JP2007077059A - Medicinal composition for injection - Google Patents
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- JP2007077059A JP2007077059A JP2005266143A JP2005266143A JP2007077059A JP 2007077059 A JP2007077059 A JP 2007077059A JP 2005266143 A JP2005266143 A JP 2005266143A JP 2005266143 A JP2005266143 A JP 2005266143A JP 2007077059 A JP2007077059 A JP 2007077059A
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- 238000002347 injection Methods 0.000 title claims abstract description 15
- 239000007924 injection Substances 0.000 title claims abstract description 15
- 239000000203 mixture Substances 0.000 title abstract description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000000126 substance Substances 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- FIITXXIVUIXYMI-UHFFFAOYSA-N 3-[(2-nitroimidazol-1-yl)methoxy]butane-1,2,4-triol Chemical compound OCC(O)C(CO)OCN1C=CN=C1[N+]([O-])=O FIITXXIVUIXYMI-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000243 solution Substances 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 31
- 235000011187 glycerol Nutrition 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000001146 hypoxic effect Effects 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- -1 nucleic acid hydroxide Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 150000004959 2-nitroimidazoles Chemical class 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- OCEGXQKQPUJRMV-UHFFFAOYSA-N [3,4-diacetyloxy-2-(acetyloxymethoxy)butyl] acetate Chemical compound CC(=O)OCOC(COC(C)=O)C(COC(C)=O)OC(C)=O OCEGXQKQPUJRMV-UHFFFAOYSA-N 0.000 description 2
- 239000008365 aqueous carrier Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
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- 230000001603 reducing effect Effects 0.000 description 2
- BPQVNNUTMUVYCD-UHFFFAOYSA-N 3-[(2-nitro-1H-imidazol-5-yl)methoxy]butane-1,2,4-triol Chemical compound OCC(O)C(CO)OCC1=CN=C([N+]([O-])=O)N1 BPQVNNUTMUVYCD-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer 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
- 229920000084 Gum arabic Polymers 0.000 description 1
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- 239000002841 Lewis acid Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
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- 239000013543 active substance Substances 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000006907 apoptotic process Effects 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
- 239000011230 binding agent Substances 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- SXSKBECMUBMQGC-UHFFFAOYSA-N trimethyl-(2-nitroimidazol-1-yl)silane Chemical compound C[Si](C)(C)N1C=CN=C1[N+]([O-])=O SXSKBECMUBMQGC-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、医薬用の組成物に関し、更に詳細には、注射剤に好適な医薬用の組成物に関する。 The present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition suitable for injection.
２−ニトロイミダゾール誘導体は、癌放射線療法において、放射線抵抗性を有する、低酸素性の癌細胞の、放射線感受性を高め、放射線療法の効果を高める有用な薬剤であることが既に知られている。この様な２−ニトロイミダゾール誘導体の内でも、１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールは、親水性が高く、神経細胞への移行性が殆ど存しないため、中枢毒性のない放射線増感剤として現在臨床試験中である。（例えば、特許文献１、特許文献２、特許文献３を参照）又、かかる物質においては、この様な低酸素性細胞に対する放射線増感効果以外にも、核酸水酸化物消去作用（例えば、特許文献４を参照）、アポトーシス・シグナル保持作用（例えば、特許文献５を参照）などが存し、癌治療においては有用な薬剤であると言える。 2-Nitroimidazole derivatives are already known to be useful drugs for enhancing the radiosensitivity and the effect of radiotherapy of cancer cells with radioresistance and hypoxic cancer in cancer radiotherapy. Among such 2-nitroimidazole derivatives, 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole is highly hydrophilic and has almost no migration to nerve cells. Therefore, it is currently in clinical trials as a radiosensitizer without central toxicity. (See, for example, Patent Document 1, Patent Document 2, and Patent Document 3.) In addition to such a radiosensitizing effect on hypoxic cells, such substances have nucleic acid hydroxide scavenging action (for example, patents). Reference document 4), apoptosis signal retention action (for example, refer to patent document 5), etc. exist, and can be said to be a useful drug in cancer treatment.
