WO2009061152A2

WO2009061152A2 - Composition for prevention and treatment of pain containing curcumin or pharmaceutically acceptable salt thereof as an active ingredient

Info

Publication number: WO2009061152A2
Application number: PCT/KR2008/006576
Authority: WO
Inventors: Seog Bae Oh; Sung Jun Jung; Seong Ah Kim; Dong-Kuk Ahn; Hyun Jeong Kim; Heung Sik Na
Original assignee: Snu R & Db Foundation; Korea University Industry and Academy Cooperation Foundation
Priority date: 2007-11-08
Filing date: 2008-11-07
Publication date: 2009-05-14
Also published as: KR20090047637A; WO2009061152A3

Abstract

The present invention relates to a composition for prevention and treatment of pain containing curcurnin or pharmaceutically acceptable salts thereof as an active ingredient. The composition for prevention and treatment of pain according to the present invention may significantly inhibit the activation of TRPVl which causes all pain including dentalgia and inflammation induced by various stimulants such as temperature, capsaicin, and acids, effectively inhibit pain caused thereby, and be produced from natural products. Thus, the composition is biologically stable and may be used in the products for treatment and alleviation of pain, including analgesics, functional toothpastes for prevention and improvement of pain, functional foods, and food additives.

Description

[DESCRIPTION]

[invention Title]

CCMPOSITION FOR PREVENTION AND TREATMENT OF PAIN CONTAINING CURCUMIN OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AS AN ACTIVE INGREDIENT

[Technical Field]

The present invention relates to a composition for prevention and treatment of pain containing curcumin or pharmaceutically acceptable salts thereof as an active ingredient.

[Background Art]

Pain is becoming a problem more than the cure of diseases such as cancer, AIDS, diabetes, and shingles for the patient. It is reported that chronic pain decreases the actual life-span of patients by not only reducing the immunocompetence of humans, but also taking away the will-to-life mentally. Until now, non^¬ narcotic analgesics (for example, aspirin, acetaminophen, NSAID drugs) or weak narcotic analgesics (for example, codeine) have been prescribed in the treatment of weak pain, and strong narcotic analgesics (for example, morphines and fentanyl patch) have been used as a last resort in the treatment of severe pain. When non-narcotic analgesics are used, most of them have a mechanism of synthesis inhibition of pain mediators via cyclooxygenase enzyme inhibition. Although they don't have any tolerance or physical dependence, they show a certain limitation in analgesic efficacy by a ceiling effect. In case of narcotic analgesics, they don't have any ceiling effect, but have many problems such as tolerance and physical dependence, respiration inhibition effects and kidney disorders. To solve these pain- related problems, the development of strong analgesics without any side effects is urgently needed. To achieve this goal, the development of a novel material with a new pain inhibition mechanism is needed.

Transient Receptor Potential Vanilloid (TRPV) or Vanilloid Receptor (VR) is a promising target for the development of analgesics, a receptor on the neuronal membrane activated by stimulant compounds such as capsaicin, a main pungent ingredient of red pepper, and also known as a capsaicin receptor. The receptor is known to exist in a portion of a sensory neuron, where its expression is regulated by nerve growth factors. The receptor is known to selectively introduce Ca^21" particularly as cation channels. Recently, Julius et al. confirmed the existence of TRPVl (or VRl) by cloning the receptor, and it was revealed that the receptor conducts a variety of noxious stimulants, such as hydrogen ions and thermal stimulants (> 43 ^"C) as well as capsaicins (vanilloid) (Tominaga et al., 1998, Neuron 21, pp531-543) . From these results, it has been proposed that vanilloid receptors play a role as an integral regulator, performing essential functions. Recently, knockout rats with their vanilloid receptors removed were produced (Caterina et al., 2000, Science 288, pp306-313; Davis et al., 2000, Nature 405, ppl83-187) . They were not different from normal rats in general behaviors, but showed that their responses to thermal stimulants and heat hyperalgesia were significantly attenuated. The effect of the receptor on transmission of noxious stimulants was reconfirmed. Pain may be treated or moderated by inhibiting the activation of the vanilloid (capsaicin) receptors, and thus studies on the vanilloid receptor antagonists are being actively performed in different places.

