containing 5-15 mg / mL ritodrine hydrochloride and 0.3-0.7 mg / mL sulfites and having a pH of 4.7-5.5.
（２）プラスチック製容器に充填された（１）に記載の塩酸リトドリン注射製剤。 (2) The ritodrine hydrochloride injection preparation according to (1) filled in a plastic container.
（３）前記プラスチック製容器が注射器である請求項（２）に記載の塩酸リトドリン注射製剤。 (3) The ritodrine hydrochloride injection preparation according to (2), wherein the plastic container is a syringe.
（４）脱酸素剤と共に酸素難透過性包材に封入されてなることを特徴とする（２）または（３）に記載の塩酸リトドリン注射製剤。 (4) The ritodrine hydrochloride injection preparation according to (2) or (3), which is enclosed in a poorly oxygen permeable packaging material together with an oxygen scavenger.
（５）前記酸素難透過性包材は遮光性を有するものである（４）に記載の塩酸リトドリン注射製剤。 (5) The ritodrine hydrochloride injection preparation according to (4), wherein the oxygen poorly permeable packaging material has light shielding properties.
（６）高圧蒸気滅菌されたものである（１）〜（５）のいずれかに記載の塩酸リトドリン注射製剤。 (6) The ritodrine hydrochloride injection preparation according to any one of (1) to (5), which has been subjected to high-pressure steam sterilization.
本発明は、塩酸リトドリン水溶液が特定の濃度の亜硫酸塩類を含有し、特定のｐＨに調整した、トレオ体と亜硫酸付加物の生成が抑制された塩酸リトドリン注射製剤である。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い。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 is a ritodrine hydrochloride injection preparation in which an aqueous ritodrine hydrochloride solution contains a specific concentration of sulfite and is adjusted to a specific pH, and the production of threo form and sulfite adduct is suppressed. Further, since the container is made of plastic, there is no fear 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製剤は、特定の濃度の塩酸リトドリンと特定の濃度の亜硫酸塩類を含有する水溶液を特定のｐＨに調整した塩酸リトドリン注射液をプラスチック製容器に充填し、脱酸素剤とともに酸素難透過性包材に封入したもので、トレオ体と亜硫酸付加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 preparation of the present invention comprises a plastic container filled with a ritodrine hydrochloride injection solution prepared by adjusting an aqueous solution containing a specific concentration of ritodrine hydrochloride and a specific concentration of sulfite to a specific pH, and oxygenated together with an oxygen scavenger. It is a stable injectable preparation that is sealed in a poorly permeable packaging material and suppresses the formation of threo and sulfite adducts.
上記注射液中の塩酸リトドリンの濃度は、５〜１５ｍｇ／ｍＬであり、亜硫酸塩類の濃度は、０．３〜０．７ｍｇ／ｍＬである。亜硫酸塩類としては、たとえば、亜硫酸水素ナトリウム、ピロ亜硫酸ナトリウムおよび亜硫酸ナトリウムなどの亜硫酸アルカリ金属塩類を用いるのが好ましい。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、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、リン酸二カリウム、リン酸三ナトリウム、リン酸水素二ナトリウム、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。 The concentration of ritodrine hydrochloride in the injection solution is 5 to 15 mg / mL, and the concentration of sulfites is 0.3 to 0.7 mg / mL. As the sulfites, for example, alkali metal sulfites such as sodium hydrogen sulfite, sodium pyrosulfite and sodium sulfite are preferably used. 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. 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 sodium hydroxide, sodium acetate, sodium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium lactate, dipotassium phosphate, trisodium phosphate, disodium hydrogen phosphate, or ammonium acetate Etc. can be added.
