JP2014034571A - Stable granisetron-containing aqueous formulation - Google Patents
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- 229960003727 granisetron Drugs 0.000 title claims abstract description 60
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 title claims abstract description 60
- 239000013011 aqueous formulation Substances 0.000 title claims abstract description 7
- 229920003023 plastic Polymers 0.000 claims abstract description 23
- 239000004033 plastic Substances 0.000 claims abstract description 23
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- -1 polypropylene Polymers 0.000 claims abstract description 12
- 239000004743 Polypropylene Substances 0.000 claims abstract description 6
- 229920001155 polypropylene Polymers 0.000 claims abstract description 6
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 41
- 239000007788 liquid Substances 0.000 claims description 10
- 238000004806 packaging method and process Methods 0.000 claims description 10
- 239000007951 isotonicity adjuster Substances 0.000 claims description 4
- 239000006172 buffering agent Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 4
- 239000000872 buffer Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 abstract 1
- 239000012929 tonicity agent Substances 0.000 abstract 1
- 239000010410 layer Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000001802 infusion Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000004888 barrier function Effects 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 230000035699 permeability Effects 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229920001971 elastomer Polymers 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000005060 rubber Substances 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 230000005068 transpiration Effects 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 229920003049 isoprene rubber Polymers 0.000 description 3
- 229920000139 polyethylene terephthalate Polymers 0.000 description 3
- 239000005020 polyethylene terephthalate Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 229940034982 antineoplastic agent Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229920005549 butyl rubber Polymers 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000010408 film Substances 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229960003607 granisetron hydrochloride Drugs 0.000 description 2
- QYZRTBKYBJRGJB-UHFFFAOYSA-N hydron;1-methyl-n-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)indazole-3-carboxamide;chloride Chemical compound Cl.C1=CC=C2C(C(=O)NC3CC4CCCC(C3)N4C)=NN(C)C2=C1 QYZRTBKYBJRGJB-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920000098 polyolefin Polymers 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229920002725 thermoplastic elastomer Polymers 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- MFWNKCLOYSRHCJ-AGUYFDCRSA-N 1-methyl-N-[(1S,5R)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]-3-indazolecarboxamide Chemical compound C1=CC=C2C(C(=O)NC3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-AGUYFDCRSA-N 0.000 description 1
- 238000012371 Aseptic Filling Methods 0.000 description 1
- 241001411320 Eriogonum inflatum Species 0.000 description 1
- 229920000219 Ethylene vinyl alcohol Polymers 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000012266 Needlestick injury Diseases 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000004715 ethylene vinyl alcohol Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940048352 granisetron 1 mg Drugs 0.000 description 1
- RZXDTJIXPSCHCI-UHFFFAOYSA-N hexa-1,5-diene-2,5-diol Chemical compound OC(=C)CCC(O)=C RZXDTJIXPSCHCI-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010102 injection blow moulding Methods 0.000 description 1
- 238000001746 injection moulding Methods 0.000 description 1
- 239000005001 laminate film Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- SOQBVABWOPYFQZ-UHFFFAOYSA-N oxygen(2-);titanium(4+) Chemical group [O-2].[O-2].[Ti+4] SOQBVABWOPYFQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 description 1
- 229920000052 poly(p-xylylene) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000011112 polyethylene naphthalate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
本発明は、抗悪性腫瘍剤（シスプラチン等）投与及び放射線照射に伴う消化器症状（悪心、嘔吐）の改善のために使用されている５-ＨＴ３受容体拮抗型制吐剤であるグラニセトロンを含有する安定な水性製剤に関する。さらに詳しくは、グラニセトロン１ｍｇを含有した、液量約５０〜約１００ｍLの水溶液を収納したプラスチック製容器から構成されている安定なグラニセトロン含有水性製剤に関する。 The present invention contains granisetron, which is a 5-HT 3 receptor antagonistic antiemetic used to improve gastrointestinal symptoms (nausea, vomiting) associated with administration of antineoplastic agents (cisplatin, etc.) and irradiation. To a stable aqueous formulation. More specifically, the present invention relates to a stable granisetron-containing aqueous preparation comprising a plastic container containing 1 mg of granisetron and containing an aqueous solution having a liquid volume of about 50 to about 100 mL.