Conventional vanilloid receptor antagonists include capsazepine, benzamide derivatives (Korean Patent Publication No. 2006-0058769), 4- (methylsulfonylamino) phenyl analogue (Korean Patent Publication No. 2005-0004006), hydroxyl tetrahydro-naphthalenylurea derivatives (Korean Patent Publication No. 2004-0108784), amide compounds (Korean Patent Publication No. 2004-0048393), urea compounds (Korean Patent Publication No. 2004-0041610), N-hydroxy, urea and amide compounds (Korean Patent Publication No. 2004-0034804), thiocarbamic acid derivatives (Korean Patent Publication No. 2002-0030020) and thiourea derivatives (Korean Patent Publication No. 2002-0030009) . However, most of these vanilloid (capsaicin) receptor anatagonists are synthesized by organic chemical methods, and among materials with biological stability as a natural vegetable ingredient, few have been reported so far. Although capsazepine, as a vanilloid receptor antagonist, has an in-vitro antagonistic effect, it is known that the antagonist has any in vivo analgesic effect. According to recent experiments, it is very difficult to manufacture capsazepine in an aqueous solution due to its poor solubility and the antagonist is metabolically so unstable even after the administration that it becomes immediately extinct in vivo. Thus, it is known that due to these problems, the antagonist does not have any analgesic effect in the receptor activation inhibition mechanism.

Although curcumin, a main ingredient of curry (Curcuma longa L.), is a natural product which does not have vanilloid rings and is known to have anticancer effect (Mosley CA, Liotta DC, Snyder JP, Adv. Exp. Med. Biol. 2007; 595; 77-103), anti- inflammatory action and cure for dementia (Yang F et al., J. Biol. Chem. 2005 Feb 18, 280(7), 5892-5901; Korean Patent Publication No. 2002-0073847), regulation of gastric acid secretion (Kim DC et al., Biol. Pharm. Bull. 2005 Dec; 28(12); 2220-2224), alleviation of symptom of diabetes (Sharma S et al., Clin. Exp. Pharmacol. Physiol. 2006 Oct; 33(10); 940-945), and anti-wrinkle effect (Korean Patent Publication No. 2005- 0010093) , there are none reported on the efficacy as an analgesic.

Thus, the present inventors researched on new materials which may selectively antagonize the vanilloid (capsaicin) receptor among natural products, and confirmed that curcumin inhibited the activation of vanilloid (capsaicin) receptors and the action of capsaicin was inhibited. From the result, it was to be understood that curcumin may be used as an analgesic, thus leading to the completion of the present invention.

[Disclosure] [Technical Problem] The object of the present invention is to provide a composition for prevention and treatment of pain containing curcumin and pharmaceutically acceptable salts thereof as an active ingredient.

Another object of the present invention is to provide a food composition for prevention or improvement of pain containing curcumin and pharmaceutically acceptable salts thereof as an active ingredient.

Yet another object of the present invention is to provide a functional toothpaste for prevention or improvement of pain containing curcumin and pharmaceutically acceptable salts thereof as an active ingredient.

[Technical Solution] In order to accomplish the above object, the present invention provides a composition for prevention and treatment of pain containing curcumin and pharmaceutically acceptable salts thereof as an active ingredient.

In addition, the present invention provides a food composition for prevention or improvement of pain containing curcumin and pharmaceutically acceptable salts thereof as an active ingredient.

Furthermore, the present invention provides a functional toothpaste for prevention or improvement of pain containing curcumin and pharmaceutically acceptable salts thereof as an active ingredient.

[Advantageous Effects]

The composition for prevention and treatment of pain containing curcumin of chemical formula 1 according to the present invention or pharmaceutically acceptable salts thereof may significantly inhibit the activation of TRPVl which causes all pain including dentalgia and inflammation induced by various stimulants such as temperature, capsaicin, and acids, effectively inhibit pain caused thereby, and be produced from natural products. Thus, the composition is biologically stable and may be used in the products for treatment and alleviation of pain, including analgesics, functional toothpastes for prevention and improvement of pain, functional foods, and food additives.