本発明のプラスチック製容器としては、水蒸気透過性の少ない材料が望ましい。これらの観点から、ポリプロピレン、ポリエチレン、ポリスチレン、ポリアミド、ポリ(４−メチルペンテン−１)、アクリル樹脂、アクリロニトリルーブタジエン−スチレン共重合体、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、環状オレフィンポリマーや環状オレフィンコポリマー等の環状ポリオレフィン、非晶性ポリアリレートなどのポリオレフィン、ポリエステルで光学的に透明な材料で形成されることが好ましい。特に環状ポリオレフィン、ポリプロピレン、ポリエチレンが望ましい。 For the plastic container of the present invention, a material having low water vapor permeability is desirable. From these viewpoints, polypropylene, polyethylene, polystyrene, polyamide, poly (4-methylpentene-1), acrylic resin, acrylonitrile-butadiene-styrene copolymer, polyethylene terephthalate, polyethylene naphthalate, cyclic olefin polymer, cyclic olefin copolymer, etc. It is preferably formed of an optically transparent material such as a cyclic polyolefin, a polyolefin such as amorphous polyarylate, or a polyester. Cyclic polyolefin, polypropylene, and polyethylene are particularly desirable.
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、注射針の取り付け部を有する外筒、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。 The container can be in the form of a plastic ampoule, plastic vial, etc., 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 thing of the syringe form comprised with the slidable gasket and the plunger attached to this gasket rear end is preferable. In this case, the injection solution is sealed in the internal space. As the gasket, any material having the above-described functions may be used. 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 employ 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る。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る。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。 The packaging material used in the present invention has poor oxygen permeability. The material forming the packaging material has no oxygen permeability or is extremely low, for example, aluminum foil, aluminum vapor deposition film, aluminum oxide vapor deposition film, silicon oxide vapor deposition film, polyvinyl alcohol, ethylene vinyl alcohol. Examples thereof include a laminate film having a copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride, etc. as a gas barrier layer. When it is necessary to visually recognize the inside from the outside of the packaging material when it is used as a package, aluminum oxide vapor-deposited film, silicon oxide vapor-deposited film, polyvinyl alcohol, ethylene vinyl alcohol copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride It is preferable to employ a highly transparent gas barrier layer such as, etc., but if necessary, an aluminum foil, an aluminum vapor-deposited film or the like may be employed to form a light-shielding packaging material.
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（登録商標：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（登録商標：日本曹達（株）製）等が挙げられる。 As the oxygen scavenger, those containing iron compounds such as iron hydroxide, iron oxide and iron carbide as active ingredients can be used. Examples of the commercially available products include AGELESS (registered trademark: manufactured by Mitsubishi Gas Chemical Co., Inc.), Modulan (manufactured by Nippon Kayaku Co., Ltd.), Secur (registered trademark: manufactured by Nippon Soda Co., Ltd.), and the like.
本発明では、プラスチック製容器を使用するため、保存中にプラスチックを透過してくる酸素により、亜硫酸塩類が消費され、亜硫酸塩類による類縁物質の生成の抑制効果が損なわれる恐れがある。そのため、容器の酸素透過性を積極的に利用し、脱酸素剤と共に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、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。また、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で行うことなどによって行われる。 In the present invention, since a plastic container is used, sulfites are consumed by oxygen permeating through the plastic during storage, and the effect of suppressing the production of related substances by sulfites may be impaired. For this reason, by actively utilizing the oxygen permeability of the container and sealing the plastic container filled with ritodrine hydrochloride injection solution with oxygen scavenger with oxygen poorly permeable packaging material, long-term storage stability even at room temperature 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 carried out by bubbling the injection solution with nitrogen and filling the container under a nitrogen atmosphere.
以下に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。 The present invention will be described in detail below, but the present invention is not limited to the following examples.
（調製例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、ピロ亜硫酸ナトリウム０、０．０５、０．１５、０．２５、０．３５、０．５０ｇ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２．１７５ｇを加え、水酸化ナトリウムを加えてｐＨ５．２５に調整した。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）を調製した。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。
(Preparation Example 1)
In 450 mL of water for injection, 5.0 g of ritodrine hydrochloride and 1.45 g of sodium chloride were added, and 0, 0.05, 0.15, 0.25, 0.35, and 0.50 g of sodium pyrosulfite were added and dissolved by stirring. After ritodrine hydrochloride and sodium chloride were completely dissolved, 2.175 g of glacial acetic acid was added, and sodium hydroxide was added to adjust to pH 5.25. Water for injection was added to make the total volume 500 mL, and ritodrine hydrochloride injection solution (10 mg / mL) was prepared. 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.
