JPH05503704A - Use of local anesthetics in the manufacture of pharmaceutical preparations for iontophoresis - Google Patents
Use of local anesthetics in the manufacture of pharmaceutical preparations for iontophoresisInfo
- Publication number
- JPH05503704A JPH05503704A JP3503925A JP50392591A JPH05503704A JP H05503704 A JPH05503704 A JP H05503704A JP 3503925 A JP3503925 A JP 3503925A JP 50392591 A JP50392591 A JP 50392591A JP H05503704 A JPH05503704 A JP H05503704A
- Authority
- JP
- Japan
- Prior art keywords
- iontophoresis
- pharmaceutical preparations
- local anesthetics
- robivacaine
- manufacture
- 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.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 イオン導入用医薬製剤の製造における 局所麻酔剤の使用 発明の分野 本発明は、イオン導入（ｉｏｎｔｏｐｈｏｒｅｓｉｓ）用医薬製剤の製造の際の ロビバカイン（ｒｏｐｉｖａｃａｉｎｅ）の製薬上許容される塩の使用に関する 。[Detailed description of the invention] In the production of pharmaceutical preparations for iontophoresis Use of local anesthetics field of invention The present invention provides a method for producing pharmaceutical preparations for iontophoresis. Concerning the use of pharmaceutically acceptable salts of ropivacaine .
発明の背景 局所麻酔剤の普通の使い方は、末梢神経におけるインパルスの発生及び伝導を抑 制するために組織の表面に塗布するか、又は組織若しくは血管床中に注射するこ とである。局所麻酔剤は神経をブロックすることにより、痛感を減少させるため に使用される。痛みからの解放は、外科手術における局所麻酔のための使用によ り、又は種々の疾患における痛みの低下のため使用されるときに得られる。この 効果は局所麻酔剤の単回施用により、又は長時間の痛みの軽減を必要とするとき には数回の施用により得られている。Background of the invention The common use of local anesthetics is to inhibit the generation and conduction of impulses in peripheral nerves. It can be applied to the surface of tissues or injected into tissues or vascular beds to control That is. Local anesthetics reduce the sensation of pain by blocking nerves. used for. Relief from pain comes from its use as a local anesthetic in surgical procedures. It is obtained when it is used for pain relief or for the reduction of pain in various diseases. this Effectiveness can be achieved by a single application of local anesthetic or when long-term pain relief is required. has been obtained by several applications.
近年新しい局所麻酔剤の施用法が開発された。これはイオン導入法と称される。New local anesthetic application methods have been developed in recent years. This is called iontophoresis.
そのとき電流によって無疵の組織、例えばヒトの皮膚中にイオン化された物質が 導入される。装置はイオン形態の薬を含有する１つの貯留器及び貯留器の上に１ つと遠位の皮膚の局所に１つとの２つの電極よりなる。At that time, the electric current releases ionized substances into intact tissue, such as human skin. be introduced. The device contains one reservoir containing the drug in ionic form and one reservoir above the reservoir. It consists of two electrodes, one locally on the skin and one distally.
従来の技術 イオン導入法は、例えばＧａｎｇａｒｏｓａ Ｌｏｕｉｓ Ｐ によりＭｅｔｈ ａｎｄ Ｆｉｎｄ Ｅｘｐｔ、 Ｃ１１ｎ、 Ｐｈａｒ＋＋ａｃｏ１．３（２ ）、８９〜３４頁（１９８］）に、又Ｔｙ１．ｅ Ｐ、により Ｐｈａｒｍａｃ ｅｕｔｉｃａｌ Ｒｅ−５ｅａｒｃｈ ３巻、６号、１９８６に記載されている 。Conventional technology The iontophoresis method is, for example, a method using Meth by Gangarosa Louis P. and Find Expt, C11n, Phar++aco1.3(2 ), pp. 89-34 (198]), and Ty1. eP, by Pharmac Described in eutical Re-5earch Volume 3, No. 6, 1986 .
局所麻酔剤ロピバカインは、例えば１０８５１００５９９に記載されている。The local anesthetic ropivacaine is described, for example, in 1085100599.