グラニセトロン１ｍｇ製剤は、抗悪性腫瘍剤（シスプラチン等）投与及び放射線照射に伴う消化器症状（悪心、嘔吐）の改善のための５-ＨＴ３受容体拮抗型制吐剤としてガラスアンプルまたはプレフィルドシリンジに充填された１ｍLの水性注射剤として販売されている。本１ｍL注射剤の投与は、生理食塩水や糖類を含む輸液剤に混注して希釈した後、点滴静注することが一般的であり、「カイトリル（登録商標）注１ｍｇ」（中外製薬（株））の名称でガラスアンプル（液量１ｍL）や「グラニセトロン静注液１ｍｇシリンジ「サワイ」」（沢井製薬（株））の名称でプレフィルドシリンンジ（液量１ｍL）などが販売されている。
近年、上述のグラニセトロンのように、使用に際して輸液剤等に混合し希釈して投与される有効成分を含有する医薬品のなかには、始めから投与時の濃度に希釈された有効成分濃度でバッグやボトル形態のプラスチック製輸液剤容器に充填されたプレミックス製剤化が試みられてきている。予め混合されていることで、輸液剤への混注時の「針刺しの危険性の減少」、「汚染リスクの軽減」等、医療現場において潜在的に憂慮される医療過誤の防止に寄与することができ、併せて「作業時間の短縮」も可能となるため、医療経済性にも貢献することができる。
このようなプレミックス製剤としては、「カイトリル（登録商標）点滴静注バッグ３ｍｇ／５０ｍＬ」（中外製薬（株））や「カイトリル（登録商標）点滴静注バッグ３ｍｇ／１００ｍＬ」（中外製薬（株））などが販売されている。しかし、グラニセトロン１ｍｇを含有した安定なプレミックス製剤は知られていない。
Granisetron 1 mg preparation is filled in glass ampules or prefilled syringes as 5-HT 3 receptor antagonist antiemetics for the improvement of gastrointestinal symptoms (nausea and vomiting) associated with administration of antineoplastic agents (cisplatin, etc.) and irradiation Sold as a 1 mL aqueous injection. The administration of this 1 mL injection is generally carried out by infusion by infusion after infusion containing saline and saccharides, followed by intravenous infusion. “Kytril (registered trademark) Note 1 mg” (Chugai Pharmaceutical Co., Ltd.) )) And glass ampoules (liquid volume 1 mL) and “Granisetron IV Injection 1 mg Syringe Sawai” (Sawai Pharmaceutical Co., Ltd.) are sold as prefilled syringe (liquid volume 1 mL).
In recent years, as in the case of granisetron described above, some pharmaceuticals containing active ingredients mixed and infused with an infusion for use are used in the form of bags or bottles with active ingredient concentrations diluted from the beginning to the concentration at the time of administration. Attempts have been made to make premix formulations filled in plastic infusion containers. Premixing can contribute to the prevention of medical errors that are potentially a concern in the medical field, such as “reducing the risk of needle stick” and “reducing the risk of contamination” when co-injected into an infusion. In addition, since “working time can be shortened”, it is possible to contribute to medical economics.
Examples of such premixed preparations include “Kaitril (registered trademark) intravenous drip bag 3 mg / 50 mL” (Chugai Pharmaceutical Co., Ltd.) and “Kaitril (registered trademark) intravenous drip bag 3 mg / 100 mL” (Chugai Pharmaceutical Co., Ltd. )) Etc. are sold. However, no stable premix formulation containing 1 mg of granisetron is known.