[Description of Drawings]

Fig. 1 is a current graph showing that the capsaicin- induced current was blocked by curcumin according to an embodiment of the present invention.

Fig. 2 is a current graph showing that the capsaicin- induced current introduced for a very short time was blocked by curcumin according to an embodiment of the present invention.

Fig. 3 is a current graph showing that the capsaicin- induced current was blocked by curcumin according to another embodiment of the present invention.

Fig. 4 is a current graph showing that the capsaicin- induced current was blocked by curcumin according to yet another embodiment of the present invention. Fig. 5 is a graph showing the inhibition rates of capsaicin vs . the concentrations of curcumin according to an embodiment of the present invention.

Fig. 6 is a graph showing the avoidance delay times of the thermal sensitization by a mouse vs. the doses of capsaicin according to an embodiment of the present invention. Fig. 7 is a graph showing the avoidance delay times of the thermal sensitization by a mouse vs. the concentrations of curcumin .

Fig. 8 is a graph showing the avoidance delay times of the thermal sensitization by a mouse vs. the concentrations of a conventional TRPVl inhibitor according to a comparative example of the present invention.

CAP : Capsaicin

Cur : Curcumin

[Best Mode]

The present invention provides a composition for prevention and treatment of pain containing curcumin represented by the following chemical formula 1 or pharmaceutically acceptable salts thereof as an active ingredient.

[Chemical Formula l]

The curcumin of chemical formula 1 according to the present invention is a yellow compound with the chemical formula C_2IH₂OO₆ and a molecular weight of 368.38, and a natural material which has vanilloid rings. Curcumin of chemical formula 1, a main ingredient of Curcuma longa L. (curry) , may be extracted from the Curcuma longa L. by a well known method in the art to which the present invention belongs, or commercially available.

The present invention includes not only curcumin represented by the above chemical formula 1 or pharmaceutically acceptable salts thereof, but also all the possible solvates and hydrates which may be prepared from these.

Curcumin of chemical formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed from free acids is useful. The acid addition salts may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid or phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyl alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonates, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycollate, malate, tartrate, methanesulfonate, propanesulfonates, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate.

The acid addition salts according to the present invention may be prepared by conventional methods, for example dissolving curcumin of chemical formula 1 in excess of an acid aqueous solution and precipitating the resulting salts in a water-miscible solvent, for example methanol, ethanol, acetone or acetonitrile. The salts may be also prepared by heating equal volumes of curcumin of chemical formula 1 and an acid or an alcohol in water, and subsequently evaporating and drying the mixture or suction filtering the precipitated salts.

Tn addition, pharmaceutically acceptable metal salts may be prepared using bases. Alkali metal or alkaline earth metal salts may be obtained by for example, dissolving the compound in excess of alkali metal hydroxide or alkaline earth metal hydroxide solutions, filtering the insoluble compound salts, evaporating and drying the filtrate. As a metal salt, synthesis of sodium, potassium or calcium salts are suitable for pharmaceutical purposes. In addition, the corresponding silver salt may be obtained by reacting an alkali metal or an alkaline earth metal with an appropriate silver salt (ex. silver ni trate) .

A composition containing curcumin of chemical formula 1 or pharmaceut Lcally acceptable salts thereof as an active ingredient may be useful as a composition for prevention and treatment of pain such as acute pain, neuropathic pain, postoperative pain, migraine, arthralgia, or dentalgia, heat pain, and the like. Preferably, it may be also useful as a composition for prevention and treatment of pain induced by heat .

Curcumin of the above chemical formula 1 inhibits electric signals generated in the vanilloid sub-type 1 (TRPVl) of transient receptor potential channels included in the capsaicin receptor which mediates pain.

