【発明の詳細な説明】[Detailed description of the invention]
本発明は、２−（２，６−ジクロロアニリノ）
フエニル酢酸（一般名：ジクロフエナツク）の塩
基性アミ酸塩を主成分とする坐剤に関する。
ジクロフエナツクのナトリウム塩は、臨床上価
値ある消炎作用、鎮痛作用を有し非ステロイド系
抗炎症薬としてリウマチ、関節炎、神経痛、筋肉
痛、腰痛などの治療に広く用いられている。本品
は水に難溶性であるために内服薬として経口的に
投与されるが、内服の場合胃液の強い酸性のため
ジクロフエナツクとなりこれが胃壁を刺激し胃障
害を生じている。このため腸溶錠その他の製剤上
の工夫がなされているが完全には胃腸障害を防止
するには至つていない。また、経口投与では吸収
が遅く作用発現が遅いといつた問題も存在してい
る。この様な問題点を解決する為、近年坐剤化が
特に消炎鎮痛解熱剤で盛んに行なわれている。し
かしながら、直腸の面積は胃腸に比較して小さ
く、投与による単位面積当りの薬物濃度はおのず
と高くなり粘膜への刺激性が大きな問題となる。
特に、消炎鎮痛解熱剤は胃腸障害からわかる様に
粘膜刺激が強く、恐らく直腸においても強いこと
が予測される。この為、直腸へ投与する場合、基
剤の選択等の方法により刺激をより少なくしよう
とする試みが行なわれているがおのずと限界があ
る。
本発明者らは、かかる問題点を解決すべく鋭意
研究を続けたところ、ジクロフエナツクの塩基性
アミノ酸塩を直腸投与製剤として投与することに
より、直腸から速やかに吸収され原薬物坐剤より
同等もしくは高い血中濃度が得られると同時に粘
膜への影響が極度に低下することを見い出した。
塩基性アミノ酸としては、１型、d1型のリジ
ン、アルギニン、ヒスチジンである。ジクロフエ
ナツクの塩基性アミノ酸塩は、ジクロフエナツク
と塩基性アミノ酸とがモル比で１：１に結合して
おり次の一般式で示される。
The present invention provides 2-(2,6-dichloroanilino)
This invention relates to a suppository whose main ingredient is a basic amic acid salt of phenylacetic acid (generic name: diclofenac). The sodium salt of diclofenac has clinically valuable anti-inflammatory and analgesic effects and is widely used as a non-steroidal anti-inflammatory drug in the treatment of rheumatism, arthritis, neuralgia, muscle pain, low back pain, etc. This product is sparingly soluble in water, so it is administered orally as an oral medication, but when taken internally, the strongly acidic gastric juice turns into diclofenac, which irritates the stomach wall and causes gastric disorders. For this reason, enteric-coated tablets and other formulations have been devised, but they have not completely prevented gastrointestinal disorders. In addition, oral administration has the problem of slow absorption and slow onset of action. In order to solve these problems, suppositories have recently been widely used, especially for anti-inflammatory, analgesic, and antipyretic agents. However, the area of the rectum is smaller than that of the stomach and intestines, and the drug concentration per unit area upon administration is naturally high, causing irritation to the mucous membranes, which poses a major problem.
In particular, anti-inflammatory, analgesic, and antipyretic agents are expected to cause strong mucosal irritation, as evidenced by gastrointestinal disorders, and are likely to be strong in the rectum as well. For this reason, when administering to the rectum, attempts have been made to reduce irritation through methods such as selecting a base, but these naturally have their limitations. The present inventors continued intensive research to solve these problems, and found that by administering the basic amino acid salt of diclofenac as a rectal preparation, it was rapidly absorbed from the rectum and was equivalent to or higher than the original drug suppository. It was found that while the blood concentration was obtained, the effect on mucous membranes was extremely reduced. Basic amino acids include type 1 and d1 lysine, arginine, and histidine. The basic amino acid salt of diclofenac has diclofenac and a basic amino acid combined in a molar ratio of 1:1 and is represented by the following general formula.
