JPS5859913A - Diazepam enema - Google Patents
Diazepam enemaInfo
- Publication number
- JPS5859913A JPS5859913A JP15929081A JP15929081A JPS5859913A JP S5859913 A JPS5859913 A JP S5859913A JP 15929081 A JP15929081 A JP 15929081A JP 15929081 A JP15929081 A JP 15929081A JP S5859913 A JPS5859913 A JP S5859913A
- Authority
- JP
- Japan
- Prior art keywords
- diazepam
- enema
- polyethylene glycol
- solution
- propylene glycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940031382 diazepam enema Drugs 0.000 title claims abstract description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 51
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229960003529 diazepam Drugs 0.000 claims abstract description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 19
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 19
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 235000019441 ethanol Nutrition 0.000 claims abstract description 14
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 9
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 9
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000019445 benzyl alcohol Nutrition 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical class OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 claims abstract description 4
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical class O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims abstract description 4
- ZYVXHFWBYUDDBM-UHFFFAOYSA-N N-methylnicotinamide Chemical compound CNC(=O)C1=CC=CN=C1 ZYVXHFWBYUDDBM-UHFFFAOYSA-N 0.000 claims abstract description 3
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims abstract 2
- 229940074774 glycyrrhizinate Drugs 0.000 claims description 3
- 235000001968 nicotinic acid Nutrition 0.000 claims description 3
- 239000011664 nicotinic acid Substances 0.000 claims description 3
- 229960003512 nicotinic acid Drugs 0.000 claims 1
- 210000000664 rectum Anatomy 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 6
- 239000007864 aqueous solution Substances 0.000 abstract description 5
- 238000004090 dissolution Methods 0.000 abstract description 3
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 abstract description 2
- 208000005392 Spasm Diseases 0.000 abstract 1
- 238000001802 infusion Methods 0.000 abstract 1
- 239000002085 irritant Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 24
- 230000007794 irritation Effects 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 241000792859 Enema Species 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 229940095399 enema Drugs 0.000 description 9
- 239000007920 enema Substances 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 241000283977 Oryctolagus Species 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 210000000436 anus Anatomy 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 235000005152 nicotinamide Nutrition 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- KFLRWGSAMLBHBV-UHFFFAOYSA-M sodium;pyridine-3-carboxylate Chemical compound [Na+].[O-]C(=O)C1=CC=CN=C1 KFLRWGSAMLBHBV-UHFFFAOYSA-M 0.000 description 2
- 208000002091 Febrile Seizures Diseases 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022086 Injection site pain Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038669 Respiratory arrest Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 230000000774 hypoallergenic effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- -1 polyethylene chloride Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ZBCAZEFVTIBZJS-UHFFFAOYSA-M sodium;2-benzamidoacetate Chemical compound [Na+].[O-]C(=O)CNC(=O)C1=CC=CC=C1 ZBCAZEFVTIBZJS-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、吸収性、持続性が優ｎ１低刺激性のジアゼパ
ム注腸液に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a diazepam enema solution that is absorbable, long-lasting, and hypoallergenic.
ジアゼパム（７−クロロ−１，３−ジヒドロ−１−メチ
ル−５−フェニル−２ Ｈ − １． ４−ベンゾジア
ゼピン−２−オン）は従来から鎮静効果、筋肉弛緩効果
に加え、強い抗けいｎん効果を有するため、けい１ん時
の治療に用いらｆている。Diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1.4-benzodiazepine-2-one) has traditionally had sedative and muscle relaxing effects, as well as strong anticonvulsant effects. Because of its effectiveness, it is used to treat seizures.
また、ジアゼパム注射剤も知らｎているが、静脈内注射
の際に注射液が血管外に漏ｎた場合、強い刺激や炎症を
起すこと、注射時性々にして呼吸停止ないし抑制を起す
ことがあるため、注射は２分以上かけて慎重に行う必要
があること、あるいは注射時に疼痛があることなど、使
用に当って不都合が多かった。Also, diazepam injections are known, but if the injection solution leaks outside the blood vessel during intravenous injection, it can cause strong irritation and inflammation, and respiratory arrest or depression may occur during injection. Because of this, there were many inconveniences in its use, such as the need to carefully administer the injection over two minutes or pain during injection.