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。 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.
（試験例１）
調製例１により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℃にて保存し、３箇月経過後の塩酸リトドリン含量、トレオ体及び亜硫酸付加物の含量を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％）。
(Test Example 1)
Each of the ritodrine hydrochloride injection-filled prefilled syringe packages obtained in Preparation Example 1 was stored at 40 ° C., and the ritodrine hydrochloride content, threo form and sulfite adduct content after 3 months were measured by HPLC, The results are shown in Table 1 (in the table, the value is an average value of n = 3, and the unit is%).
測定にあたっては日局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。塩酸リトドリンの含量は、標準溶液中の内標準物質のピーク面積を１００として、試料溶液中の内標準物質のピーク面積に対するリトドリンのピーク面積から、その割合を塩酸リトドリン含量として算出した。トレオ体及び亜硫酸付加物の含量は、試料溶液中のリトドリンのピーク面積に対するトレオ体及び亜硫酸付加物のピーク面積の割合として算出した。 In the measurement, the JP ritodrine hydrochloride purity test was applied mutatis mutandis and the test was carried out by the internal standard method. The content of ritodrine hydrochloride was calculated as the ritodrine hydrochloride content from the peak area of ritodrine with respect to the peak area of the internal standard substance in the sample solution, with the peak area of the internal standard substance in the standard solution being 100. The content of threo form and sulfite adduct was calculated as the ratio of the peak area of threo form and sulfite adduct to the peak area of ritodrine in the sample solution.
測定の結果、試験例１の製剤は、保存条件下３箇月にわたって有意な含量低下は認められなかった。しかし、ピロ亜硫酸ナトリウム０．１ｍｇ／ｍＬ以下においては３箇月経過後にトレオ体の増加が認められ、０．３〜０．７ｍｇ／ｍＬの範囲では、トレオ体の生成が抑制された。また、亜硫酸付加物はピロ亜硫酸ナトリウムの量とともに増加する傾向があり、１．０ｍｇ／ｍＬ以上では顕著な増加が認められた。 As a result of the measurement, the content of the preparation of Test Example 1 was not significantly decreased over 3 months under storage conditions. However, when sodium pyrosulfite was 0.1 mg / mL or less, an increase in threo form was observed after 3 months, and in the range of 0.3 to 0.7 mg / mL, the production of threo form was suppressed. In addition, the sulfite adduct tends to increase with the amount of sodium pyrosulfite, and a remarkable increase was observed at 1.0 mg / mL or more.
（調製例２）
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、ピロ亜硫酸ナトリウム０．１５ｇ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２．１７５ｇおよび、氷酢酸又は水酸化ナトリウムを加えてｐＨ５．５０、４．７０、４．００、３．００に調整した。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）を調製した。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。
(Preparation Example 2)
In 450 mL of water for injection, 5.0 g of ritodrine hydrochloride and 1.45 g of sodium chloride were added, and 0.15 g of sodium pyrosulfite was added and dissolved by stirring. After ritodrine hydrochloride and sodium chloride were completely dissolved, the pH was adjusted to 5.50, 4.70, 4.00, and 3.00 by adding 2.175 g of glacial acetic acid and glacial acetic acid or sodium hydroxide. Water for injection was added to make the total volume 500 mL, and ritodrine hydrochloride injection solution (10 mg / mL) was prepared. 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.
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。 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.
（試験例２）
調製例２により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℃にて保存し、３箇月経過後の塩酸リトドリン含量、トレオ体及び亜硫酸付加物の含量をＨＰＬＣにて測定し、その結果を表２に示した（表中、値はｎ＝３の平均値，単位は％）。
(Test Example 2)
Each of the ritodrine hydrochloride injection-filled prefilled syringe packages obtained in Preparation Example 2 was stored at 40 ° C., and the ritodrine hydrochloride content, threo form and sulfite adduct content after 3 months were measured by HPLC, The results are shown in Table 2 (in the table, the value is an average value of n = 3, and the unit is%).