したがって、本発明の目的は、グラニセトロン１ｍｇを含有したプラスチック製のバッグまたはボトル製剤である安定なグラニセトロン含有水性製剤を提供することである。 Accordingly, it is an object of the present invention to provide a stable granisetron-containing aqueous formulation which is a plastic bag or bottle formulation containing 1 mg of granisetron.
前記課題は以下の構成によって解決される。
（１）本発明は、グラニセトロン１ｍｇおよび等張化剤および緩衝剤およびｐＨ調節剤を含有し、ｐＨが５．０〜７．０の範囲で、液量が約５０〜約１００ｍLである水溶液を、プラスチック製容器に収納した安定なグラニセトロン含有水性製剤である。
（２）前記プラスチック製容器が、ポリプロピレン製である上記（１）に記載の安定なグラニセトロン含有水性製剤。
（３）前記プラスチック製容器は、ゴム状弾性体が備えられたバッグまたはボトルからなる上記（１）または（２）に記載の安定なグラニセトロン含有水性製剤。
（４）前記グラニセトロン含有水性製剤が、包装容器に収納されたものである上記（１）〜（３）のいずれかに記載の安定なグラニセトロン含有水性製剤。
The said subject is solved by the following structures.
(1) The present invention comprises an aqueous solution containing 1 mg of granisetron, an isotonic agent, a buffering agent and a pH adjusting agent and having a pH in the range of 5.0 to 7.0 and a liquid volume of about 50 to about 100 mL. It is a stable granisetron-containing aqueous preparation housed in a plastic container.
(2) The stable granisetron-containing aqueous preparation according to (1), wherein the plastic container is made of polypropylene.
(3) The stable granisetron-containing aqueous preparation according to the above (1) or (2), wherein the plastic container comprises a bag or a bottle provided with a rubber-like elastic body.
(4) The stable granisetron-containing aqueous preparation according to any one of (1) to (3), wherein the granisetron-containing aqueous preparation is contained in a packaging container.
本発明によって提供されるグラニセトロン含有水性製剤は、グラニセトロン１ｍｇを含有した、液量約５０〜約１００ｍLの水溶液がプラスチック製容器に充填密封されたものである。
本発明のグラニセトロン含有水性製剤は、既に販売されている水性注射剤中の有効成分であるグラニセトロンが点滴静注するのに適した濃度まで生理食塩水等で希釈された状態で製剤化されたプレミックスタイプの水性製剤のことである。
本発明における、プレミックスタイプの水性製剤のグラニセトロン濃度は０.０１〜０．０２ｍｇ／ｍＬであり、０．０２ｍｇ／ｍＬであることが投与時間の観点から好ましい。水性製剤の液量は約５０〜約１００ｍＬであり、約５０ｍＬであることが同様の観点から好ましい。本発明の液量の値に約を付している理由は、表示された量が確実に投与されることを保証するために、若干過量に充填されることが通常行われているからである。ここで、若干過量とは表示量より最大１０％多めであることをいう。なお、製剤化する際の原薬としては、グラニセトロン塩酸塩を用いることができる。
また、本発明では上記有効成分のほか、等張化剤、緩衝剤およびｐＨ調節剤を添加物として配合している。等張化剤としては、塩化ナトリウム、ブドウ糖などを用いることができる。緩衝剤としては、クエン酸など、特にクエン酸水和物を用いることができる。ｐＨ調節剤としては、水酸化ナトリウム、塩酸などを用いることができる。
本発明のグラニセトロン含有水性製剤のｐＨは５．０〜７．０であるが、ｐＨは５．０〜６．０であることが好ましい。本発明のグラニセトロンを含有する水性製剤を収納する容器を構成する樹脂としては、ポリプロピレン、ポリエチレン、環状ポリオレフィンなどを用いることができる。
The granisetron-containing aqueous preparation provided by the present invention is an aqueous solution containing about 1 mg of granisetron and filled with an aqueous solution of about 50 to about 100 mL in a plastic container.