そこで、注射による副作用をのがれるため、直腸内投与
（腸性）が見直さｎつつある。しかし、ジアゼパムの注
射液をそのま＼直腸内に投与した場合、その吸収社極め
て速く、静脈内注射に近い効果が得ら九るとしても、肛
門、直腸部位に熱感と便意全件う強い刺激を与えるため
、注射用製剤は注腸用製剤としては適当でない。Therefore, in order to avoid the side effects of injection, rectal administration (intestinal administration) is being reconsidered. However, if diazepam injection is administered straight into the rectum, its absorption is extremely fast and the effect is similar to that of intravenous injection, but even if it does not produce a similar effect to intravenous injection, it may cause a feeling of heat in the anus and rectum and a strong urge to defecate. Because of their irritation, injectable preparations are not suitable as enema preparations.
本発明者等は、腸性後のジアゼパムの血中濃度が有効濃
度にまで速やかに達し、かつ有効濃度の持続時間が長く
、投与した際の肛門、直腸部位に対する刺激が弱く、腸
管に損傷を与えないジアゼパム注腸液の配合組成を研究
し、本発明をなした。The present inventors have discovered that the blood concentration of diazepam after intestinal administration quickly reaches an effective concentration, that the effective concentration lasts for a long time, that when administered, the irritation to the anus and rectum is weak, and that there is no damage to the intestinal tract. The present invention was achieved by researching the formulation composition of a diazepam enema solution that does not require administration of diazepam.
本発明の注腸液の組成は、ジアゼパムを、ωプロピレン
グリコールとポリエチレングリコールの混合物（混合比
２０：１０ないしｆ０二４０）ｎｏ−ｙ・Ｗ／ｖ％ 、
（ｂ）安息香酸とその塩、グリチルリチン酸塩、馬尿酸
塩、ニコチン酸塩、ニコチン酸アばド、Ｎ−メチルニコ
チン酸アミド及びイソニコチン酸アイドから選んだ一種
又は二種以上１〜ｌＷ／ｖｑｋ、（ａｌならびにエチル
アルコール及ヒ／又はベンジルアルコール０〜１０ ’
／ｖ−を含む水溶液に溶解してなる。The composition of the enema solution of the present invention is diazepam, a mixture of ω propylene glycol and polyethylene glycol (mixing ratio 20:10 to f0240) no-y W/v%,
(b) One or more selected from benzoic acid and its salts, glycyrrhizinate, hippurate, nicotinate, nicotinic acid amide, N-methylnicotinic acid amide, and isonicotinic acid ide 1 to 1 W/ vqk, (al and ethyl alcohol and/or benzyl alcohol 0-10'
/v- in an aqueous solution.
ジアゼパムは水に難治性であるが、プロピレングリコー
ル、ポリエチレングリコール、エチルアルコール、ベン
ジルアルコール等に溶解ｆることが知らｎ、注射液に用
いらｎている。こｎらの溶剤にジアゼパムを溶解した溶
液を家兎の直腸内に投与した場合の血中濃度の推移は図
に示すとおりである。プロピレングリコールφ）は血中
濃度の速やかな上昇という点では優ｎているが、有効血
中濃度の維持時間では劣つ喪。Although diazepam is refractory to water, it is known to be soluble in propylene glycol, polyethylene glycol, ethyl alcohol, benzyl alcohol, etc., and is used in injection solutions. The graph shows the change in blood concentration when a solution of diazepam dissolved in these solvents is administered into the rectum of a domestic rabbit. Although propylene glycol (φ) is superior in terms of rapid increase in blood concentration, it is inferior in terms of maintaining effective blood concentration.
またｓｏ１以上の高濃度では直腸管壁での脱水現象など
によシ粘膜の充血、剥離などの損傷が認めらｎた。ポリ
エチレングリコール（Ｃ）は血中濃度の上昇はプロピレ
ングリコールに劣るが、血中濃度の維持という点では勝
っており、−激性も弱かった。一方、ポリエチレングリ
コールにプロピレングリコール’ｅ６０：４０の割合で
配合した溶液ω）では、有効血中濃度に達するまでの時
間が早く、かつ有効血中濃度の維持時間が長かった。ま
た、この系に水を加えたポリエチレンクリコール：フロ
ピレンクリコール：水が４０：３０：３０の水溶液で社
直腸からの吸収性が優ｎ、直腸の刺激も弱く、蔓に改善
さｎることがわかった。なお、ポリエチレングリコール
としては分子量２（１０〜４０００ のものが好適に
用いらｎる。In addition, at high concentrations of SO1 or higher, damage such as hyperemia and peeling of the mucous membrane due to dehydration in the rectal wall was observed. Although polyethylene glycol (C) was inferior to propylene glycol in increasing blood concentration, it was superior in maintaining blood concentration and was less violent. On the other hand, in solution ω) containing polyethylene glycol and propylene glycol in a ratio of 60:40, it took a short time to reach the effective blood concentration, and the effective blood concentration was maintained for a long time. In addition, an aqueous solution of polyethylene glycol: fluoropylene glycol: water in the ratio of 40:30:30 with water added to this system has excellent absorption from the rectum, is less irritating to the rectum, and does not improve the appearance of tendrils. I understand. Note that polyethylene glycol having a molecular weight of 2 (10 to 4,000) is preferably used.