発明の要点 本発明によれば驚（べきことに、塩酸塩の形態の局所麻酔剤ロビバカインはイオ ン導入の場合特に有用であることが見出された。以前の局所麻酔剤、例えばリド カイン及びブビバカインはエピネフリンと共に使用されている。エピネフリンは 有意な刺激なしに以前から使用されている局所麻酔剤が皮膚に浸透することを可 能にするために必要である。上記の局所麻酔剤はそれ自身が血管収縮効果を有し ているので、エピネフリンとの組み合わせを必要としない。局所麻酔剤の塩酸溶 液ヘエピネフリンを添加することは貯蔵安定性を不十分にするので、このことは 極めて重要である。Key points of the invention According to the present invention, surprisingly, the local anesthetic robivacaine in the form of its hydrochloride is It has been found to be particularly useful when introducing Previous local anesthetics, e.g. lido Caine and buvivacaine have been used with epinephrine. Epinephrine is Allows previously used local anesthetics to penetrate the skin without significant irritation. It is necessary to enable the The local anesthetics mentioned above have vasoconstrictive effects themselves. does not require combination with epinephrine. Hydrochloric acid solution of local anesthetic This is because adding epinephrine to liquid hair makes storage stability insufficient. extremely important.
本発明に従って使用される局所麻酔化合物は、製薬上許容される塩の形態である 。ロピバカイン塩酸塩を使用することが特に好ましい。The local anesthetic compound used according to the invention is in the form of a pharmaceutically acceptable salt. . Particular preference is given to using ropivacaine hydrochloride.
この局所麻酔剤は、ゼリー又は溶液中に配合される。This local anesthetic is formulated into a jelly or solution.
この局所麻酔組成物は、０．２５〜１０重量％、好ましくは０．５〜２重量％の 局所麻酔化合物を含有する。The local anesthetic composition contains 0.25-10% by weight, preferably 0.5-2% by weight. Contains local anesthetic compounds.
医薬製剤 ゼリー ０，５％ ロビバカイン塩酸塩−水物 ５．３ｈ９ヒドロキシプロピルメチル セルロース４０００ｃｐｓ ２４．５７！９注射用水 添加して１０００／に ロビバカイン塩酸塩−水物とヒドロキシプロピルメチルセルロースとを注射用水 に溶解する。水で容量を調整して１．００Ｑｌとする。得られた溶液をオートク レーブ処理ロビバカイン塩酸塩−水物 ８．５ＪＺ９ヒドロキシプロピルメチル セルロース４０００ｃｐｓ ９．８ｋｇ注射用水 添加して４００１に ロビバカイン塩酸塩−水物とヒドロキシプロピルメチルセルロースとを注射用水 に溶解する。水で容量を調整して４００１とする。得られた溶液をオートクレー ブ処理する。pharmaceutical formulations Jelly 0.5% Robivacaine hydrochloride-hydrate 5.3h9 hydroxypropylmethyl Cellulose 4000cps 24.57!9 Water for injection added to 1000/ Robivacaine hydrochloride-water and hydroxypropyl methylcellulose in water for injection dissolve in Adjust the volume with water to 1.00Ql. The resulting solution was placed in an auto-cooker. Reve-treated Robivacaine Hydrochloride-Aqueous 8.5JZ9 Hydroxypropylmethyl Add cellulose 4000cps 9.8kg water for injection to 4001 Robivacaine hydrochloride-water and hydroxypropyl methylcellulose in water for injection dissolve in Adjust the volume with water to 4001. The resulting solution was placed in an autoclave. process.
実施例 ３〜５ 溶液 ５ 富９／ １１． １０１１９／ ｍｌ、２０ｍｇ／ 菖１０ビバカイ ン塩酸塩−水物 ０．５３ｋｑ １．０６Ｊ１９ ２゜１．：ｌ＋ｇ水酸化ナト リウム ２Ｍ ｐＨ５，０〜６．０に 精 製 水 添加して １００Ｊ１９ １００＆９１００＆ｗにロピバカインを 水に溶解する。水酸化ナトリウムを添加してｐＨ５，０〜１３．０とする。得ら れた溶液をオートクレーブ処理する。Examples 3 to 5 Solution 5 Rich 9/11. 10119/ml, 20mg/Iris 10 Vivakai Hydrochloride-hydrate 0.53kq 1.06J19 2゜1. :l+g sodium hydroxide Rium 2M pH 5.0 to 6.0 Add purified water and add ropivacaine to 100J19 100&9100&w Soluble in water. Sodium hydroxide is added to adjust the pH to 5.0-13.0. Obtained Autoclave the solution.
現在知られている最良の本発明の実施態様は、実施例４による製剤を使用するこ とである。The best currently known embodiment of the invention is to use the formulation according to Example 4. That is.