The granisetron-containing aqueous preparation of the present invention is pre-formulated in a state diluted with physiological saline or the like to a concentration suitable for intravenous infusion of granisetron, which is an active ingredient in already marketed aqueous injections. It is a mixed type aqueous preparation.
In the present invention, the granisetron concentration of the premix type aqueous preparation is 0.01 to 0.02 mg / mL, and preferably 0.02 mg / mL from the viewpoint of administration time. The liquid volume of the aqueous preparation is about 50 to about 100 mL, and is preferably about 50 mL from the same viewpoint. The reason why the value of the liquid amount of the present invention is approximated is that a slight overdose is usually performed to ensure that the indicated amount is reliably administered. . Here, the slightly excessive amount means that it is a maximum of 10% more than the display amount. In addition, granisetron hydrochloride can be used as the drug substance for formulation.
In the present invention, an isotonic agent, a buffering agent and a pH adjusting agent are added as additives in addition to the above active ingredients. As the isotonic agent, sodium chloride, glucose and the like can be used. As the buffer, citric acid or the like, particularly citric acid hydrate can be used. As the pH adjuster, sodium hydroxide, hydrochloric acid or the like can be used.
The pH of the granisetron-containing aqueous preparation of the present invention is 5.0 to 7.0, but the pH is preferably 5.0 to 6.0. Polypropylene, polyethylene, cyclic polyolefin, etc. can be used as the resin constituting the container for storing the aqueous preparation containing granisetron of the present invention.
本発明のプラスチック製容器は、バッグまたはボトルのいずれの形状でもよく、水性製剤の液量、適用の部位・方法によって適宜選択できる。本発明のプラスチック製容器、例えば、バッグを製造する場合には、単層フィルムはもちろんのこと、低溶出性や低薬剤吸着性に優れた接液層としての内層、あるいは密着性を向上するための熱シール層としての内層、バッグとしての柔軟性をだすため、あるいは水蒸気バリア性をだすための中間層、耐久性をだすための外層、などを有した多層フィルムを用いることができる。単層フィルムとしては、ポリプロピレン、ポリエチレン、ポリ塩化ビニル等を用いることができる。バッグまたはボトル等のプラチック製容器は、射出成形、ブロー成形、インフレーション成形などの公知の各種成形手段と必要に応じてヒートシール、高周波融着あるいは超音波融着等の公知の各種シール手段を組み合わせるなど、公知の方法で製造することができる。特にソフトバッグ等、柔軟なバッグ形状のものであることが望ましい。 The plastic container of the present invention may be in the shape of a bag or bottle, and can be appropriately selected depending on the amount of the aqueous preparation and the site / method of application. In the case of producing a plastic container of the present invention, for example, a bag, not only a single layer film but also an inner layer as a liquid contact layer excellent in low elution and low drug adsorption, or adhesion is improved. A multilayer film having an inner layer as a heat seal layer, an intermediate layer for providing flexibility as a bag or a water vapor barrier property, an outer layer for providing durability, and the like can be used. As the single layer film, polypropylene, polyethylene, polyvinyl chloride or the like can be used. For plastic containers such as bags or bottles, various known molding means such as injection molding, blow molding, and inflation molding are combined with various known sealing means such as heat sealing, high frequency fusion or ultrasonic fusion as necessary. Etc., and can be produced by a known method. In particular, a flexible bag shape such as a soft bag is desirable.