更に、ジアゼパムの吸収を阻害せず、腸管に対する損傷
等を増強することなしに、溶解度を高める物質を検索し
、溶解補助剤として、安息香酸とその塩、グリチルリチ
ン酸塩、馬尿酸塩。Furthermore, we searched for substances that increase the solubility of diazepam without inhibiting its absorption or increasing damage to the intestinal tract, and used benzoic acid and its salts, glycyrrhizinate, and hippurate as solubilizing agents.
ニコチン酸塩、ニコチン酸アミド、ｙ−メチルニコチン
酸アミド及びイソニコチン酸から選んだ１ｓ又は！穐以
上１に１〜１Ｖｖチ、好ましくは４〜ＩＷ／７％ｔ−加
えることによって、例えば低温で保存した場合の結晶析
出を防ぐことができた。こｎ以上の量では浸透圧の上昇
あるいは刺激の発生などの点で好ましくない。Is selected from nicotinic acid salt, nicotinamide, y-methylnicotinamide and isonicotinic acid or! By adding 1 to 1 Vv, preferably 4 to IW/7% t, to 1 or more, it was possible to prevent crystal precipitation when stored at a low temperature, for example. If the amount exceeds n, it is undesirable in terms of an increase in osmotic pressure or the occurrence of irritation.
上記溶解補助剤の内、安息香酸とその塩は注射剤におい
て知らｎているが、注腸液に用いた場合は若干の確腸刺
激性がある。しかし、他の溶解補助剤は本発明者等によ
ル見い出さｎ、Ｎ腸刺激性はなく、溶解補助効果も優ｎ
てお９、よシ有効であった。こｎら溶解補助剤の効果と
直腸刺激性を表に示す。Among the above-mentioned solubilizing agents, benzoic acid and its salts are known for injections, but when used in enema fluids, they have some intestinal irritation. However, other solubilizing agents have been found by the present inventors to be non-intestinal irritating and have excellent solubilizing effects.
9, it was very effective. The effects and rectal irritation of these solubilizing agents are shown in the table.
表の溶解量の試験は、分子量４００のポリエチレンクリ
コール３０ ｗ／ｖｆ６ 、 フロピレンゲリコール
２ ａ Ｗ／ｖチ、エチルアルコール６Ｗ／ｖチ及び各
溶解補助剤５ Ｗ／ｖ ％を含む水溶液中における、８
℃でのジアゼパムの溶解量を示す。The dissolution amount test in the table was conducted in an aqueous solution containing 30 w/vf of polyethylene glycol with a molecular weight of 400, 2 a w/v of fluoropylene gellicol, 6 w/v of ethyl alcohol, and 5 w/v% of each solubilizing agent. in, 8
The amount of diazepam dissolved in °C is shown.
また、直腸刺激性の試験は、上駅組成の溶液にジアゼパ
ムを０５Ｗ／、％溶解した注腸液を家兎の直腸にジアゼ
パム１ｏｖ４／動物を投与し、伊藤らの方法（東邦医会
誌２Ｔ、 ５２−７３．１９８０）により、ｉσ腸の肉
眼及び組織所見より、次の判定基準で行った。In addition, the rectal irritation test was conducted by administering diazepam 1 ov4/animal to the rectum of domestic rabbits with an enema solution containing 05 W/% diazepam dissolved in a solution with the composition of Kamieki, using the method of Ito et al. (Toho Medical Society Journal 2T, 52). -73.1980), the following judgment criteria were used based on the macroscopic and histological findings of the iσ intestine.