生物試験 パイロットスタディにおいて、皮膚内の針の挿入はレーザードツプラーフローメ トリーにより測定して血流の著しい増加を引き起こすことが観察された。即ち、 針の挿入及び注射された薬の両方の正味の循環効果の評価の際、針の挿入自体の 効果が考慮される場合には陵内注射は皮膚の血流に対する、即ち血流の増加だけ ではなく減少も示す薬の効果を明らかにする適当な試験法であることになろう。biological test In a pilot study, intradermal needle insertion was performed using a laser Doppler flow meter. was observed to cause a significant increase in blood flow as measured by the tree. That is, In assessing the net circulatory effect of both the needle insertion and the injected drug, the needle insertion itself If the effect is considered, intracranial injections only affect blood flow to the skin, i.e. increase blood flow. This would be an appropriate test method to clarify the effect of a drug that also shows a decrease in blood pressure.
臨床使用されている局所麻酔剤の陵内注射によって引き起こされる皮膚血流の変 化を評価するため次の試験を使用した。試験された薬はリドカイン、ブビバカイ ン及び新持続性局所麻酔剤ロピバカインであった。Changes in skin blood flow caused by intracranial injection of local anesthetics used clinically. The following test was used to evaluate the The drugs tested were lidocaine, bubivacay and a new long-acting local anesthetic, ropivacaine.
材料及び方法 健康な若い男性のボランティアについて研究を実施した。試験群（ｎ＝１．２、 平均年齢３１．７オ、範囲２５〜４５）においては、針の挿入、食塩水の注射、 リドカイン、ブピバカイン及び新局所麻酔剤ロピバヵインの注射の皮膚血流に対 する効果を検討した。皮膚の未処置の区域を対照として用いた。Materials and methods A study was conducted on healthy young male volunteers. Test group (n=1.2, Mean age 31.7 years, range 25-45), needle insertion, saline injection, Effects on skin blood flow of injections of lidocaine, bupivacaine, and the new local anesthetic ropivacaine We examined the effects of An untreated area of skin was used as a control.
６人のボランティアがこの試験に関与した。無作為パターンに従い種々の試験サ イトにおいて次の操作を実施した。Six volunteers were involved in this study. Various test samples according to random pattern The following operations were performed at the site.
この試験においては、未処置の対照区域において、針の挿入の後及び次のとおり 局所麻酔剤の注射（針を通して０．７ｍＩりの後測定：リドカイン１ｍｇ、ブビ バヵイン０．２５膳（及び０．７５＊ｑ、ロビバヵインｏ、２５肩９及び０．７ ５票９゜溶液をコード化して異なった溶液の注射について二重盲検を可能にした 。ｐｎは食塩６．０１ リドカイン６．７、そしてブピバカイン及びロビバヵイ ンの溶液は全て５．５であった。陵内注射は全て同一の人によって行われた。原 曲流値をめて後、皮肉への針の挿入又は注射を正確に２分間前して行った。In this study, in an untreated control area, after needle insertion and injection of local anesthetic (measured after 0.7 mI through the needle: lidocaine 1 mg, bubi Vacaine 0.25 servings (and 0.75 * q, lobivacaine o, 25 shoulders 9 and 0.7 The 5-vote 9° solution was coded to allow double-blind testing of injections of different solutions. . pn is salt 6.01, lidocaine 6.7, and bupivacaine and rovivacaine. All solutions were 5.5. All intramuscular injections were performed by the same person. original After taking the tortuosity value, insertion of the needle or injection into the skin was performed exactly 2 minutes beforehand.
針の挿入又は液の注射後のその循環効果を明らかにするための測定は、１つのサ イトにおいて３０秒以内に開始した。Measurements to reveal its circulatory effect after insertion of a needle or injection of a liquid can be carried out in one sample. It started within 30 seconds at the site.
第一のサイトにおいて第１の注射の２０分後に記録を開始した。２分後記録用プ ローブを次のサイトに移動させた、等々。このようにして最初の２つの組におい て２０．４０及び６０分に各サイトにおいて記録を取った。第三の組においては 針の挿入又は注射の９０分後にも記録を取った。Recordings began 20 minutes after the first injection at the first site. 2 minutes later Moved the robe to the next site, etc. In this way, the first two sets of Recordings were taken at each site at 20.40 and 60 minutes. In the third set Recordings were also taken 90 minutes after needle insertion or injection.
未処置の区域を対照として用いた。Untreated areas were used as controls.
