JP2005154367A - Analgesic agent for neuropathic pain containing propafenone - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an analgesic agent extremely effective for suppressing neuropathic pain and having little side action. <P>SOLUTION: This analgesic agent for the neuropathic pain contains propafenone or its pharmaceutically permissible salt as an active component. This invention further discloses an analgesic agent for neuropathic pain containing propafenone hydrochloride as an active component. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an analgesic for alleviating pain due to neuropathic pain comprising propafenone and a pharmaceutically acceptable salt thereof as an active ingredient.

Neuropathic pain is refractory pain that results from a primary disorder or malfunction of the peripheral or central nervous system. Neuropathic pain is caused by neuropathy caused by trauma, infection, cancer, ischemia, diabetes, and other metabolic disorders, but the mechanism of its development is unclear, and is generally an abnormal persistent sensory nerve. It is thought to be caused by ignition. The main symptoms of neuropathic pain include persistent pain such as tightening and burning, as well as intermittent and seizure intense pain, with features such as hypoperception, hypersensitivity, and allodynia.
Specific diseases of neuropathic pain include trigeminal neuralgia, postherpetic neuralgia, posttraumatic peripheral nerve injury pain, diabetic neuropathy, post-brachial plexus withdrawal pain, phantom limb pain, and spinal disease In addition to pain caused by trauma, multiple sclerosis, syringomyelia, spinal cord tumors, brain tumors, cancer pain in which the analgesic effect of narcotic analgesics such as morphine is insufficient.
Treatment (improvement) refers to the effect of suppressing neuropathic pain by administering a drug after the nerve has been injured, and returning pain by returning the abnormal pain threshold to near normal values. Says to exert a calming or disappearing effect.

As a treatment method for such diseases, there is a nerve block therapy using a local anesthetic, but there is a drawback in that it is almost ineffective in a case that lasts for a long time, and the treatment itself takes a long time. Various analgesics have also been tried, but there are still few effective analgesics. Furthermore, it is known that neuropathic pain is less effective for analgesics, particularly narcotic analgesics, which are effective for normal nociceptive pain. For example, morphine has a strong analgesic action against nociceptive pain, but it has been reported that it has little effect on neuropathic pain (Non-patent Document 1).
The Lancet 353, 1959-1966, 1999

  An object of the present invention is to provide an analgesic that is extremely effective in suppressing neuropathic pain and has few side effects.

As a result of intensive studies to solve the above problems, the present inventors have unexpectedly found that propafenone, which is originally used as an antiarrhythmic drug, is surprisingly extremely effective in suppressing neuropathic pain. The headline and the present invention were completed.
That is, the present invention provides an analgesic for neuropathic pain comprising propafenone and a pharmaceutically acceptable salt thereof as an active ingredient.

  The neuropathic pain analgesic agent containing the propaphenone of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient exhibits an excellent analgesic action against neuropathic pain.

で表されるプロパフェノンの塩酸塩であり、その作用機序としてはNa⁺チャネルの活動電位最大脱分極速度の抑制と考えられており、Vaughan Williams 分類の第Ｉｃ群に属し、頻脈性不整脈治療剤として用いられている。しかし、プロパフェノンまたはその塩が、神経因性疼痛に対して優れた鎮痛効果を有することは今まで全く知られていなかった。
プロパフェノンは、頻脈性不整脈治療剤として、内服薬として市販されており、また副作用出現率は抗不整脈剤の中では低くこれらを本発明の鎮痛剤として有効に用いることができる。 Propafenone hydrochloride used as a representative example of the active ingredient of the present invention has the following formula:

Propaphenone hydrochloride represented by the formula, and its mechanism of action is thought to be the suppression of the action potential maximum depolarization rate of the Na ⁺ channel, belongs to the group Ic of the Vaughan Williams classification, and tachyarrhythmia It is used as a therapeutic agent. However, it has never been known until now that propaphenone or a salt thereof has an excellent analgesic effect on neuropathic pain.
Propafenone is marketed as an internal medicine as a therapeutic agent for tachyarrhythmia, and the incidence of side effects is low among antiarrhythmic agents, and these can be used effectively as an analgesic of the present invention.

When a neuropathic pain analgesic agent containing the active ingredient of the present invention, typically propaphenone hydrochloride, is administered to a patient, it is orally administered in the form of a tablet, pill, granule, solution, capsule, or the like, or It is administered parenterally in the form of injections such as intravenous injection and intramuscular injection, suppositories, ointments, gels, creams, solutions, lotions, poultices, tapes and the like.
The dose of the active ingredient according to the present invention varies depending on the degree of symptoms, patient age, sex, body weight, administration method, dosage form, timing of administration, interval, etc., but usually 1-1000 mg per adult per day Preferably, the dose is administered in the range of 20-200 mg once to several times a day. What is necessary is just to increase / decrease the said dosage suitably as needed.
When preparing an oral preparation, add excipients to the main ingredient and, if necessary, binders, disintegrants, lubricants, coloring agents, flavoring agents, etc., and add tablets, granules, powders, capsules by conventional methods. An agent.

