KR20140075362A - Pharmaceutical composition for treating pain comprising dapoxetine - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising dapoxetine or a pharmaceutically acceptable salt thereof as an active ingredient for treating pain. More specifically, the dapoxetine inhibits the voltage-dependent sodium channel 1.7 (hNav1.7) of humans. As the dapoxetine developed for treating premature ejaculation is identified to concentration dependently inhibit the voltage dependent sodium channel 1.7 (Nav1.7) which is known as a pain gene of human, the dapoxetine is expected to be valuably used as a therapeutic agent for pain.

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for treating pain,

The present invention relates to a pharmaceutical composition for the treatment of pain comprising a large amount of dapoxetine as an active ingredient.

Pain is a problem more than treatment of essential diseases in patients such as cancer, AIDS, diabetes, and herpes zoster. It has been reported that chronic pain not only reduces the immune capacity of humans, but also reduces the mental libido, thereby shortening the real survival time of these patients. To date, these pain treatments have been prescribed for non-narcotic analgesics (such as aspirin, acetaminophen, NSAID drugs, etc.) or mild narcotic analgesics (for example codeine) for mild pain, (Eg, morphin, fentanyl patch) is the final choice for the drug. In the case of non-narcotic analgesic agents, most of them inhibit the synthesis of the pain mediator through the inhibition of cyclooxygenase. However, they are not tolerated or physically dependent. However, ceiling effect limits the analgesic efficacy. But there are many side effects such as tolerance and physical dependence, respiratory depression, and kidney failure. In order to solve such pain problems, it is urgently required to develop a powerful and non-adverse analgesic. For this, it is necessary to develop a new substance having a new pain suppression mechanism.

SCN9A, a gene for voltage-dependent sodium channel Nav1.7, is a genetic pain disorder that causes pain on small stimuli by lowering the threshold of voltage dependency of activation when a mutation occurs. "Primary erythromelalgia ), Which inhibits the inactivation of the sodium channel and inhibits the "paroxysmal extreme (Park et al., 2004) pain disorder "(Waxman and Dib-Hajj, Trends Mol Med. 11 (12): 555-62, 2005; Choi et al, Neurology 67: 1563-1567, 2006) (Cox et al, Nature 444: 894-898, 2006; Goldberg et al, Clin. Genet. 71: 311-319), which causes a lack of gene expression, , 2007).

Accordingly, the present inventors confirmed that dapoxetine developed as a treatment for premature ejaculation inhibits the voltage-dependent sodium channel 1.7 (Nav1.7) known as a human pain gene in a concentration-dependent manner, And the present invention has been completed.

It is an object of the present invention to provide a pharmaceutical composition for treating pain comprising dapoxetine or a pharmaceutically acceptable salt thereof as an active ingredient. The above-mentioned dapoxetine is characterized by inhibiting the voltage-dependent sodium passage 1.7 (hNav1.7) of man.

In order to accomplish the above object, the present invention provides a pharmaceutical composition for treating pain comprising dapoxetine represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the above dapoxetine is characterized by inhibiting the voltage-dependent sodium passage 1.7 (hNav1.7) of man.

≪ Formula 1 >

In the present invention, "dapoxetine" is a compound represented by the above formula (1), and also includes (S) - (+) - N, N-dimethyl- ) -Propanamine or (S) - (+) - N, N-dimethyl- alpha - [2- (1-naphthalenyloxy) ethyl-benzenemethanamine].

In the present invention, "pain" means pain such as acute pain, neuropathic pain, post-operative pain, migraine, arthralgia or toothache.

The dapoxetine according to the present invention is preferably contained in an amount of 0.1 to 50% by weight based on the total weight of the composition. However, the composition is not limited thereto, and may vary depending on the condition of the patient, the type of disease, and the progress of the disease.

The preferred dose of the dapoxetine according to the present invention will vary depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, in order to obtain the desired effect, it is preferable to administer it at 0.01 mg / kg to 10 g / kg, preferably 1 mg / kg to 1 g / kg per day. The administration may be carried out once a day or divided into several doses. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

The dapoxetine according to the present invention can be used in the form of a general pharmaceutical preparation, which can be administered orally or parenterally in various formulations in actual clinical administration. In addition, when formulating, in addition to the active ingredient dapoxetine, one or more pharmaceutically acceptable carriers may be prepared. The pharmaceutically acceptable carrier may be a mixture of saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components. If necessary, an antioxidant, , And other conventional additives such as a bacteriostatic agent may be added.

Solid formulations for oral administration may include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient, such as starch, calcium carbonate ), Sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. The liquid preparations for oral administration include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like May be included.

Further, the pharmaceutical composition of the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, or intramuscular injection. For formulation into a parenteral dosage form, the above-mentioned multipotentin (dapoxetine) is mixed with a stabilizer or a buffer in water to prepare a solution or suspension, which is then formulated in unit dosage forms of ampoules or vials.

