Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1998-02-27
1999-12-28
Harrison, Robert H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514817, 514818, 514970, A61K 31165, A61K 4712
Patent
active
060082569
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a composition for local anesthesia. More specifically, the present invention relates to a pharmaceutical composition for local anesthesia which has a duration of local anesthetic action suitable for minor dental operations such as tooth extraction and excellent storage stability.
BACKGROUND ART
For operations in the fields of oral surgery and dental treatment, in particular, for tooth extraction and other in dental treatment, anesthetics for local injection (agents for local anesthesia) containing lidocaine (2-diethylamino-N-(2,6-dimethyl-phenyl)acetamide) as an active ingredient have been used. For example, "Xylocaine.RTM. Cartridge for Dental Use" (Fujisawa Pharmaceutical Co., Ltd.) is clinically used. This agent for local anesthesia is a composition for topical administration which contains 20 mg of lidocaine hydrochloride and 0.0125 mg of epinephrine per 1 ml of parenteral solution. The agent is usually used in an amount of 0.3-1.8 ml to carry out infiltration anesthesia or block anesthesia (see, a package insert of the drug).
Agents for local anesthesia are generally formulated with a catecholamine such as epinephrine which has angiotonic effect on local capillary blood vessels to reduce blood flow. The effect of the catecholamine is to decrease bleeding in a filed of operation by lowering blood flow, and to reduce transmigration (diffusion) of an anesthetic agent being an active ingredient into blood and maintain high concentration of the anesthetic agent in the local tissue to achieve a prolonged local anesthetic effect (Collins, V. J., Principles of Anesthesiology, 2nd Ed., Lea and Febiger, Philadelphia, 1976; as a review about agents for dental local anesthesia, see, Dental Outlook, special edition, "Medical practice of tooth extraction," 4. Dental local anesthetics, pp.84-94, 1979).
However, when the aforementioned agent for local anesthesia is used for dental operations such as tooth extraction, which may be completed in a short period of time such as in several to 10 minutes, the local anesthetic effect tends to be maintained longer than required. In a consequence, oral and glossal benumbedness may remain several hours after the operation, and difficulties may arise in eating and drinking. In addition, a catecholamine such as epinephrine constricts blood vessels to decrease blood flow in a tissue and increases local oxygen consumption. For this reason, when vasoconstriction is maintained for longer hours than needed, tissue necrosis and delay of wound healing may possibly be caused. Accordingly, a development of an agent for local anesthesia has been desired which have a duration suitable for short-time operations such as tooth extraction.
A content ratio of a catecholamine added to a local anesthetic is generally recommended to be around 1/50,000-1/200,000 (g/ml) based on the volume (ml) of a local anesthetic agent (see, the above-described "Dental Outlook," special edition, "Medical practice of tooth extraction," p.92, right column), and dental lidocaine preparations which have been clinically used so far contain 1/80,000 (g/ml, 0.0125 mg/ml) of epinephrine. The inventor of the present invention conducted various studies to provide an agent for local anesthesia which has a duration suitable for short-time dental operations such as tooth extraction, and as a result, they found that a necessary and sufficient duration of local anesthetic action for a dental anesthesia can be achieved by adding about 1/200,000 of epinephrine (g/ml, 0.005 mg as a free base per ml).
Catecholamines such as epinephrine and norepinephrine are known to be unstable under neutral or alkaline conditions, and readily oxidized by an oxidizing agent such as oxygen, and colored to give a red or pale red to brown solution (Fukushima et al., "Incompatibilities of Parenteral Injections," published by Fuji Print Co., Ltd., Press Dept., 1982, Section of "Adrenal Hormone Preparations", pp.384-395). Grubstein et al. (Grubstein, B. and Milano, E., Drug Development and Industrial P
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Murakami, Craig S., MD., Buffered Local Anesthetics and Epinephrne Degradation, pp. 192-195.
Zur Prufung der Wirksamkeit von Stabilisatoren bei Epinephrin-Modellosungen, H. Wollmann, et al, Pharmazie 38 (1983), H.1, pp. 37-42.
Drug Development and Industrial Pharmacy, 18 (14), 1549-1566 Stablization of Epinephrine in a Local Anesthetic Injectable Solution Using Reduced Levels of Sodium Metabisulfite and EDTA, B. Grubstein et al.
Haraguchi Mitsuhiro
Ono Kazuhiro
Osada Takashi
Suzuki Yukio
Harrison Robert H.
Showa Yakuhin Kako Co. Ltd.
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