０：刺激を認めず、１：ごく軽微な刺激、２：軽度の刺
激、゛３：中等度の刺激、４ 強度の刺激
表 ジアゼパム溶液における溶解補助剤の効果及び直腸
刺激性
グリチルリチン酸ジカリウム ６．５０馬尿酸ナト
リウム ７．５０
ニコチン酸ナトリウム ６．５０ニコチン酸ア
ミド １．３ＯＮ−メチルニコチン酸アミ
ド ７．６ ０イソニコチン酸アずド
６５ ０９市販注射液：ジアゼバムαＳｖ
／ｙ％＊プロピレングリコール４・−、エチルアルコー
ル１・−１安息香酸ナトリウム及び安息香ＩＩ Ｓ ｖ
／／ｖ％、ベンジルアルコールＩｓ−を含む水溶液
なお、ジアゼパムの溶解性ｔａＩめる六め、必要ならば
、・〜１・＊／Ｖ−のエチルアルコール及び／又はベン
ジルアルコールが加えらｎる。こｎ以上の量では直腸部
位に対する刺激性が強くなるため好ましくない。0: No irritation, 1: Very slight irritation, 2: Mild irritation, 3: Moderate irritation, 4: Strong irritation table Effect of solubilizing agent in diazepam solution and rectal irritation dipotassium glycyrrhizinate 6. 50 Sodium hippurate 7.50 Sodium nicotinate 6.50 Nicotinic acid amide 1.3 ON-Methylnicotinic acid amide 7.6 0 Isonicotinic acid azdo
65 09 Commercially available injection: Diazebam αSv
/y%*Propylene glycol 4.-, ethyl alcohol 1.-1 Sodium benzoate and Benzoic II S v
//v % of benzyl alcohol Is−. Note that the solubility of diazepam is increased, and if necessary, .about.1·*/V− of ethyl alcohol and/or benzyl alcohol is added. If the amount exceeds n, the irritation to the rectal region becomes strong, which is not preferable.
以上のとおシ、本発明のジアゼパム注腸液は、ジアゼパ
ムｆ５■／ｄ以下量を充分に溶解きせることができ、吸
収性、持続性が優れ、直腸の刺激性が市販注射液を用い
た場合に比べて低いことがわかる。In light of the above, the diazepam enema solution of the present invention can sufficiently dissolve an amount of diazepam f5■/d or less, has excellent absorption and sustainability, and has less rectal irritation than a commercially available injection solution. It can be seen that it is relatively low.
本発明の注腸液は小児の熱性けいｎん、重積状態勢のけ
いｎん時の処置及び麻酔前、麻酔導入時、麻酔中、術後
等に、放入で１０〜２４）ダ／人、小児Ｔ〜１２才で１
０■／人、１〜６オでＳ■／人を肛門から注入して使用
さｎる。The enema solution of the present invention can be administered at a rate of 10 to 24 days per person for treatment of febrile convulsions in children, convulsions of status quorum status, and before anesthesia, during induction of anesthesia, during anesthesia, and after surgery. , 1 for children T to 12 years old
It is used by injecting S■/person from the anus at 0 ■/person and 1 to 6 degrees.
以下に本発明の実施例を示す。Examples of the present invention are shown below.
実施例 １
ジアゼパムｏ、 ｓ １２分子量４００のポリエチレン
クリコール３０９、ｊロビレングリコール３０．９及び
エチルアルコールＴｆ／の混合溶液に溶解し、安息香酸
ナトリウム４ｇ、安息香酸０．１ｇ及び水を加えて１０
０１とした。この溶液を２Ｍｌずつ注腸用容器に充填し
、ジアゼパム１０■含有製剤をする。Example 1 Diazepam o, s 12 was dissolved in a mixed solution of polyethylene glycol 309 with a molecular weight of 400, j robylene glycol 30.9 and ethyl alcohol Tf/, and 4 g of sodium benzoate, 0.1 g of benzoic acid and water were added. 10
It was set to 01. Fill 2 ml of this solution into an enema container to prepare a preparation containing 10 μl of diazepam.
実施例 ２
ジアゼパムｏ、 ｓ ｇ ２、分子１１５００のポリエ
チレンクリコール５ａＩＩ、プロピレンクリコール２Ｓ
ｇ及びエチルアルコール８ｇの混合溶液に溶解し、安息
香酸す） ＩＪウム５ｇ、安息香酸１１４Ｉ及び水を加
えてＩＨＩ ＪＩ７とした。この溶液を２１ずつ注腸用
容器に充填し、ジアゼパム１０■含有製剤とする。Example 2 Diazepam o, s g 2, polyethylene glycol 5aII of molecule 11500, propylene glycol 2S
The mixture was dissolved in a mixed solution of 8 g of benzoic acid and 8 g of ethyl alcohol, and 5 g of benzoic acid, 114 I of benzoic acid, and water were added to prepare IHI JI7. This solution is filled into 21 enema containers each to form a preparation containing 10 μl of diazepam.