The present invention relates to a pharmaceutical composition for treating pain comprising multipoxetin as an active ingredient, wherein a voltage-dependent sodium channel 1.7 (Nav1.7) known as a human pain gene, which is a dapoxetine developed as a treatment for premature ejaculation, , Dapoxetine is expected to be useful as a pain treatment agent.

Figure 1 shows the results of measuring the inhibitory effect of human voltage-dependent sodium channel 1.7 (hNav1.7) on human dapoxetine in a concentration-dependent resting state (Tonic block.) Cells were maintained at a fixed voltage of -120 mV After depolarization at 0 mV for 30 ms and every 30 sec for 20 ms, the decrease of current by 0.03 - 10 μM drug was measured.
Figure 2 shows the result of measuring the inhibitory effect of human voltage-dependent sodium channel 1.7 (hNav1.7) by multiparasthin (dapoxetine) in a use-dependent block. Cells were depolarized 10 times per second (10 Hz) at 0 mV for 20 ms at a fixed voltage of -120 mV in the presence of 0.03 - 10 μM of the drug, and the decrease in the last eleventh current was measured.
FIG. 3 shows the results of measurement of the inhibitory effect of human voltage-dependent sodium channel 1.7 (hNav1.7) on human dapoxetine in an inactivated state block. Cells were depolarized to 0 mV for 500 ms at a fixed voltage of -120 mV in the presence of 0.03 - 10 μM of drug, followed by a short recovery to -80 mV for 80 ms, followed by depolarization to 0 mV Respectively.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

Example  One. On the dapoxetine  Voltage Dependence of Human Influence by Sodium Channel 1.7 (hNav1.7)

Human embryonic kidney (HEK) cell line humidified atmosphere of 37% CO ₂ ℃ which supplies the 5 (hNav1.7-HEK) until used in the experiment stably expressing the 1.7 (hNav1.7) voltage-sensitive sodium channel the human Were maintained in Dulbecco's modified eagle medium (DMEM) medium containing 10% fetal bovine serum (FBS). The current of hNav1.7 was measured from these cells at 22 ° C using a whole-cell patch-clamp recording method using an Axopatch 200B amplifier. The composition of the solution used in the measurement is as follows. Intracellular solution: 140 mM CsF, 1 mM EGTA, 10 mM NaCl, 10 mM HEPES (pH 7.3 / CsOH, 310 mOsmol / L with sucrose); Extracellular solution: 140 mM NaCl, 3 mM KCl, 1 mM MgCl ₂ , 1 mM CaCl ₂ , 10 mM glucose, 20 HEPES (pH 7.3 / NaOH, 320 mOsmol / L with sucrose). The recording was started after 4 minutes, and the current was fixed at -120 mV. Cells were stimulated with depolarization voltages at various times and heights according to the purpose of the experiment. In order to minimize the error, the depolarization voltage was set so that the series resistance did not exceed 2 MΩ and was compensated by using series resistance compensation of 90% using the amplifier internal circuit. Blocking of hNav1.7 by dapoxetine in a concentration-dependent resting state (Tonic, Fig. 1) cells were depolarized every 30 sec at 0 mV for 20 ms at a fixed voltage of -120 mV, The decrease in current due to uM drug was measured. In the case of use-dependent (FIG. 2), cells were depolarized 10 times per second (10 Hz) at 0 mV for 20 ms at a fixed voltage of -120 mV in the presence of 0.03-10 μM of drug The decrease in the last eleventh current was measured. The inactivated state block (FIG. 3) was depolarized to 0 mV for 500 ms at a fixed voltage of -120 mV in the presence of 0.03 - 10 uM of drug, briefly restored to -80 mV for 80 ms, The decrease in current caused by depolarization at 0 mV was measured. Blocking by the drug hNav1.7 current in each condition was obtain a relative value compared to the current in the absence of drugs, by using this, the concentration (IC ₅₀₎ is the current hNav1.7 50% inhibition by the drug .

Concentrations of dapoxetine in the blood are increased to 0.87 uM and 1.46 uM, respectively (Priligy data sheet) at doses of 30 mg or 60 mg used for treatment of premature ejaculation. Therefore, hNav1.7 can be inhibited by 30% or more by the frequency-dependent blocking action, and in the case of blocking in the inactivated state, it can be used as an analgesic agent because the ion channel of 50% or more is inhibited.

Claims (5)

A pharmaceutical composition for treating pain comprising dapoxetine represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
≪ Formula 1 >

2. The pharmaceutical composition according to claim 1, wherein the dapoxetine inhibits the voltage-dependent sodium passage 1.7 (hNav1.7) of human. The pharmaceutical composition according to claim 1, wherein the pain is acute pain, neuropathic pain, post-operative pain, migraine, arthralgia or toothache. The pharmaceutical composition for treating pain according to claim 1, wherein the dapoxetine is contained in an amount of 0.1 to 50 wt% based on the total weight of the composition. The pharmaceutical composition for treating pain according to any one of claims 1 to 4, wherein the pharmaceutical composition is in the form of tablets, powders, ointments, cataplasms, percutaneous absorbents or liquid preparations.

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