  Excipients include starch acrylate, gum arabic, lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide calcium silicate, magnesium silicate, etc., binders include polyvinyl alcohol, calcium citrate, Carboxyvinyl polymer, carboxymethyl ethyl cellulose, polyvinyl ether, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, dextrin, sodium polyphosphate, pectin, etc. Magnesium, talc, polyethylene glycol, aluminum stearate, lactose, magnesium carbonate, carmellose calcium, carmelo Sodium, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, hydrochloric acid, orange oil, fennel, cocoa powder, mint brain, aromatic acid, mint oil, cinnamon Oil or the like is used. Tablets and granules can be coated with sugar coating, gelatin coating, etc. if necessary.

When preparing an injection, an isotonic agent, a pH adjuster, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a preservative, etc. are added to the main drug as necessary. Subcutaneous and intramuscular injection. In that case, if necessary, it can also be made into a freeze-dried product by a conventional method.
Examples of pH adjusters include inorganic acids such as hydrochloric acid and phosphoric acid, or alkali metal salts thereof, inorganic bases such as sodium hydroxide, organic acids such as lower fatty acids, citric acid and lactic acid, or alkali metal salts thereof, arginine. Organic bases such as ethanolamine can be used.

As the suspending agent, ethanol, carrageenan, agar, methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, crystalline cellulose, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like can be used.
As solubilizers, use absolute ethanol, urea, lactic acid, tartaric acid, polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, tuna gol, castor oil fatty acid ethyl ester, etc. Can do.

  Suppositories, ointments, gels, creams, solutions, lotions, poultices, tapes and the like can be prepared by appropriately selecting commonly used or commonly used ones.

Examples of the present invention are shown below.
In this study, the Chung model, which is known as a model of hyperalgesia close to human neuropathic pain (various neuralgia, etc.), and a method of expressing pain by a mechanism different from the Chung model Both formalin tests used to see the effect of drugs on pain were used. As described above, in this test, peripheral action analgesic effects can be detected more reliably by using methods having different pain onset mechanisms.

Example 1
The analgesic effect on the formalin test in rats using propaphenone hydrochloride was investigated. Propafenone hydrochloride is suspended in physiological saline and injected subcutaneously into the left footpad of rats at a volume of 0.05 mL / site, 30 minutes later, formalin (0.1 mL / site, sc) is administered, immediately after administration (phase 1). ) And the formalin test to observe the symptoms of pain in 4 minutes after 28 minutes (Phase 2). The test compound was divided into three experiments and examined, and the analgesic effect was evaluated as the total number of pain responses induced by formalin. The results are shown in Tables 1 and 2.

Table 1

結果
塩酸プロパフェノン（1mg/部位）は１及び２相において痛みの症状の合計値がコントロール（生理食塩液）と比較して有意な減少がみられ、神経因性疼痛に対する鎮痛効果が確認された。 Table 2

Results Propafenone hydrochloride (1 mg / site) showed a significant decrease in the total pain symptoms in the first and second phases compared to the control (saline solution), confirming the analgesic effect on neuropathic pain. .

Example 2
We investigated the analgesic effect on pain hypersensitivity (Chung model) in rats using propaphenone hydrochloride. Propafenone hydrochloride is dissolved or suspended in physiological saline and administered subcutaneously to the left footpad of rats at a volume of 0.05 mL / site, and the maximum pressure reached 15.0 g after 20, 40 and 60 minutes. The pain threshold (Von Fray test) was measured using a Van Fray measuring device (Ugo Basil Co., Ltd.) set to 20 seconds, and the analgesic effect was examined. In addition, the test compound was divided into five experiments and examined. The results are shown in Table 3.

結果
塩酸プロパフェノン（1mg/部位）は、コントロール（生理食塩液）と比較して投与後20及び40分の疼痛閾値に有意な上昇が認められ、神経因性疼痛に対する鎮痛作用が確認された。 Table 3

Results Propafenone hydrochloride (1 mg / site) showed a significant increase in the pain threshold at 20 and 40 minutes after administration compared to the control (physiological saline), confirming the analgesic action against neuropathic pain.

  From the above test results, when propaphenone was administered to a pain model rat, a high analgesic effect was observed, suggesting that it is very useful as an analgesic for neuropathic pain.

  It can be used as an analgesic for neuropathic pain.

Claims (4)

  An analgesic for neuropathic pain comprising propafenone or a pharmaceutically acceptable salt thereof as an active ingredient.   The analgesic for neuropathic pain according to claim 1, comprising propafenone hydrochloride as an active ingredient.   A method for reducing pain by administering an analgesic for neuropathic pain containing an effective amount of propafenone or a pharmaceutically acceptable salt thereof to a patient having neuropathic pain.   Use of propaphenone or a pharmaceutically acceptable salt thereof for the manufacture of an analgesic for neuropathic pain.