実施例 ３
ジアゼパムｏ、 ｓ ｇ ＠、分子量３００のポリエチ
レンクリコールｓｏｙ、プロピレンゲＩＪ ：ｌ−＃１
ｓ９及Ｕエチルアルコール８ｇの混合溶液に溶解し、ニ
コチン酸ナトリウム５ｇ及び水を加えてＩＤＤｌｄとし
た。この溶液は１祠中ジアゼパムを５ダ含む。Example 3 Diazepam o, s g @, polyethylene glycol soy with a molecular weight of 300, propylene gel IJ: l-#1
It was dissolved in a mixed solution of 8 g of s9 and U ethyl alcohol, and 5 g of sodium nicotinate and water were added to prepare IDDld. This solution contains 5 Da of diazepam in 1 da.
実施例 ４
ジアゼパム１２５ｇ’ｔ、分子量４０００のポリエチレ
ンクリコール２７．５ｇ、プロピレンクリコール２１５
ＩＩ及びエチルアルコール１０ｊｉの混合溶液に溶解し
、ニコチン酸アミド６Ｉｉ及び水を加えて１００−とし
た。本則は１−中２．５■のシアーゼパムを含有する。Example 4 125 g't of diazepam, 27.5 g of polyethylene glycol with a molecular weight of 4000, 215 g of propylene glycol
It was dissolved in a mixed solution of II and 10ji of ethyl alcohol, and nicotinic acid amide 6Ii and water were added to make 100-. The main formula contains 1 to 2.5 parts of cyazepam.
実施例 ５
ジアゼパムＬＳ９ｆ、分子量４００のポリエチレンク９
＝ｔ−ルｓａｇ、プロピレングリコール３ａＩ及びエ
チルアルコール６ｇの混合溶液に溶解し、グリチルリチ
ン酸ジカリウム５９に少量の水に溶かして加え、更に水
を加えて１０ｇ１ ｄとした。この溶液を２１ずつ注腸
用容器に充填し、ジアゼパム１０ダ含有製剤とする。Example 5 Diazepam LS9f, polyethylene chloride 9 with a molecular weight of 400
=t-ru sag, propylene glycol 3aI, and 6 g of ethyl alcohol were dissolved in a mixed solution, and dipotassium glycyrrhizinate was dissolved in a small amount of water and added, and water was further added to make 10 g 1 d. This solution is filled into enema containers in batches of 21 to give a preparation containing 10 dazepam.
実施例 ６
ジアゼバム０．５９ｆ、分子量４００のポリエチレンク
リコール３０ｇ、プロピレングリコール３０ｇ及びエチ
ルアルコール７ｇの混合溶液に溶解し、瑯尿諧ナトリウ
ムＳ、！？及び水を加えて１００１１／とした。この溶
液２ｗｌずつを注腸用容器に充填し、ジアゼパム１０■
含有製剤とする。Example 6 0.59 f of diazebam, 30 g of polyethylene glycol with a molecular weight of 400, 30 g of propylene glycol, and 7 g of ethyl alcohol were dissolved in a mixed solution of 0.59 f of diazebam, and diazebum sodium S,! ? and water was added to make 10011/. Fill 2 wl of this solution into an enema container and add 10 ml of diazepam.
Containing formulation.
実施例 Ｔ
ジアゼパムｏ、 ｓ ＩＩｙ 、分子ｆ ４ｇ１０のポ
リエチレンクリコール２４９、プロピレングリコールｓ
ｓｐ、エチルアルコールＴｇ及びベンジルアルコール１
ｇの混合溶液に溶解し、Ｋ−メチルニコチン酸アずド５
ｇ及び水を加えて１００ Ｉｔ／とした。この溶液２１
１／ずつ管注勝用容器に充填し、シア上ハム１０Ｍ９含
有製剤とする。Example T diazepam o, s IIy, molecule f 4g10 polyethylene glycol 249, propylene glycol s
sp, ethyl alcohol Tg and benzyl alcohol 1
Dissolve in a mixed solution of K-methylnicotinic acid 5
g and water were added to make 100 It/. This solution 21
Pour 1/2 into a container for pouring into a tube to prepare a preparation containing Shea Joham 10M9.