上述した陵内試験操作をブピバカイン及びロビバカインに適用したとき・ブ１′ ′カイト０・７５“９の注射１まパノドカイン１菖９の後に見られる増加と同様 であるが、それより持続性の血流の著しい増加を生じた。ブピバカイン０、２５ １１９の注射は、食塩水の注射後と同様の皮膚血流の比較的小さい増加を示した 。この知見は低濃度に比して高濃度の局所麻酔剤の方が血流の増大が著しいとい う以前の研究と一致する。しかし、ロビバカインの注射は食塩水に比して血流の 減少を引き起こし、０．２５Ｎ９を注射した時最も著しく、この新しい局所麻酔 薬の独特の効果を示した。When the above-described in-house test procedure was applied to bupivacaine and lobivacaine, bu1' Similar to the increase seen after injections of Kite 0.75"9 to Panodocaine 1 Iris 9 However, it produced a significant and more sustained increase in blood flow. Bupivacaine 0, 25 119 injections showed a relatively small increase in skin blood flow similar to that after saline injections. . This finding suggests that high-concentration local anesthetics cause a more significant increase in blood flow than low-concentration local anesthetics. This is consistent with previous research. However, robivacaine injections reduce blood flow compared to saline. This new local anesthesia caused a decrease, most markedly when injected with 0.25N9. It showed the unique effects of the drug.
結論 ロピバカインの独特の効果から、該化合物がイオン導入の場合特に有用であると いう結論を引き出すことができる。その血流の低下のために、ロビバカインはエ ピネフリンを添加せずに使用することができる。エピネフリンは局所麻酔組成物 の貯蔵安定性を低下させる。conclusion The unique effects of ropivacaine make the compound particularly useful in iontophoresis. It is possible to draw the following conclusion. Because of its reduced blood flow, robivacaine Can be used without the addition of pinephrine. Epinephrine is a local anesthetic composition Decreases the storage stability of
要 約 書 イオン導入用の医薬製剤の製造のためのロピバヵインの製薬上許容される塩の使 用。Summary book Use of pharmaceutically acceptable salts of ropivacaine for the manufacture of pharmaceutical preparations for iontophoresis for.
国際調査報告 国際調査報告international search report international search report
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9000288A SE9000288D0 (en) | 1990-01-26 | 1990-01-26 | NEW USE |
| SE9000288-2 | 1990-01-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05503704A true JPH05503704A (en) | 1993-06-17 |
Family
ID=20378368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3503925A Pending JPH05503704A (en) | 1990-01-26 | 1991-01-24 | Use of local anesthetics in the manufacture of pharmaceutical preparations for iontophoresis |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0597833A1 (en) |
| JP (1) | JPH05503704A (en) |
| KR (1) | KR927003530A (en) |
| AU (1) | AU650002B2 (en) |
| CA (1) | CA2073028A1 (en) |
| HU (1) | HU210322B (en) |
| SE (1) | SE9000288D0 (en) |
| WO (1) | WO1991011182A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6295469B1 (en) | 1997-11-14 | 2001-09-25 | Alza Corporation | Formulation for electrically assisted delivery of lidocaine and epinephrine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE40994T1 (en) * | 1983-08-01 | 1989-03-15 | Astra Laekemedel Ab | L-N-N-PROPYLPIPECOLIC-2,6-XYLIDIDE AND ITS PRODUCTION. |
-
1990
- 1990-01-26 SE SE9000288A patent/SE9000288D0/en unknown
-
1991
- 1991-01-24 WO PCT/SE1991/000053 patent/WO1991011182A1/en not_active Application Discontinuation
- 1991-01-24 AU AU72312/91A patent/AU650002B2/en not_active Ceased
- 1991-01-24 KR KR1019920701761A patent/KR927003530A/en not_active Application Discontinuation
- 1991-01-24 HU HU9202444A patent/HU210322B/en not_active IP Right Cessation
- 1991-01-24 JP JP3503925A patent/JPH05503704A/en active Pending
- 1991-01-24 CA CA002073028A patent/CA2073028A1/en not_active Abandoned
- 1991-01-24 EP EP91903251A patent/EP0597833A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP0597833A1 (en) | 1994-05-25 |
| HU9202444D0 (en) | 1992-10-28 |
| AU650002B2 (en) | 1994-06-09 |
| CA2073028A1 (en) | 1991-07-27 |
| HU210322B (en) | 1995-03-28 |
| WO1991011182A1 (en) | 1991-08-08 |
| AU7231291A (en) | 1991-08-21 |
| SE9000288D0 (en) | 1990-01-26 |
| HUT65098A (en) | 1994-04-28 |
| KR927003530A (en) | 1992-12-18 |
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