When curcumin of chemical formula 1 of the present invention was administered to a HEK 293 cell where a capsaicin ion channel is expressed or to a trigeminal ganglion neuron, the current generated by capsaicin was significantly cut off (See Figs. 1 to 4) and it was shown that the inhibition rate was increased with the increase in doses of curcumin (See Fig. 5) . In the face avoidance experiment of white rats suffering from heat pain, it was shown that a heat pain reaction induced by capsaicin was alleviated by administering curcumin to the rats and the face avoidance time by heat was increased (See Fig. 7) . From these results, the composition according to the present invention may be also useful particularly in the prevention and treatment of pain induced by heat.

A composition containing curcumin of chemical formula 1 according to the present invention or pharmaceutically acceptable salts thereof as an active ingredient may be used in the form of general medicinal preparation.

Curcumin of the present invention may be administered in various formulations including oral and parenteral when clinically administered. When the composition is prepared, it may be prepared by including one or more pharmaceutically acceptable carriers in addition to the curcumin, an active ingredient. The pharmaceutically acceptable carriers may be used with saline, sterile water, Ringer' s solution, buffered saline, dextrose solution, malto dextrin solution, glycerol, ethanol, and mixture of one or more of these components. If necessary, they may further contain other common additives such as antioxidant, buffered solution, and bacteriostat .

Solid preparations for oral administration include tablets, pills, powders, and capsules. These solid preparations may be prepared by mixing curcumin with at least one excipients, for example starch, calcium carbonate, sucrose, lactose and gelatin. Lubricants such as magnesium stearate and talc in addition to a single excipient may be used.

In addition, liquid preparations for oral administration include suspensions, solutions, emulsions and syrups. In addition to water, a simple diluent, and liquid paraffin, various excipients, for example, wetting agents, sweeteners, flavors, preservatives, and the like may be included. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspending agents, emulsions, lyophilisations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like may be used as non-aqueous solutions and suspending agents . As the base material for the suppository formulation, witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerinated gelatin, and the like may be used.

Furthermore, the pharmaceutical composition of: the present invention may be parenterally administered. The parenteral routes may be by subcutaneous, intravenous or intramuscular injection. To prepare a parenteral formulation, a solution or suspension may be prepared by mixing the curcumin with a stabilizer or a buffer in water, and a unit dosage form such as an ampoule or a vial may be prepared.

An amount of the curcumin according to the present invention may be preferably included in the ranges from 0.1% to 50% by weight based on a total weight of the composition. However, the above ranges are not to be limited to this, but may depend on the conditions of the patient, kinds of diseases, and severities of diseases.

A preferable dose of the curcumin according to the present invention depends on the conditions and body weight of the patient, the severity of the disease, drug forms, administration routes, and duration, but may be appropriately selected by those skilled in the art. However, 0.01 rag/kg to 10 mg/kg a day, and preferably 1 rag/kg to 1 g/kg a day may be administered. The doses may be administered once or several times a day. Thus, the doses do not limit the range of the present invention in any way.

Furthermore, the present invention provides a food composition for prevention and improvement of pain containing curcumin and sitologically acceptable food supplement additives, exhibiting prevention and improvement effects of pain. The food composition of the present invention may be added to health foods for purposes of prevention and improvement of pain. When the curcumin of the present invention is used as an additive, the curcumin may be added directly, used together with other foods or food ingredients, and appropriately used by conventional methods. The amount of mixture of active ingredients may be appropriately determined according to the purpose of use (prevention, health or treatment) . Generally, when food or beverage is produced, the curcumin of the present invention is added in the range of 1 to 20 % by weight, and preferably 5 to 10 % by weight based on the components. However, the amount may be less than the above amount for health and hygienic purposes or in case of a long time use for health regulation purposes, and the amount of the active ingredient may be used more than the above ranges because there's no problem with the safety.

There is no certain limitation in kinds of the above foods. Examples of the foods to which the above material may be added include all the common health foods, including beverages, gums, vitamin complexes and health supplement foods.

The beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient like common beverages. The natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As a sweetener, natural sweeteners such as thaumatin and stevia extract, and synthetic sweeteners such as saccharin and b aspartame may be used. The ratio of the natural carbohydrate may be generally in the range of about 0.01 to 0.04 g per 100 mi of the composition of the present invention and preferably about 0.02 to 0.03 g.