本発明のプラスチック製容器には、内容物の適切な排出を行う目的から輸液セットの瓶針などが刺通できるゴム状弾性体が備えられていることが好ましい。プラスチック製容器がバッグである場合は、一端がバッグ内と連通する筒状ポート部材の他端がいわゆるゴム栓であるゴム状弾性体で封止された排出口をバッグに設けることが好ましく、ボトルである場合は、ボトルの口部をゴム栓で封止したものであることが好ましい。これらのプラスチック製容器に備えられたゴム状弾性体は、熱可塑性エラストマー等のゴム弾性を有する合成樹脂、イソプレンゴムあるいはブチルゴム等の合成ゴム、特に熱可塑性エラストマー、イソプレンゴムまたはブチルゴムで形成するのが、グラニセトロンの安定性の面から好ましい。
本発明のプラスチック製容器であるバッグの排出口のゴム栓またはボトルのゴム栓などのゴム状弾性体の少なくともグラニセトロン含有水性製剤と接触する面は、フッ素系樹脂あるいはパリレン樹脂等でラミネートあるいは蒸着等の手段により被覆されていても良い。
The plastic container of the present invention is preferably provided with a rubber-like elastic body through which a bottle needle or the like of an infusion set can be inserted for the purpose of appropriately discharging the contents. When the plastic container is a bag, it is preferable that the bag is provided with a discharge port in which one end communicates with the inside of the bag and the other end of the cylindrical port member is sealed with a rubber-like elastic body that is a so-called rubber plug. In this case, the bottle mouth is preferably sealed with a rubber stopper. The rubber-like elastic body provided in these plastic containers is formed of a synthetic resin having rubber elasticity such as thermoplastic elastomer, synthetic rubber such as isoprene rubber or butyl rubber, particularly thermoplastic elastomer, isoprene rubber or butyl rubber. From the viewpoint of stability of granisetron.
The surface in contact with at least the granisetron-containing aqueous preparation of a rubber-like elastic body such as a rubber stopper of a bag outlet or a bottle stopper of a plastic container of the present invention is laminated or vapor-deposited with a fluororesin or parylene resin. It may be covered by the means.
本発明のプラスチック製容器内は無菌である必要があるので、通常充填密封後に滅菌される。この際の滅菌は、本発明の容器をそのまま滅菌しても良いし、包装容器に密封した後、滅菌しても良い。この場合の滅菌手段としては、常用される湿熱滅菌、特に高圧蒸気滅菌によることが望ましい。なお、無菌充填にて、容器内にグラニセトロンを含有する水性製剤を充填したものであっても良い。
本発明のグラニセトロン含有水性製剤は、充填される水溶液が約５０〜約１００ｍＬと小容量であるため、保管時の蒸散による液量減少が無視できない。よって、ある程度の水蒸気透過性を有する通常のプラスチック製容器で形成された容器、特に該容器がソフトバッグ等の軟質なバッグである場合、水蒸気の蒸散を抑制するため、本製剤を包装容器で密封包装してグラニセトロン含有水性製剤包装体とすることが好ましい。包装容器としては、袋状の包装容器の開口からグラニセトロン含有水性製剤を挿入し公知のシール手段で密封包装できるものや、グラニセトロン含有水性製剤を収納する収納部を有するブリスター容器本体を構成するボトムと、該ボトムの開口を公知のシール手段で密封するフィルムとを有するブリスター容器などが挙げられる。
包装容器に用いる素材は水蒸気バリア性に優れたものを用いることが好ましく、このようにすることによって、グラニセトロン含有水性製剤は長期にわたってより安定に保存することが確実となる。水蒸気バリア性に優れた素材として、具体的には、アルミナ蒸着フィルム、アルミ蒸着フィルムやアルミ箔層を有するラミネートフィルム、あるいはシリカ蒸着フィルム、ポリエチレンテレフタレート、エチレンビニルアルコール重合体、ポリビニルアルコール、ポリ塩化ビニリデン、ポリエチレンナフタレート、ポリアミド、あるいはこれらの樹脂を層成分として有する積層体からなる多層フィルムなどが挙げられる。さらに、アルミ箔や遮光インキ層等の光をカットする効果をもつ層成分を有するフィルムを用いてもよい。このような構成とすることにより、水性製剤の蒸散を効果的に防止することができる。特に、本発明のグラニセトロン含有水性製剤のように、液量が約５０〜約１００ｍＬと小容量で、有効期間が３年と長期の安定性が要求される場合は、蒸散を防ぐことが重要となる。
なお、本発明において水蒸気バリア性を有するとは、水蒸気透過度が４ｇ/ｍ２・２４ｈ以下であることを言い、プラスチック製容器自体が水蒸気バリア性を有する場合には蒸散防止の目的での包装容器の使用は求められない。
Since the plastic container of the present invention needs to be sterile, it is usually sterilized after filling and sealing. In this case, the container of the present invention may be sterilized as it is, or may be sterilized after being sealed in a packaging container. As sterilization means in this case, it is desirable to use wet heat sterilization, particularly high pressure steam sterilization. The container may be filled with an aqueous preparation containing granisetron by aseptic filling.