〔薬理実験例〕[Example of pharmacological experiment]
１ 直腸吸収効果
24時間絶食したビーグル犬（体重約10Kg）の直
腸へ肛門より５cmの探部へ坐剤を挿入した。投与
後、経時的に頚静脈より1.5ml採血し常法によつ
て得た血漿中の各試料の濃度を高速液体クロマト
グラフ法によつて測定した。
投与量は0.0032mM／Kg、0.0064mM／Kg、
0.016mM／Kg、0.032mM／Kgで各試料の坐剤は
次の様にして調製した。
粉砕し100メツシユの篩を通過した試料0.5ｇ及
びウイテプソールH15 4.5ｇを正確に秤量し、こ
れを42〜45℃の油溶上で加熱溶融し充分混合す
る。混合後、約１ｇづつ坐剤型に分注し、20KHz
の超音波洗浄器を用いて１分間超音波撹拌を行な
いながら固化させる。固化後、密封し５℃の低温
室に保存し投与に必要な量だけ切り取つて使用し
た。血漿中の各試料の最高濃度を表１に示す。
1. Effect of rectal absorption A suppository was inserted into the rectum of a beagle dog (weighing approximately 10 kg) that had been fasted for 24 hours at a probing site 5 cm from the anus. After administration, 1.5 ml of blood was collected from the jugular vein over time, and the concentration of each sample in the plasma obtained by a conventional method was measured by high performance liquid chromatography. Dosage is 0.0032mM/Kg, 0.0064mM/Kg,
Suppositories of each sample at 0.016mM/Kg and 0.032mM/Kg were prepared as follows. Accurately weigh 0.5 g of the sample that has been crushed and passed through a 100-mesh sieve and 4.5 g of Uitepsol H15, melt them by heating on an oil solution at 42 to 45°C, and mix thoroughly. After mixing, dispense approximately 1g each into suppositories, and mix at 20KHz.
Solidify while performing ultrasonic stirring for 1 minute using an ultrasonic cleaner. After solidification, it was sealed and stored in a cold room at 5°C, and the amount required for administration was cut out and used. The maximum concentration of each sample in plasma is shown in Table 1.
【表】
２ ABPCによる直腸粘膜への影響
直腸から吸収されにくいアミノベンジルペニシ
リンナトリウム（ABPC）、セフアロチンナトリ
ウム等が消炎鎮痛剤の存在下で吸収されることが
最近認められた。（日本薬学会近畿支部例会1979
年）この吸収作用は粘膜への刺激によつていると
説明されている。従つて、これら難吸収性物質の
吸収が減弱するか全く無くなれば、当然、直腸刺
激が減少したことを証明したことになる。そこ
で、ABPCを用いて直腸粘膜への影響を調べた。
24時間絶食した雄性家兎（体重2.5〜3.0Kg）の
直腸に各試料とABPCを含有する坐剤を肛門より
３cmの探部に挿入した。投与量は試料を0.0024、
0.0048、0.00705及び0.0096mM／Kg、ABPCを15
mg／Kgとした。ABPCの血中濃度の測定は経時的
に耳静脈より0.5ml採血し常法によつて得た血漿
を用い、micrococuss letewus（ミクロコツカス
ルテウス）を用いるミクロバイオアツセイ法に
よつて行なつた。また、坐剤は次の様にして調製
した。
粉砕し100メツシユの篩を通過した試料を
0.016mM及びABPC 0.1ｇを正確に秤量し、これ
にウイテプソールH15を加えて全量を１ｇとし42
〜45℃の油溶上で加熱溶融し充分混合する。混合
後、坐剤型に注入し20KHzの超音波洗浄器を用い
て１分間超音波撹拌しながら固化させる。また、
同様にして試料の濃度が0.032mM、0.047mM、
0.063mMである坐剤を調製する。固化後、密封
し５℃の低温室で保存し投与に必要な量だけ切り
取つて使用した。結果を表２に示す。[Table] 2. Effects of ABPC on the rectal mucosa It has recently been found that aminobenzylpenicillin sodium (ABPC), cephalothin sodium, etc., which are difficult to absorb from the rectum, are absorbed in the presence of anti-inflammatory analgesics. (Pharmaceutical Society of Japan Kinki Branch Regular Meeting 1979
) This absorption effect is explained to be due to stimulation of mucous membranes. Therefore, if the absorption of these poorly absorbable substances is reduced or completely eliminated, this would naturally prove that rectal irritation has been reduced. Therefore, we investigated the effect on the rectal mucosa using ABPC. A suppository containing each sample and ABPC was inserted into the rectum of a male rabbit (weight 2.5 to 3.0 kg) that had been fasted for 24 hours through a probe 3 cm from the anus. The dose is 0.0024 for the sample,