In addition, the functional food of the present invention

10 may contain various nutrients, vitamins, minerals

(electrolytes) , flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerins, alcohols, and sparkling components for

]5 carbonated beverages. In addition, the composition of the present invention may also contain natural juice or fruit to be presented as fruit drink or vegetable drink. These may be used either alone or in combination of two or more kinds. The blending rate of these additives is not particularly limited,

20 and is generally selected in the range of about 0 to 20 parts by weight to 100 part by weight of the composition of the invention.

The present invention also provides a functional 5 toothpaste containing curcumin or pharmaceutically acceptable salts thereof exhibiting prevention and improvement effects of pain.

Because curcumin may effectively reduce dentalgia enhanced by heat, a composition containing curcumin according to the present invention as an active ingredient may be widely used in a functional toothpaste etc. as a component. The composition may be substantially a solid or paste, for example, tooth powder, dental tablet, toothpaste, gel or cream. Carriers for these solid or paste oral preparations may generally contain polishing materials. Examples of polishing materials may include water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dehydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, tri-magnesium phosphate, calcium carbonate, aluminum silicate, zirconium silicate, silica, bentonite and mixtures thereof.

The present invention also provides a method for prevention and treatment of pain comprising administering a therapeutically effective amount of curcumin represented by the following chemical formula 1 or pharmaceutically acceptable salts thereof as an active ingredient to a patient. <Chemical Formula 1>

The method for prevention and treatment of pain according to the present invention may be useful as a method for prevention and treatment of pain including acute pain, neuropathic pain, postoperative pain, migraine, arthralgia and dentalgia.

Furthermore, the present invention provides a use of curcumin represented by the following chemical formula 1 or pharmaceutically acceptable salts thereof in the manufacture of medicines for prevention and treatment of pain. <Chemical Formula 1>

The use of curcumin or pharmaceutically acceptable salts thereof in the manufacture of medicines for prevention and treatment of pain may be also useful in the manufacture of medicines for prevention and treatment of pain including acute pain, neuropathic pain, postoperative pain, migraine, arthralgia and dentalgia.

[Mode for Invention]

Hereinafter, the present invention will be described in more detail with reference to the following embodiments.

However, the following embodiments are provided only to illustrate the present invention, and the present invention is not limited to them.

<Embodiment 1> Measurement of effects of curcumin on the activation of TRPVl (1) The effect of curcumin on the activation of TRPVl in HEK293 where TRPVl is expressed

Human embryonic kidney (HEK) 293 cells (American Type Culture, Manassas, VA) were seeded into 12-well culture plates. The next day 0.5 to 2 //g/well of pcDNA constructs of TRPVl or mutants of TRPVl were transfected into cells using a lipofectamine 2000 transfection reagent (Invitrogen) . After 18- 24 h, the transfected cells were trypsinized and used for whole cell recordings. Subsequently, after the cell membrane potential was held at -60 niV, a generally stable membrane potential using a voltage clamping method, currents generated by administering capsaicin and curcumin were observed.

The voltage clamping method is a method to insert a recording electrode into a cell and hold a membrane potential in order to manipulate the interior of the cell. In its normal resting state, a cell has a potential difference across its membrane. The cell membrane has a potential called a resting membrane potential. The resting membrane potential is generally -60 to -70 niV, and there is almost no current across the cell membrane. A drug which may stimulate cells in the voltage clamping method used for this research generates electric signals, and the signals are recorded as currents.

