JP2007106736A - Pharmaceutical composition for parenteral injection - Google Patents
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- JP2007106736A JP2007106736A JP2005345368A JP2005345368A JP2007106736A JP 2007106736 A JP2007106736 A JP 2007106736A JP 2005345368 A JP2005345368 A JP 2005345368A JP 2005345368 A JP2005345368 A JP 2005345368A JP 2007106736 A JP2007106736 A JP 2007106736A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 36
- 238000002347 injection Methods 0.000 title claims abstract description 23
- 239000007924 injection Substances 0.000 title claims abstract description 23
- 239000000126 substance Substances 0.000 claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 239000000243 solution Substances 0.000 claims abstract description 24
- 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 18
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 claims abstract description 12
- 229960004025 sodium salicylate Drugs 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims abstract description 10
- 235000010234 sodium benzoate Nutrition 0.000 claims abstract description 10
- 239000004299 sodium benzoate Substances 0.000 claims abstract description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
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- 238000009472 formulation Methods 0.000 abstract description 18
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- 239000011780 sodium chloride Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 241000894007 species Species 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
- 239000005711 Benzoic acid Substances 0.000 description 1
- WJIKCKZWIQWOPV-SSDOTTSWSA-N C=C([C@@H](CO)O)OC[n]1c([N+]([O-])=O)ncc1 Chemical compound C=C([C@@H](CO)O)OC[n]1c([N+]([O-])=O)ncc1 WJIKCKZWIQWOPV-SSDOTTSWSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-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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- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
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- 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
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 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
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
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- 229920002678 cellulose Polymers 0.000 description 1
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- 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
- 229960003624 creatine Drugs 0.000 description 1
- 239000006046 creatine Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 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
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 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
- 230000004060 metabolic process Effects 0.000 description 1
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- 238000000034 method Methods 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
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 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
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
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- 230000001737 promoting effect Effects 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 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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- 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,
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 aqueous carriers, the crystal structure is destroyed and much labor is required to dissolve, and the crystals during storage It can also be said that the usability is impaired, such as the risk of precipitation. Furthermore, although said to have water solubility, 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 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.
一方、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）化学式２に表されるカルボン酸及び／又はその塩を０．０００１〜０．５質量部を含有する医薬組成物は全く知られていないし、この様な構成を取ることにより、前記化合物の溶解量が増大し、溶状も安定することも全く知られていない。化学式２に表される化合物の内、安息香酸は防腐剤として医薬組成物で使用されることが知られている。（例えば、特許文献６を参照）又、サリチル酸は経皮吸収促進作用検討対象となることが知られている。（例えば、特許文献７を参照）しかしながら、かかる成分が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水への溶解度を向上せしめる作用を有することも、更には、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の安定性を向上せしめる作用を有す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 the structure shown in the following chemical formula 1 is 2) carvone represented by chemical formula 2 A pharmaceutical composition containing 0.0001 to 0.5 parts by mass of an acid and / or a salt thereof is not known at all, and by taking such a constitution, the amount of the compound dissolved is increased and the dissolved state is also stable. It is not known at all to do. Of the compounds represented by Chemical Formula 2, benzoic acid is known to be used in pharmaceutical compositions as a preservative. (See, for example, Patent Document 6) Salicylic acid is known to be a subject for studying the effect of promoting transdermal absorption. (See, for example, Patent Document 7) However, it is also possible that such a component has the effect of improving the solubility of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole in water. Furthermore, it has not been known at all that it has an action of improving the stability of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole.
（但し、式中Ｒ１は水酸基又は水素原子を表す。）
(In the formula, R1 represents a hydroxyl group or a hydrogen atom.)
本発明はこの様な状況下為されたものであり、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 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、前記化学式２に表されるカルボン酸及び／又はその塩を併用させることにより、この様な製剤化が為しうることを見出し、発明を完成させるに至った。即ち、本発明は、以下に示すとおりである。
（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）前記化学式２に表されるカルボン酸及び／又はその塩を０．０００１〜０．５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３に表される立体構造の異性体と化学式４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 earnest research efforts, the present invention is represented by the
(1) 1) 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole having the structure shown in Chemical Formula 1 is 2) Carvone represented by Chemical Formula 2 A pharmaceutical composition comprising 0.0001 to 0.5 parts by mass of an acid and / or a salt thereof.