かかる１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールは、２つの不斉炭素を有し、ＲＲ体、ＳＳ体、ＳＲ体、ＲＳ体の４つの立体異性体が存し、現在臨床応用が考えられているのは、ＳＲ体とＲＳ体のラセミ体である。これらの１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールは何れも結晶性に優れる、水溶性も脂溶性も有する、腫瘍親和性が高いなどの特性を有しており、それは非環状糖ヌクレオシド類似構造に起因するものであると言われている。言い換えれば、結晶性と水溶性、脂溶性の両親媒性とは、腫瘍に対する効果と密接に結びついたものであると言える。 Such 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole has two asymmetric carbons and has four stereoisomers of RR, SS, SR, and RS. It is the racemate of the SR form and the RS form that the body exists and is currently considered for clinical application. These 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazoles all have excellent crystallinity, water solubility and fat solubility, and high tumor affinity. It is said that it is caused by a non-cyclic sugar nucleoside-like structure. In other words, it can be said that crystallinity, water solubility, and fat solubility amphiphilicity are closely related to the effect on tumors.
その反面、結晶性の良さと両親媒性であることとは、水性担体への溶かしやすさの点では、結晶構造を崩して、溶かすために多くの労力を要し、且つ、保存時における結晶の析出の危険性を有するなど、使用性を損なっているとも言える。更に、水溶性を有するとは言うものの、結晶の析出の危険性を回避した溶解度は１〜３質量％程度であり、投与のために必要となるベヒクル量は多くなり、注射剤としての投与は、点滴にならざるを得ず、この点滴投与形態と、かかる化合物の代謝速度の速さと勘案すると、生体利用性の低下が懸念される。更に、化学式１に表される化合物の水性担体溶液の安定性が、室温以上では損なわれやすい為に、５℃などの低温保存しなければならず、低温保存条件が更に溶解性を制限する面も存する。即ち、かかる化合物の効果を向上させる手段として、製剤における有効成分である後記化学式１の化合物の濃度を向上せしめることが示唆されているが、かかる化学式１に表される化合物の溶解度を向上させる手段については全く知られていないのが現状であると言える。 On the other hand, good crystallinity and amphiphilic properties mean that in terms of solubility in an aqueous carrier, the crystal structure is destroyed and much labor is required to dissolve, and the crystals at the time of storage are stored. It can also be said that the usability is impaired, such as the risk of precipitation. Furthermore, although said to be water-soluble, the solubility avoiding the risk of crystal precipitation is about 1 to 3% by mass, the amount of vehicle required for administration increases, and administration as an injection is not possible. In view of this drip dosage form and the high metabolic rate of such compounds, there is a concern about a decrease in bioavailability. Furthermore, since the stability of the aqueous carrier solution of the compound represented by Chemical Formula 1 is easily impaired at room temperature or higher, it must be stored at a low temperature such as 5 ° C., and the low-temperature storage conditions further limit the solubility. Also exist. That is, as a means for improving the effect of such a compound, it has been suggested to improve the concentration of the compound represented by the following chemical formula 1, which is an active ingredient in the preparation, but means for improving the solubility of the compound represented by the chemical formula 1 It can be said that the situation is completely unknown.
他方、１）次に示す化学式１に構造を示す１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールを１質量部に対し２）グリセリンを０．０００１〜１質量部を含有する、医薬用の組成物は全く知られておらず、この様な構成の医薬組成物が、ベヒクルの存在下、溶解性に優れることも全く知られていなかった。 On the other hand, 1) 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole having a structure shown in the following chemical formula 1 is 2 parts by mass of 2) glycerol 0.0001-1 No pharmaceutical composition containing parts by weight is known at all, and it has not been known at all that the pharmaceutical composition having such a composition is excellent in solubility in the presence of a vehicle.
本発明はこの様な状況下為されたものであり、次に示す化学式１に表される化合物の注射製剤における濃度を向上せしめる手段を提供することを課題とする。 The present invention has been made under such circumstances, and an object of the present invention is to provide means for improving the concentration of the compound represented by the following chemical formula 1 in an injection preparation.