Whole cell currents were amplified using an EPC 10 amplifier (HEKA) . Recording electrodes were made from borosilicate glass and had resistances of 3 to 5 MΩ when filled with standard intracellular solutions. For whole cell experiments, we used an external bath medium of the following composition: 140 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM glucose, and 10 mM N- [2-hydroxyethyl]piperazine-N' - [2- ethanesulfonic acid] (HEPES), with pH adjusted to 7.4 using NaOH. The recording electrode solution contained 140 mM CsCl₂, 10 mM HEPES, 5 mM EGTA, and mM 3 MgATP, with pH adjusted to 7.3 using CsOH. All drug solutions were applied to cells by local perfusion through a capillary tube (1.1 mm inner diameter) positioned near the cell of interest. The solution flow was driven by gravity (flow rate, 1 to 5 in#/min) . In addition, another drug administration method was to administer a small amount of drugs around the cell directly using a pressure transducer (Picopump, WPI) . After administration, currents were filtered at 5 kHz (-3 dB, 4-pole Bessel) and analyzed using a personal computer equipped with PULSE software (HEKA) . The calculated junction potential between the recording electrode and solutions used for all cells during sealing was 4 mV (pipette negative, using PULSE software) . No junction potential correction was applied. Experiments were performed at room temperature (18 to 22⁰C) .

The experimental results were shown in the Fig. 1. As shown in Fig. 1, it was to be understood that in the

HEK293 ceils where the TRPVl is expressed, currents were generated by capsaicin after the cell membrane potential was held at -60 liiV and CAP at 200 nM was administered for 3 seconds. It was also to be understood that after curcumin at 5 μM was pretreated for 2 minutes, capsaicin-induced currents were decreased when capsaicin was administered simultaneously with curcumin. It was to be understood that these capsaicin-induced currents were recovered in 10 minutes after curcumin was removed .

Fig. 2 is a graph showing the current size when capsaicin was administered for a very short time (0.5 second) . In Fig. 2 as also shown in Fig. 1, it was to be understood that the size of the capsaicin-induced currents produced from the administration of capsaicin for a very short time was blocked when curcumin was administered simultaneously with capsaicin, and if curcumin was washed with the extracellular solution, the size of capsaicin-induced currents was recovered into the initial size. Thus, it was confirmed that curcumin acted as a pain inhibitor induced by capsaicin.

(2) The effect of curcumin on the activation of TRPVl in a trigeminal ganglion neuron where there is a TRPVl Trigeminal ganglion (hereinafter, referred to as "TG") neurons were rapidly removed from the neonatal rat under aseptic conditions and stored in HBSS solution (Gibco) . The TG obtained thereby was digested in 0.1 % collagenase and 1 % collageriase/dispase (Boehringer Mammheim) in HBSS for 10 min respectively, followed by 10 min in 0.25% trypsin (Sigma), all at 37⁰C. The TG neurons were washed in DMEM (Gibco) 3 times and resuspended in F12 media with 10 % FBS (Gibco) and 1 % penicillin/streptomycin (Sigma) . The TG neurons were then mechanically dissociated with fire-polished glass pipettes, centrifuged, resuspended in F12 media, and then plated on polyorithine (Sigma) and laminin (Sigma) -coated glass coverslips. The cells thus obtained were maintained at 37 ^°C in a 5% CO₂ incubator (Oh, S. B et al., Chemokines and glycoprotein produce pain hypersensitivity by directly exciting primary nociceptive neurons. J. Neurosci., 21: 5027-35, 2001) .

Subsequently, currents were measured when capsaicin was administered alone or capsaicin and curcumin were administered simultaneously, respectively, and then curcumin was removed and currents were measured. The results are shown in Fig. 3. Then, capsaicin was continuously while curcumin was being intermittently and the accumulated sizes of currents were measured. The results are shown in Fig. 4. As shown in Fig. 3 and Fig. 4, it is to be understood that the capsaicin-induced currents were also cut off by curcumin even in TG neurons where there is a TRPVl.

To observe the inhibition effect of TRPVl according to the concentrations of curcumin, the capsaicin-induced currents were measured by changing the concentrations of curcumin from 1 nM to

10 μM. The results were shown in Fig. 5.

As shown in Fig. 5, when the concentration of curcumin was lower than 1 nM, the inhibition rate of capsaicin-induced currents was as much as 10 %, meaning that almost no capsaicin- induced current was cut off. However, it was confirmed that as the concentration of curcumin was gradually increased, the inhibition rate of capsaicin-induced currents was getting higher and maintained at a constant level. The concentration showing the 50 % blocking effect was 11 nM, and the maximum blocking effects were observed at 1 μM and 5 μM and the maximum inhibition rate was 67 % .