４、図面ｏ簡単す１１２ａＡ
図はジアゼパムの０．５ Ｗ／ｖチ各種溶液を家兎の直
腸内に投与（１０■／動物）したときの血中濃度の推移
を示す。ムはポリエチレングリコール（分子量４０Ｇ
）＋プロピレングリコール＋水（４０：３０：３Ｇ）溶
液、ＢＦｉプロピレングリコール溶液、ｃｉｊポリエチ
レングリコール（分子量４００）溶液、ＤＦｉポリエチ
レングリコール（分子量４６０ ）＋プロピレングリコ
ール（１０：４０）溶液。4. Diazepam diagram 112aA The figure shows the change in blood concentration of diazepam when various solutions of 0.5 W/v were administered into the rectum of domestic rabbits (10 cm/animal). Polyethylene glycol (molecular weight 40G)
) + propylene glycol + water (40:30:3G) solution, BFi propylene glycol solution, cij polyethylene glycol (molecular weight 400) solution, DFi polyethylene glycol (molecular weight 460) + propylene glycol (10:40) solution.
特許出願人 和光堂株式会社 代理人弁理士 樫 出 庄 治Patent applicant: Wakodo Co., Ltd. Representative Patent Attorney Shoji Kashi
Claims (1)
レングリコールの混合物（混合比２０：＠Ｏないし＠ｏ
： ４０ ） ５ｏ−ｒｏｔ／ｙｉ（ｈｌ安息香酸と
その塩、グリチルリチン酸塩、馬尿酸塩、ニコチン酸塩
、ニコチン酸アはド、Ｎ−メ −チルニコチン酸アばド
及びイソニコチン酸アミドから選んだ一種又は二種以上
１〜８Ｗ／ｖチ、（ａ）ならびにエチルアルコール及び
／又はベンジルアルコール０ル１０ 解したジアゼパム注腸液。[Claims] Diazepam is prepared by mixing diazepam with a mixture of (trans)propylene glycol and polyethylene glycol (mixing ratio 20: @O to @o
: 40) 5o-rot/yi (hl selected from benzoic acid and its salts, glycyrrhizinate, hippurate, nicotinate, nicotinic acid, N-methylnicotinic acid amide, and isonicotinic acid amide) A diazepam enema solution containing one or more types of diazepam (a) and ethyl alcohol and/or benzyl alcohol at 1 to 8 W/v.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15929081A JPS5859913A (en) | 1981-10-06 | 1981-10-06 | Diazepam enema |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15929081A JPS5859913A (en) | 1981-10-06 | 1981-10-06 | Diazepam enema |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5859913A true JPS5859913A (en) | 1983-04-09 |
| JPS6321650B2 JPS6321650B2 (en) | 1988-05-09 |
Family
ID=15690558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15929081A Granted JPS5859913A (en) | 1981-10-06 | 1981-10-06 | Diazepam enema |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5859913A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2887149A1 (en) * | 2005-06-17 | 2006-12-22 | Galderma Sa | PROCESS FOR SOLUBILIZING THE METRONIDAZOLE |
| CN106214636A (en) * | 2016-09-18 | 2016-12-14 | 天津金耀药业有限公司 | A kind of diazepam injection pharmaceutical composition |
-
1981
- 1981-10-06 JP JP15929081A patent/JPS5859913A/en active Granted
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8859603B2 (en) | 2004-06-17 | 2014-10-14 | Galderma S.A. | Method for solubilizing metronidazole |
| FR2887149A1 (en) * | 2005-06-17 | 2006-12-22 | Galderma Sa | PROCESS FOR SOLUBILIZING THE METRONIDAZOLE |
| WO2006134279A3 (en) * | 2005-06-17 | 2007-02-22 | Galderma Sa | Method for solubilizing metronidazole |
| EP2204174A1 (en) * | 2005-06-17 | 2010-07-07 | Galderma S.A. | Metronidazole solubilisation process with niacinamide and two glycols, and the resulting solution |
| US7981916B2 (en) | 2005-06-17 | 2011-07-19 | Galderma S.A. | Solubilizing of metronidazole |
| CN106214636A (en) * | 2016-09-18 | 2016-12-14 | 天津金耀药业有限公司 | A kind of diazepam injection pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6321650B2 (en) | 1988-05-09 |
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