この様な状況に鑑みて、本発明者らは、前記化学式１に表される化合物の注射製剤における濃度を向上せしめる手段を求めて、鋭意研究努力を重ねた結果、１）前記化学式１に構造を示す１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールを１質量部に対し２）グリセリンを０．０００１〜１質量部を含有する、医薬用の組成物が、その様な特性を有していることを見出し、発明を完成させるに至った。即ち、本発明は、以下に示す通りである。
（１）１）前記化学式１に構造を示す１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールを１質量部に対し２）グリセリンを０．０００１〜１質量部を含有することを特徴とする、医薬用の組成物。
（２）前記化学式１に表される化合物が、化学式２に表される立体構造の異性体と化学式２に表される立体構造の異性体のＲＳ・ＳＲラセミ体であることを特徴とする、（１）に記載の医薬用の組成物。
In view of such a situation, the present inventors have sought for means for improving the concentration of the compound represented by the chemical formula 1 in the injection preparation, and as a result of intensive research efforts, 1) the structure represented by the chemical formula 1 A pharmaceutical composition containing 1)-(1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole and 2) 0.0001-1 part by weight of glycerin However, it has been found that it has such characteristics, and has completed the invention. That is, the present invention is as follows.
(1) 1) 1- (1-Hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole having the structure shown in Chemical Formula 1 is 2 parts by weight of 1) 0.0001-1 mass of glycerin A pharmaceutical composition characterized by containing a part.
(2) The compound represented by the chemical formula 1 is an steric isomer represented by the chemical formula 2 and an steric isomer RS · SR racemate represented by the chemical formula 2, The pharmaceutical composition as described in (1).
（３）注射剤であることを特徴とする、（１）又は（２）に記載の医薬用の組成物。
（４）製剤における、前記化学式１に表される化合物の濃度が５〜１０質量％の溶液形態であることを特徴とする、（１）〜（３）何れか１項に記載の医薬用の組成物。
(3) The pharmaceutical composition according to (1) or (2), which is an injection.
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the concentration of the compound represented by Chemical Formula 1 in the preparation is in the form of a solution of 5 to 10% by mass. Composition.
（１）本発明の医薬用の組成物の必須成分である１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾール
本発明の医薬用の組成物は、１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールを必須成分として含有する。かかる化合物にはＲＳ体、ＳＲ体、ＲＲ体、ＳＳ体の４つの立体異性体が存し、本発明の医薬用の組成物では、これらの光学活性体を使用することも出来るし、光学活性体が混合した、ラセミ体などの混合物を使用することも出来る。特に好ましいものは、ＳＲ体とＲＳ体の体であり、これは、このラセミ体の結晶性が良いため、巨大な結晶になりやすく、この様な形態では、溶解せしめるのに困難が存し、本発明の効果が著しい為と、臨床試験において、実際に有効性が確かめられているためである。かかる化合物は、特許文献１或いは特許文献２に記載された方法に従って製造することが出来、例えば、２−ニトロ−１−トリメチルシリルイミダゾールと２−アセトキシメトキシ−１，３，４−トリアセトキシブタンとをルイス酸の存在下縮合させ、しかる後に、ナトリウムメトキシドなどを反応させて脱アセチル化することにより、製造することが出来る。この時、２−アセトキシメトキシ−１，３，４−トリアセトキシブタンの立体特性が、最終生成物の１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールにも反映される。本発明の医薬用の組成物では、かかる１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールを医薬用の組成物全量に対しては、好ましくは、５〜１０質量％、より好ましくは６〜８質量％含有する。これは少なすぎると、医薬製剤において充分な量の１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールを含有することが出来なくなるし、多すぎると本発明の効果が得られず、ベヒクルの溶解しきれない場合が存するためである。尚、本発明の医薬用の組成物の有効成分である、１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールの標準的な投与量は、１回あたり、成人男子１人で１〜１０ｇである。
(1) 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole, which is an essential component of the pharmaceutical composition of the present invention, (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole is contained as an essential component. Such a compound has four stereoisomers of RS, SR, RR, and SS, and these optically active substances can be used in the pharmaceutical composition of the present invention. It is also possible to use a mixture of racemic bodies mixed with the body. Particularly preferred