(2) The compound represented by Chemical Formula 1 is an steric isomer represented by Chemical Formula 3 and an steric isomer RS · SR racemate represented by Chemical Formula 4, The pharmaceutical composition as described in (1).
（３）化学式２に表されるカルボン酸及び／又はその塩が、サリチル酸ナトリウム及び／又は安息香酸ナトリウム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）注射剤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。
（５）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）〜（４）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), wherein the carboxylic acid and / or salt thereof represented by Chemical Formula 2 is sodium salicylate and / or sodium benzoate.
(4) The pharmaceutical composition according to any one of (1) to (3), which is an injection.
(5) The pharmaceutical composition according to any one of (1) to (4), 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.
本発明によれば、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提供することができる。 According to the present invention, it is possible to provide means for improving the concentration of the compound represented by Chemical Formula 1 in an injection preparation.
（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
（２）本発明の医薬用の組成物の必須成分である化学式２の成分
本発明の医薬用の組成物は、化学式２に表されるカルボン酸及び／又はその塩を含有することを特徴とする。化学式２に表されるカルボン酸としては、具体的には、安息香酸及びサリチル酸が好適に例示できる。又、これらのカルボン酸の塩としては、生理的に許容されるもので有れば特段の限定はなく、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム、マグネシウム等のアルカリ土類金属塩、アンモニウム塩、トリエタノールアミン塩、トリエチルアミン塩等の有機アミン塩類、リジン塩、アルギニン塩等の塩基性アミノ酸塩等が好ましく例示できる。これらの中ではアルカリ金属塩がより好ましく、中でもナトリウム塩が特に好ましい。かかる成分は、唯一種を含有することも出来るし、二種以上を組み合わせて含有することも出来る。これらの成分は、前記化学式１に表される化合物の溶解度を向上せしめるとともに、その溶状を安定させ、低温域でも結晶の析出などが起こらないようにさせる作用を有する。この様な効果を奏するためには、化学式２に表されるカルボン酸及び／又はその塩は、０．００１〜５質量％含有することが好ましく、より好ましくは０．００２〜２質量％である。化学式１の化合物の量との量比では、化学式１の化合物１質量部に対して、０．０００１〜０．５質量部、より好ましくは、０．０００５〜０．４質量部含有されることが好ましい。この範囲より低いところでは溶状改善作用を発現しない場合が存し、多すぎても効果が頭打ちになったり、却って阻害されたりする場合が存するためである。かかる成分の添加は、副次的効果として、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安定性を向上せしめる作用を有する。かかる成分は、通常の保存状態では安定に存在するが、過酷な保存状態では徐々に分解し、その定量値が低下する。前記クレアチンは共存することにより、この分解を抑制し、定量値の低下を抑制する。
(2) The component of Chemical Formula 2, which is an essential component of the pharmaceutical composition of the present invention, is characterized in that it contains the carboxylic acid represented by Chemical Formula 2 and / or a salt thereof. To do. Specific examples of the carboxylic acid represented by Chemical Formula 2 include benzoic acid and salicylic acid. Further, these carboxylic acid salts are not particularly limited as long as they are physiologically acceptable. For example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metals such as calcium and magnesium, and the like. Preferred examples include organic amine salts such as salts, ammonium salts, triethanolamine salts and triethylamine salts, and basic amino acid salts such as lysine salts and arginine salts. Among these, alkali metal salts are more preferable, and sodium salts are particularly preferable. Such a component can contain only one species or a combination of two or more species. These components have the effect of improving the solubility of the compound represented by Chemical Formula 1, stabilizing the state of the solution, and preventing crystal precipitation from occurring even at low temperatures. In order to achieve such an effect, the carboxylic acid represented by
（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、安息香酸ナトリウムを水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９６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. As Comparative Example 1, a solution in which sodium benzoate was replaced with water was prepared in the same manner. At this time, the time required for dissolution was also measured. The prepared preparation was stored at 5 ° C. for 96 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） ６ 質量％
安息香酸ナトリウム ２．５質量％
水 残余
Compound of formula 1 (racemate) 6% by mass
Sodium benzoate 2.5% by mass
Water residue
以下に示す処方に従って、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２として、サリチル酸ナトリウムを水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９６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２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
化学式１の化合物（ラセミ体） ６ 質量％
サリチル酸ナトリウム ２．５質量％
水 残余
Compound of formula 1 (racemate) 6% by mass
Sodium salicylate 2.5% by mass
Water residue
以下に示す処方に従って、本発明の医薬組成物３（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３として、サリチル酸ナトリウムを生理食塩水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９６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３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 3 of the present invention (injection solution) was prepared. That is, the prescription ingredients were weighed into a container and dissolved by shaking by hand. As Comparative Example 3, a solution in which sodium salicylate was replaced with physiological saline was similarly prepared. At this time, the time required for dissolution was also measured. The prepared preparation was stored at 5 ° C. for 96 hours to confirm the stability of the preparation (presence of crystal precipitation). The results are shown in Table 3. 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） ６ 質量％
サリチル酸ナトリウム ２．５質量％
生理食塩水 残余
Compound of formula 1 (racemate) 6% by mass
Sodium salicylate 2.5% by mass
Saline residual
サリチル酸ナトリウムと化学式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４に示す。これより、０．１質量％のサリチル酸ナトリウム添加でも溶解性の改善効果を奏することが判る。尚（）内の数字は医薬組成物番号を示す。 In order to obtain the optimum amount ratio between sodium salicylate 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 4. From this, it can be seen that even when 0.1% by mass of sodium salicylate is added, there is an effect of improving the solubility. In addition, the number in () shows a pharmaceutical composition number.