0.0048, 0.00705 and 0.0096mM/Kg, ABPC 15
mg/Kg. The blood concentration of ABPC was measured by a microbioassay method using micrococus letewus, using plasma obtained by collecting 0.5 ml of blood from the ear vein over time and using a conventional method. Further, suppositories were prepared as follows. The sample that has been crushed and passed through a 100 mesh sieve is
Accurately weigh 0.016mM and 0.1g of ABPC, add Witepsol H15 to make the total amount 1g42
Heat and melt on an oil solution at ~45°C and mix thoroughly. After mixing, the mixture is injected into a suppository mold and solidified with ultrasonic stirring for 1 minute using a 20KHz ultrasonic cleaner. Also,
Similarly, the concentration of the sample was 0.032mM, 0.047mM,
Prepare suppositories that are 0.063mM. After solidification, it was sealed and stored in a cold room at 5°C, and the amount required for administration was cut out and used. The results are shown in Table 2.
【表】
本発明に係るジクロフエナツクの塩基性アミノ
酸塩を坐剤として製剤化する場合、これらの塩を
１坐剤当り30〜120mg含有することが必要である。
坐剤基剤は、カカオ脂、ウイテプソール
類、ポ
リエチレングリコール類、流動パラフイン、ワセ
リン等が用いられ、必要に応じて一般に知られて
いる界面活性剤、着色剤、安定剤を用いることも
できる。また、本坐剤で用いられる剤型として
は、常温で固型、体温で溶融する肛門坐剤、液状
の基剤に分散させた軟膏状あるいはかん腸液状の
もの、例えば直腸投与ソフトカプセル、直腸投与
注入器等を用いる剤型等が用いられる。
実施例 １
ジクロフエナツク１−リジン塩をよく粉砕し、
100メツシユの篩を通過したもの100mgにウイテプ
ソール
H15 ２ｇを加えて42〜45℃において均
一に溶融混合し常法に従つて坐剤を成型しジクロ
フエナツク１−リジン塩の坐剤を得た。
実施例 ２
製剤例１と同様にしてジクロフエナツク１−ア
ルギニン塩（１坐剤中100mg含有）及びジクロフ
エナツク１−ヒスチジン塩（１坐剤中100mg含有）
の坐剤を得た。[Table] When the basic amino acid salts of diclofenac according to the present invention are formulated as suppositories, it is necessary to contain 30 to 120 mg of these salts per suppository.
As the suppository base, cacao butter, uitepsols, polyethylene glycols, liquid paraffin, vaseline, etc. are used, and if necessary, commonly known surfactants, colorants, and stabilizers can also be used. In addition, the dosage forms used for this suppository include rectal suppositories that are solid at room temperature and melt at body temperature, ointment-like or enema liquid dispersed in a liquid base, such as soft capsules for rectal administration, and injection for rectal administration. A dosage form using a container etc. is used. Example 1 Diclofenuc 1-lysine salt was thoroughly ground,
2 g of Witepsol H15 was added to 100 mg of the product that passed through a 100-mesh sieve, and the mixture was melted and mixed uniformly at 42 to 45°C, and a suppository was molded according to a conventional method to obtain a suppository of diclofenac 1-lysine salt. Example 2 Diclofenuc 1-arginine salt (containing 100 mg in 1 suppository) and diclofenac 1-histidine salt (containing 100 mg in 1 suppository) were prepared in the same manner as in Formulation Example 1.
of suppositories were obtained.