are SR and RS isomers, which have good crystallinity of this racemate, so that they are likely to form huge crystals. In such a form, it is difficult to dissolve, This is because the effect of the present invention is remarkable and its effectiveness has been confirmed in clinical trials. Such a compound can be produced according to the method described in Patent Document 1 or Patent Document 2, for example, 2-nitro-1-trimethylsilylimidazole and 2-acetoxymethoxy-1,3,4-triacetoxybutane. It can be produced by condensation in the presence of a Lewis acid and then deacetylating by reacting with sodium methoxide or the like. At this time, the steric properties of 2-acetoxymethoxy-1,3,4-triacetoxybutane are also observed in the final product 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole. Reflected. In the pharmaceutical composition of the present invention, such 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole is preferably used in an amount of 5 to 5 based on the total amount of the pharmaceutical composition. 10 mass%, More preferably, it contains 6-8 mass%. If this amount is too small, it will not be possible to contain a sufficient amount of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole in the pharmaceutical preparation. This is because there are cases where the effect cannot be obtained and the vehicle cannot be completely dissolved. The standard dose of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole, which is an active ingredient of the pharmaceutical composition of the present invention, is 1 to 10 g per adult male.
（２）本発明の医薬用の組成物の必須成分であるグリセリン
本発明の医薬組成物は、グリセリンを必須成分として含有することを特徴とする。グリセリンの含有量は、前記１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールの含有量に対して、０．０００１〜１質量部、より好ましくは０．０００５〜０．０５質量部であることが好ましい。かかる成分は、水や生理食塩水などのベヒクルの存在下、１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールのベヒクルに対する溶解度を向上せしめ、必要ベヒクル量を減じる作用を有する。必要ベヒクル量が減じることにより、効果に必要な製剤の投与量を減じることが出来、これにより投与過程に於いて、代謝により有効成分である１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールが無為に排泄されるのを抑制することが出来る。製剤全量に対しては、グリセリンは０．００１〜５質量％含有されることが好ましく、０．００４〜０．２質量％であることが特に好ましい。これは、少なすぎると溶解性向上効果を奏さない場合が存し、多すぎると、投与に際しての取り扱い性を損なう場合が存するためである。
(2) Glycerin as an essential component of the pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is characterized by containing glycerin as an essential component. The content of glycerin is 0.0001 to 1 part by mass, more preferably 0.0005, based on the content of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole. It is preferable that it is -0.05 mass part. This component improves the solubility of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole in the presence of a vehicle such as water or saline, and reduces the amount of vehicle required. Has a reducing effect. By reducing the amount of the necessary vehicle, the dosage of the preparation necessary for the effect can be reduced, and thereby, in the administration process, 1- (1-hydroxymethyl-2,3-dihydroxypropyl, which is an active ingredient by metabolism, can be reduced. ) It is possible to prevent oxymethyl-2-nitroimidazole from being excreted unnecessarily. It is preferable that 0.001-5 mass% of glycerol is contained with respect to the formulation whole quantity, and it is especially preferable that it is 0.004-0.2 mass%. This is because if the amount is too small, the solubility-improving effect may not be achieved, and if the amount is too large, the handleability during administration may be impaired.