化学式１の化合物（ラセミ体） 表４に記載の質量％
サリチル酸ナトリウム 表４に記載の質量％
水 残余
Compound of Chemical Formula 1 (Racemic Compound) Mass% listed in Table 4
Sodium salicylate Mass% listed in Table 4
Water residue
安息香酸ナトリウムと化学式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５に示す。これより、０．００６５質量％の安息香酸ナトリウム添加でも溶解性の改善効果を奏することが判る。尚（）内の数字は医薬組成物番号を示す。 In order to determine the optimum amount ratio between sodium benzoate 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 is considered to be about 5% by mass. The results are shown in Table 5. From this, it can be seen that even when 0.0065% by mass of sodium benzoate is added, the effect of improving the solubility is exhibited. In addition, the number in () shows a pharmaceutical composition number.
化学式１の化合物（ラセミ体） 表５に記載の質量％
安息香酸ナトリウム 表５に記載の質量％
水 残余
Compound of Chemical Formula 1 (Racemic) Mass% as described in Table 5
Sodium benzoate% by mass listed in Table 5
Water residue
以下に示す処方に従って、本発明の医薬組成物３７（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４として、サリチル酸ナトリウムを生理食塩水に置換したものを同様に作成した。医薬組成物３７と比較例４を過酷条件下（５５℃）での保存試験の結果を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定量値として図１に示す。縦軸は残存率（％）を示し、横軸は保存日数を示す。定量はＨＰＬＣを用いて行った。ＨＰＬＣの条件はＯＤＳカラム４．６ｍｍ×２５０ｍｍ、カラム温度４０℃、移動相１％メタノールリン酸緩衝水溶液（５ｍＭ、ｐＨ６）、流速１ｍｌ／分、検知ＵＶ３２０ｎｍであった。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 37 of the present invention (injection solution) was prepared. That is, the prescription ingredients were weighed into a container and dissolved by shaking by hand. As Comparative Example 4, a solution in which sodium salicylate was replaced with physiological saline was similarly prepared. The results of the storage test of the pharmaceutical composition 37 and Comparative Example 4 under severe conditions (55 ° C.) are shown as quantitative values of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole. It is shown in 1. The vertical axis indicates the remaining rate (%), and the horizontal axis indicates the number of storage days. Quantification was performed using HPLC. The HPLC conditions were ODS column 4.6 mm × 250 mm, column temperature 40 ° C., mobile phase 1% methanol phosphate buffer aqueous solution (5 mM, pH 6), flow rate 1 ml / min, detection UV 320 nm. 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％
サリチル酸ナトリウム ０．７５質量％
水 残余
Compound of formula 1 (racemate) 5% by mass
Sodium salicylate 0.75% by mass
Water residue
以下に示す処方に従って、本発明の医薬組成物３８（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５として、安息香酸ナトリウムを生理食塩水に置換したものを同様に作成した。医薬組成物３８と比較例５を過酷条件下（５５℃）での保存試験の結果を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定量値として図２に示す。縦軸は残存率（％）を示し、横軸は保存日数を示す。定量はＨＰＬＣを用いて行った。ＨＰＬＣの条件はＯＤＳカラム４．６ｍｍ×２５０ｍｍ、カラム温度４０℃、移動相１％メタノールリン酸緩衝水溶液（５ｍＭ、ｐＨ６）、流速１ｍｌ／分、検知ＵＶ３２０ｎｍであった。本発明の注射製剤は、製剤安定性に優れることが判る。 A pharmaceutical composition 38 (injection solution in the form of a solution) of the present invention was prepared according to the formulation shown below. That is, the prescription ingredients were weighed into a container and dissolved by shaking by hand. As Comparative Example 5, a solution in which sodium benzoate was substituted with physiological saline was similarly prepared. The results of the storage test of the pharmaceutical composition 38 and Comparative Example 5 under severe conditions (55 ° C.) are shown as quantitative values of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole. It is shown in 2. The vertical axis indicates the remaining rate (%), and the horizontal axis indicates the number of storage days. Quantification was performed using HPLC. The HPLC conditions were ODS column 4.6 mm × 250 mm, column temperature 40 ° C., mobile phase 1% methanol phosphate buffer aqueous solution (5 mM, pH 6), flow rate 1 ml / min, detection UV 320 nm. 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％