Since the granisetron-containing aqueous preparation of the present invention has a small volume of about 50 to about 100 mL of an aqueous solution to be filled, a decrease in liquid volume due to transpiration during storage cannot be ignored. Therefore, in order to suppress the vaporization of water vapor, in a case where the container is formed of a normal plastic container having a certain level of water vapor permeability, especially when the container is a soft bag or the like, the preparation is sealed in a packaging container. It is preferable to wrap and make a granisetron-containing aqueous preparation package. As a packaging container, a granisetron-containing aqueous preparation can be inserted through an opening of a bag-like packaging container and hermetically sealed with a known sealing means, or a blister container main body having a storage part for storing a granisetron-containing aqueous preparation, And a blister container having a film for sealing the opening of the bottom with a known sealing means.
The material used for the packaging container is preferably a material excellent in water vapor barrier property. By doing so, it is ensured that the granisetron-containing aqueous preparation is more stably stored over a long period of time. Specific examples of materials excellent in water vapor barrier properties include alumina vapor-deposited films, aluminum vapor-deposited films and laminate films having aluminum foil layers, silica vapor-deposited films, polyethylene terephthalate, ethylene vinyl alcohol polymers, polyvinyl alcohol, and polyvinylidene chloride. , Polyethylene naphthalate, polyamide, or a multilayer film composed of a laminate having these resins as layer components. Furthermore, you may use the film which has a layer component with the effect of cutting light, such as aluminum foil and a light shielding ink layer. By setting it as such a structure, the transpiration | evaporation of an aqueous formulation can be prevented effectively. In particular, as in the case of the granisetron-containing aqueous preparation of the present invention, it is important to prevent transpiration when the liquid volume is as small as about 50 to about 100 mL and a long-term stability of 3 years is required. Become.
In the present invention, having water vapor barrier property means that the water vapor permeability is 4 g / m 2 · 24 h or less, and when the plastic container itself has water vapor barrier property, packaging for the purpose of preventing transpiration. The use of containers is not required.
本発明のグラニセトロン含有水性製剤は、グラニセトロンの実質的な変質や含有量の低下のない安定性に優れた製剤を提供できる。 The granisetron-containing aqueous preparation of the present invention can provide a preparation excellent in stability without substantial deterioration of granisetron and content reduction.
次に、実施例を挙げて本発明をさらに詳細に説明するが、本発明はこれらに限定されるわけではない。
（実施例１）
グラニセトロン塩酸塩０．９ｇ、塩化ナトリウム３６０ｇ、クエン酸水和物１．６ｇ、を注射用水３６Ｌに溶解し、水酸化ナトリウム適量にてｐＨを５．４付近に調整した後、注射用水にて全量を４０Ｌとし、グラニセトロン０．０２ｍｇ/ｍＬ濃度の水溶液を得た。この水溶液を０．２２μmの孔径のメンブランフィルターを用いて無菌ろ過し、グラニセトロン水溶液を調製した。
得られたグラニセトロン水溶液を１００ｍＬ容量の筒状ポート部を有する多層ポリプロピレン製のソフトバッグに該ポート部より５３ｍＬ充填し、ポート部の開口をイソプレン製ゴム栓により施栓した後、常法により高圧蒸気滅菌をして、本発明のグラニセトロン含有水性製剤を製した。さらに該グラニセトロン含有水性製剤を水蒸気透過度が２ｇ/ｍ２・２４ｈ以下である次の構成のフィルムからなる袋にヒートシール機によって密封包装し、グラニセトロン含有水性製剤包装体を得た。
フィルム構成：シリカ蒸着処理をポリエチレンテレフタレートフィルムに施した層を有する多層フィルム
EXAMPLES Next, although an Example is given and this invention is demonstrated further in detail, this invention is not necessarily limited to these.