測定の結果、試験例２の製剤は、保存条件下３箇月にわたって塩酸リトドリンの含量低下はほとんど認められなかった。しかし、ｐＨ４．００以下においては３箇月経過後にトレオ体の増加が認められた。 As a result of the measurement, almost no reduction in the content of ritodrine hydrochloride was observed in the preparation of Test Example 2 over 3 months under storage conditions. However, at pH 4.00 or less, an increase in threo form was observed after 3 months.
（調製例３）
注射用水４５０ｍＬに塩酸リトドリン２．５、７．５ｇ及び塩化ナトリウム１．４５ｇを入れ、ピロ亜硫酸ナトリウム０．１５ｇ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２．１７５ｇを加え、水酸化ナトリウムを加えてｐＨ５．２５に調製した。注射用水を加えて全量を５００ｍＬとし、塩酸リトドリン注射液（５ｍｇ／ｍＬ、１５ｍｇ／ｍＬ）を調製した。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。
(Preparation Example 3)
In 450 mL of water for injection, 2.5 and 7.5 g of ritodrine hydrochloride and 1.45 g of sodium chloride were added, and 0.15 g of sodium pyrosulfite was added and dissolved by stirring. After ritodrine hydrochloride and sodium chloride were completely dissolved, 2.175 g of glacial acetic acid was added, and sodium hydroxide was added to adjust to pH 5.25. Water for injection was added to make the total volume 500 mL, and ritodrine hydrochloride injection solution (5 mg / mL, 15 mg / mL) was prepared. 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.
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。 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.
（試験例３）
上記により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℃にて保存し、３箇月経過後の塩酸リトドリン含量、トレオ体及び亜硫酸付加物の含量をＨＰＬＣにて測定したが、試験例１のピロ亜硫酸ナトリウム０．３ｍｇ／ｍＬの場合と同様、トレオ体および亜硫酸付加物の生成量の増加は見られなかった。
(Test Example 3)
The ritodrine hydrochloride injection filled prefilled syringe package obtained as described above was stored at 40 ° C., and the ritodrine hydrochloride content, threo form and sulfite adduct content after 3 months were measured by HPLC. As in the case of sodium pyrosulfite 0.3 mg / mL in Example 1, no increase in the amount of threo compound and sulfite adduct was observed.
１ プレフィルドシリンジ
２ 外筒
２１ 先端開口
２２ 後端開口
３ ガスケット
４ 薬剤
５ 封止部材
６ プランジャー
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2019085421A (en) * | 2014-05-13 | 2019-06-06 | サントル・ホスピテリエ・レジオナル・エ・ユニヴェルシテール・ドゥ・リール | Pharmaceutical solution containing dopamine for use in the treatment of Parkinson's disease |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06298640A (en) * | 1993-04-15 | 1994-10-25 | Nippon Seiyaku Kk | Intravenons injection |
| JP2006136490A (en) * | 2004-11-11 | 2006-06-01 | Terumo Corp | Ritodrine hydrochloride injection preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH06298640A (en) * | 1993-04-15 | 1994-10-25 | Nippon Seiyaku Kk | Intravenons injection |
| JP2006136490A (en) * | 2004-11-11 | 2006-06-01 | Terumo Corp | Ritodrine hydrochloride injection preparation |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2019085421A (en) * | 2014-05-13 | 2019-06-06 | サントル・ホスピテリエ・レジオナル・エ・ユニヴェルシテール・ドゥ・リール | Pharmaceutical solution containing dopamine for use in the treatment of Parkinson's disease |
| JP7475113B2 (en) | 2014-05-13 | 2024-04-26 | サントル・ホスピテリエ・レジオナル・エ・ユニヴェルシテール・ドゥ・リール | Pharmaceutical solutions containing dopamine for use in the treatment of Parkinson's disease - Patents.com |
| 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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