安息香酸ナトリウム ０．０５質量％
水 残余
Compound of formula 1 (racemate) 5% by mass
Sodium benzoate 0.05% by mass
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 (5)
（但し、式中Ｒ１は水酸基又は水素原子を表す。） 1) 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole having a structure represented by the following chemical formula 1 is 2) carboxylic acid represented by chemical formula 2 and A pharmaceutical composition comprising 0.0001 to 0.5 parts by mass of a salt thereof.
(In the formula, R1 represents a hydroxyl group or a hydrogen atom.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005345368A JP2007106736A (en) | 2005-09-14 | 2005-11-30 | Pharmaceutical composition for parenteral injection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005266145 | 2005-09-14 | ||
| JP2005345368A JP2007106736A (en) | 2005-09-14 | 2005-11-30 | Pharmaceutical composition for parenteral injection |
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| JP2007106736A true JP2007106736A (en) | 2007-04-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2005345368A Pending JP2007106736A (en) | 2005-09-14 | 2005-11-30 | Pharmaceutical composition for parenteral injection |
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| Country | Link |
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| JP (1) | JP2007106736A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008090732A1 (en) * | 2007-01-26 | 2008-07-31 | Pola Pharma Inc. | Pharmaceutical composition |
| WO2008152764A1 (en) * | 2007-06-14 | 2008-12-18 | Pola Pharma Inc. | Pharmaceutical composition |
| JP2015091766A (en) * | 2013-09-30 | 2015-05-14 | 株式会社ポーラファルマ | Cancer therapy support system |
-
2005
- 2005-11-30 JP JP2005345368A patent/JP2007106736A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008090732A1 (en) * | 2007-01-26 | 2008-07-31 | Pola Pharma Inc. | Pharmaceutical composition |
| US8420687B2 (en) | 2007-01-26 | 2013-04-16 | Pola Pharma Inc. | Pharmaceutical composition |
| US8450356B2 (en) | 2007-01-26 | 2013-05-28 | Pola Pharma Inc. | Pharmaceutical composition |
| US8541459B2 (en) | 2007-01-26 | 2013-09-24 | Pola Pharma Inc. | Pharmaceutical composition |
| WO2008152764A1 (en) * | 2007-06-14 | 2008-12-18 | Pola Pharma Inc. | Pharmaceutical composition |
| CN101541324B (en) * | 2007-06-14 | 2011-06-15 | 株式会社宝丽制药 | Pharmaceutical composition |
| US8202898B1 (en) | 2007-06-14 | 2012-06-19 | Pola Pharma Inc. | Pharmaceutical composition |
| US8258165B2 (en) | 2007-06-14 | 2012-09-04 | Pola Pharma Inc. | Pharmaceutical composition |
| US8258166B2 (en) | 2007-06-14 | 2012-09-04 | Pola Pharma Inc. | Pharmaceutical composition |
| TWI406675B (en) * | 2007-06-14 | 2013-09-01 | Pola Pharma Inc | Pharmaceutical composition |
| JP5325779B2 (en) * | 2007-06-14 | 2013-10-23 | 株式会社ポーラファルマ | Pharmaceutical composition |
| JP2015091766A (en) * | 2013-09-30 | 2015-05-14 | 株式会社ポーラファルマ | Cancer therapy support system |
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