（３）本発明の医薬用の組成物
本発明の医薬用の組成物は、前記必須成分を含有し、癌の治療用、取り分け、放射線による癌治療における、低酸素性癌細胞の放射線に対する感受性を高める目的で好適に使用される。癌の種類としては、肺ガンや膵癌が好適に例示できる。製剤としては、経口投与製剤、注射製剤何れもが可能であるが、代謝が早いことから注射製剤であることが好ましい。注射製剤としては、点滴投与用の製剤も含み、点滴投与製剤であることが好ましい。これは、有効成分である１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールの投与量が多いため、投与に必要な製剤量が多くなり、一時の投与では危険が生じる場合が存するためである。この様な注射用製剤としては、溶液形態でも、凍乾形態でも特に制限はないが、安定した溶解性が得られる点で、溶液形態であることが好ましい。溶液形態に於いてベヒクルとしては、純水でも、生理食塩水でも、等張処理されていても良いグルコース溶液などが好適に例示できる。
(3) Medicinal composition of the present invention The medicinal composition of the present invention contains the above-mentioned essential ingredients, and is sensitive to radiation of hypoxic cancer cells in cancer treatment, particularly, cancer treatment by radiation. It is preferably used for the purpose of enhancing. Suitable examples of cancer include lung cancer and pancreatic cancer. As preparations, both oral administration preparations and injection preparations can be used, but injection preparations are preferred because of rapid metabolism. Injectable preparations include preparations for infusion administration and are preferably infusion administration preparations. This is because the dose of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole, which is an active ingredient, is large, and the amount of preparation necessary for administration increases. This is because there may be dangers. Such an injectable preparation is not particularly limited in a solution form or a freeze-dried form, but is preferably a solution form in terms of obtaining stable solubility. Preferred examples of the vehicle in the form of solution include pure water, physiological saline, and glucose solution that may be isotonic.
本発明の医薬用の組成物には、前記必須成分以外に、必要に応じて、医薬の製剤において通常使用される任意の製剤成分を、本発明の効果を損ねない範囲において、含有することが出来る。この様な任意成分としては、例えば、マクロゴールの様な多価アルコール類、塩化ナトリウムのような等張化剤、リン酸塩のような緩衝塩、結晶セルロースや澱粉のような賦形剤、ポリオキシエチレン硬化ヒマシ油のような非イオン界面活性剤、ラウリル硫酸ナトリウムのようなアニオン界面活性剤、アラビアゴムのような増粘多糖類、ステアリン酸マグネシウムのような滑沢剤、着色剤、矯味矯臭剤、ヒドロキシプロピルセルロースのような結合剤、「オイドラギット」（登録商標）の様な被覆剤等が例示できる。溶液形態の注射用の医薬組成物において、特に好ましい形態は、必須成分とベヒクル以外の成分を含有しない形態である。 The pharmaceutical composition of the present invention may contain, in addition to the essential components, any formulation components that are usually used in pharmaceutical formulations, if necessary, within a range that does not impair the effects of the present invention. I can do it. Examples of such optional components include polyhydric alcohols such as macrogol, isotonic agents such as sodium chloride, buffer salts such as phosphate, excipients such as crystalline cellulose and starch, Nonionic surfactants such as polyoxyethylene hydrogenated castor oil, anionic surfactants such as sodium lauryl sulfate, thickening polysaccharides such as gum arabic, lubricants such as magnesium stearate, colorants, flavoring Examples include flavoring agents, binders such as hydroxypropylcellulose, and coating agents such as “Eudragit” (registered trademark). In the pharmaceutical composition for injection in the form of a solution, a particularly preferable form is a form that does not contain essential components and components other than the vehicle.
本発明の医薬組成物は、前記必須成分や任意成分を常法によって処理することにより製造することが出来る。 The pharmaceutical composition of this invention can be manufactured by processing the said essential component and arbitrary components by a conventional method.
以下に、実施例を挙げて、本発明について更に詳細に説明するが、本発明がかかる実施例にのみ限定されないことは言うまでもない。 Hereinafter, the present invention will be described in more detail with reference to examples, but it goes without saying that the present invention is not limited to such examples.