Example 1
Granisetron hydrochloride 0.9g, sodium chloride 360g, citric acid hydrate 1.6g are dissolved in 36L of water for injection, pH is adjusted to around 5.4 with an appropriate amount of sodium hydroxide, and then the whole amount is added with water for injection. Was adjusted to 40 L, and an aqueous solution having a granisetron concentration of 0.02 mg / mL was obtained. This aqueous solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm to prepare a granisetron aqueous solution.
The obtained granisetron aqueous solution is filled with 53 mL of a multi-layer polypropylene soft bag having a cylindrical port portion having a capacity of 100 mL from the port portion, and the opening of the port portion is plugged with an isoprene rubber stopper, followed by high-pressure steam sterilization by a conventional method. Thus, the granisetron-containing aqueous preparation of the present invention was produced. Further, the granisetron-containing aqueous preparation was hermetically packaged with a heat sealer in a bag made of a film having the following constitution having a water vapor permeability of 2 g / m 2 · 24 h or less to obtain a granisetron-containing aqueous preparation package.
Film configuration: Multilayer film with a layer of silica vapor-deposited polyethylene terephthalate film
（試験例１） 実施例１で得られたグラニセトロン含有水性製剤包装体を４０℃７５％相対湿度の条件下で６箇月間保存し、試験開始時のグラニセトロンの含有量に対する残存率、ｐＨ、浸透圧比、採取容量、性状、不溶性異物の結果は、下記の表１に示すとおりであった。 Test Example 1 The granisetron-containing aqueous preparation package obtained in Example 1 was stored for 6 months under conditions of 40 ° C. and 75% relative humidity, and the residual ratio, pH, and penetration with respect to the granisetron content at the start of the test. The pressure ratio, sampling volume, properties, and results of insoluble foreign matter were as shown in Table 1 below.
（実施例２） 実施例１で得られたグラニセトロン含有水性製剤を水蒸気透過度が２ｇ/ｍ２・２４ｈ以下である次の構成からなるボトムに収納し、該ボトムの開口を水蒸気透過度が２ｇ/ｍ２・２４ｈ以下である次の構成からなるフィルムを用いてヒートシール機によって密封包装し、グラニセトロン含有水性製剤包装体を得た。
ボトム構成：酸化チタン配合のポリオレフィン層を有する多層フィルム
フィルム構成：ＵＶカットインキをポリエチレンテレフタレートフィルムに施した層を有する多層フィルム
(Example 2) The granisetron-containing aqueous preparation obtained in Example 1 is housed in a bottom having the following structure with a water vapor permeability of 2 g / m 2 · 24 h or less, and the bottom opening has a water vapor permeability of 2 g. Using a film having the following constitution of / m 2 · 24 h or less, the film was hermetically packaged by a heat sealer to obtain a granisetron-containing aqueous preparation package.