以下に示す処方に従って、本発明の医薬組成物１（溶液形態の注射剤）を作成した。即ち、処方成分を容器に秤込み、手で振とうさせて溶解させた。比較例１として、グリセリンを水に置換したものを、比較例２として、グリセリンをプロピレングリコールに置換したものを同様に作成した。この時、溶解に要する時間も計測した。作成した製剤は５℃に２４時間保管し、製剤の安定性（結晶析出の有無）を確かめた。結果を表１に示す。本発明の注射製剤は、製剤安定性に優れることが判る。 According to the formulation shown below, the pharmaceutical composition 1 of the present invention (solution form injection) was prepared. That is, the prescription ingredients were weighed into a container and dissolved by shaking by hand. A comparative example 1 was prepared by replacing glycerin with water, and a comparative example 2 was prepared by replacing glycerin with propylene glycol. At this time, the time required for dissolution was also measured. The prepared preparation was stored at 5 ° C. for 24 hours to confirm the stability of the preparation (presence of crystal precipitation). The results are shown in Table 1. It turns out that the injection formulation of this invention is excellent in formulation stability.
化学式１の化合物（ラセミ体） ５ 質量％
グリセリン ２．５質量％
水 残余
Compound of formula 1 (racemate) 5% by mass
Glycerin 2.5% by mass
Water residue
実施例１と同様に下記の処方に従って、本発明の医薬組成物２（溶液形態の注射剤）を作成し評価した。比較例３として、医薬組成物２のグリセリンを水に置換したものを、比較例４として、グリセリンをプロピレングリコールに置換したものも同様に作成した。結果を表２に示す。これより、更に化学式１の化合物の高いところでも、本発明の医薬組成物は結晶を析出せず、安定であることが判る。 In the same manner as in Example 1, the pharmaceutical composition 2 (injection solution in the form of a solution) of the present invention was prepared and evaluated according to the following formulation. As Comparative Example 3, a product obtained by substituting glycerin of pharmaceutical composition 2 with water, and as Comparative Example 4, a product obtained by substituting glycerin with propylene glycol were similarly prepared. The results are shown in Table 2. From this, it can be seen that the pharmaceutical composition of the present invention is stable even when the compound of the chemical formula 1 is higher, without crystal precipitation.
化学式１の化合物（ラセミ体） ７ 質量％
グリセリン ２．５質量％
水 残余
Compound of formula 1 (racemate) 7% by mass
Glycerin 2.5% by mass
Water residue
実施例２の医薬組成物２のベヒクルを変えて、同様に医薬組成物３を作成した。溶解に要した時間は３０分であり、５℃保存でも析出物は存しなかった。 A pharmaceutical composition 3 was prepared in the same manner except that the vehicle of the pharmaceutical composition 2 of Example 2 was changed. The time required for dissolution was 30 minutes, and no precipitate was present even after storage at 5 ° C.
化学式１の化合物（ラセミ体） ７ 質量％
グリセリン ２．５質量％
生理食塩水 残余
Compound of formula 1 (racemate) 7% by mass
Glycerin 2.5% by mass
Saline residual
グリセリンと化学式１の化合物（ラセミ体）の最適量比を求めるために、これらの量比を変えて溶解性を検討した。溶解後５℃に２４時間保存して不溶物の析出を見ない状態を以て「溶解」と判定した。化学式１の化合物（ラセミ体）のみでは、６質量％でも「溶解」せず、溶解は５質量％程度と思われる。結果を表３に示す。これより、０．０１質量％のグリセリン添加でも溶解性の改善効果を奏することが判る。 In order to obtain the optimum amount ratio between glycerin and the compound of Formula 1 (racemate), the solubility was examined by changing these amount ratios. After dissolution, the solution was stored at 5 ° C. for 24 hours and judged as “dissolved” when no insoluble matter was observed. Only the compound of Formula 1 (racemate) does not “dissolve” even at 6% by mass, and the dissolution seems to be about 5% by mass. The results are shown in Table 3. From this, it can be seen that even when 0.01% by mass of glycerin is added, the effect of improving the solubility is exhibited.
化学式１の化合物（ラセミ体） 表３に記載の質量％
グリセリン 表３に記載の質量％
水 残余
Compound of Chemical Formula 1 (Racemic) Mass% listed in Table 3
Glycerin Mass% listed in Table 3
Water residue
本発明は安定な放射線増感のための医薬組成物に応用できる。 The present invention can be applied to a pharmaceutical composition for stable radiosensitization.
Claims (4)
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