Bottom structure: Multi-layer film film having a polyolefin layer containing titanium oxide Structure: Multi-layer film having a layer obtained by applying UV cut ink to a polyethylene terephthalate film
（試験例２） 実施例２で得られたグラニセトロン含有水性製剤包装体を４０℃７５％相対湿度の条件下で３箇月間保存し、試験開始時のグラニセトロンの含有量に対する残存率、ｐＨ、浸透圧比、採取容量、性状、不溶性異物の結果は、下記の表２に示すとおりであった。 (Test Example 2) The granisetron-containing aqueous preparation package obtained in Example 2 was stored for 3 months under the condition of 40 ° C. and 75% relative humidity, and the residual ratio, pH, and penetration with respect to the granisetron content at the start of the test. The pressure ratio, sampling volume, properties, and results of insoluble foreign matters were as shown in Table 2 below.
表１の結果から、グラニセトロン１ｍｇを含有する水溶液をプラスチック製容器に収納したグラニセトロン含有水性製剤包装体を、４０℃７５％相対湿度の条件下で６箇月間保存した時、グラニセトロンの残存率は９５％以上を保つことがわかった。
浸透圧比および採取容量の結果から、わずかに水溶液が蒸散したことが確認されたが、安定性として問題ないレベルであった。また、ｐＨ、性状、不溶性異物は変化がないことが確認された。
表１および表２の結果から、グラニセトロン含有水性製剤を実施例１にかかる包装容器で密封包装しても、実施例２にかかる包装容器で密封包装しても、グラニセトロン含有水性製剤としての保存安定性はいずれも良好であることが確認された。
From the results in Table 1, when a granisetron-containing aqueous preparation package containing an aqueous solution containing 1 mg of granisetron in a plastic container is stored for 6 months under the condition of 40 ° C. and 75% relative humidity, the residual rate of granisetron is 95. It was found to keep more than%.
From the results of the osmotic pressure ratio and the sampling volume, it was confirmed that the aqueous solution slightly evaporated, but the stability was at a level that does not cause any problems. It was also confirmed that there was no change in pH, properties, and insoluble foreign matter.
From the results of Tables 1 and 2, storage stability as a granisetron-containing aqueous preparation can be obtained whether the granisetron-containing aqueous preparation is sealed and packaged in the packaging container according to Example 1 or the packaging container according to Example 2. It was confirmed that all the properties were good.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08507774A (en) * | 1993-03-18 | 1996-08-20 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Use of granisetron for the treatment of postoperative nausea and vomiting |
| JP2003164508A (en) * | 2001-12-03 | 2003-06-10 | Taisei Kako Co Ltd | Transfusion container |
| JP2007513129A (en) * | 2003-12-05 | 2007-05-24 | アルキメデス ディヴェロプメント リミテッド | Intranasal composition |
| JP2011063539A (en) * | 2009-09-16 | 2011-03-31 | Terumo Corp | Antiemetic |
-
2012
- 2012-08-10 JP JP2012178559A patent/JP6081102B2/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08507774A (en) * | 1993-03-18 | 1996-08-20 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Use of granisetron for the treatment of postoperative nausea and vomiting |
| JP2003164508A (en) * | 2001-12-03 | 2003-06-10 | Taisei Kako Co Ltd | Transfusion container |
| JP2007513129A (en) * | 2003-12-05 | 2007-05-24 | アルキメデス ディヴェロプメント リミテッド | Intranasal composition |
| JP2011063539A (en) * | 2009-09-16 | 2011-03-31 | Terumo Corp | Antiemetic |
Non-Patent Citations (2)
| Title |
|---|
| JPN6016007194; グラニセトロン点滴静注バッグ３ｍｇ／１００ｍＬ「マイラン」 ３ｍｇ１００ｍＬ１袋 ［平成２８年２月１９日検索］，インターネッ, 20110501, 医薬品総合検索データーベース * |
| JPN6016007195; グラニセトロン点滴静注バッグ３ｍｇ／５０ｍＬ「マイラン」３ｍｇ５０ｍＬ１袋 医薬品総合検索データーベース, 20110701, ［平成２８年２月１９日検索］，インターネッ * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112842991A (en) * | 2021-03-11 | 2021-05-28 | 北京鑫开元医药科技有限公司 | Granisetron hydrochloride injection and preparation method thereof |
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