Because curcumin blocks the capsaicin from reacting with the capsaicin receptor (TRPVl) , inhibits the activation of the TRPVl, and may reduce the pain thereby, a composition containing the curcumin of chemical formula 1 according to the present invention or pharmaceutically acceptable salts thereof as an active ingredient may be useful in the production of analgesics. <Embodiment 2> Measurement of effect of curcumin on the heat pain reaction induced by the activation of TRPVl

Experiments based on behavioral science were performed using white male Sprague-Dawley rats (250 to 300 g) .

Specifically, 6 white rats were put into a cylindrical rat binding device (height 40 to 60 mm, length 70 to 120 Dim) and tested for heat and sensitization pain. A hole was perforated on the upper part of the cylinder to apply heat stimulants, and illumination regulation was performed alternately for 12 hours while maintaining a constant temperature of 23 ^°C. Each individual was trained to get accustomed to these conditions 30 minutes before the experiment. Each of 30 βH, solution of 0.1, 1, and 5 βg capsaicin was subcutaneously injected to the left part of the face of the rat, and a radiant heat via an infrared heat stimulator was applied to the rat from the place 10 cm away from the middle part of the left face for 9 seconds. In this way, the experiment was performed twice for the several minute intervals, and an avoidance delay time was measured according to heat stimulations. The results are shown in Fig. 6. The avoidance delay time was determined by the Hargreaves method.

As shown in Fig. 6, it was known that when 0.1, 1, and 5 nig of capsaicin was subcutaneously injected, the avoidance time vs. heat stimulants was decreased concentratiori-dependently (F (3, 20) = 13.485, p<0.001) . When 5 mg of capsaicin was injected, the highest heat stimulation was recorded.

Next, 5, 25, and 50 rag/kg of curcumin was intraperitoneally injected into the rats respectively, and 5 rag of capsaicin was subcutaneously injected into the left part of the rat face. 50 and 100 /ig/kg of 5' -Iodoresiniferatoxin (IRTX), a TRPVl receptor antagonist, were also dosed as a control group. CAP was dissolved in 10 % ethanol, 10 % TWEEN 80, and 80 % saline solution. Cur was dissolved in 70 % DMSO and 30 % saline solution, and IRTX was dissolved in 1 % ethanol, 3 % TWEEN 80, and 96 % saline solution.

The results were shown in Fig. 7 and Fig. 8. Fa g. 7 is a graph showing the avoidance delay times to heat stimulation based on a subcutaneous injection of 5 rag CAP after 5, 25, and 50 mg/kg of Cur was intraperitoneally pre- treated into the rats respectively.

As shown in Fig. 7, it was known that as the amount of curcumin doses was increased, the avoidance delay time was increased (F (3, 20) = 13.485, p<0.001) . It was to be understood that the results had the same aspect as those when a conventional TRPVl receptor antagonist was administered.

Thus, curcumin alleviates the thermal sensitizing pain induced by capsaicin and may be useful in the alleviation of dentalgia where the pain may be aggravated by heat. <Preparation Example 1> Preparation of powders Curcumin 20 mg

Milk sugar 100 mg Talc 10 rag

Powders are prepared by mixing the components and filling them in an airtight pouch.

<Preparation Example 2> Preparation of tablets Curcumin 10 nig

Corn starch 100 mg

Milk sugar 100 mg

Magnesium stearate 2 mg

Tablets are prepared by mixing the components and pressing them according to a conventional production method of tablets.

<Preparation Example 3> Preparation of capsules

Curcumin 10 mg Crystalline cellulose 3 mg

Lactose 14.8 mg

Magnesium stearate 0.2 mg

Capsules are prepared by mixing the components and filling them in gelatin capsules. <Preparation Example 4> Preparation of injections Curcumin 10 nig

Mannitol 180 mg

Sterile distilled water for injection 2974 mg Na₂HPO₄, 12H₂O 26 mg

Injections are prepared with the contents of the components an ampoule (2 ml) by a conventional preparation method of injections.

<Preparation Example 5> Preparation of solutions Curcumin 20 mg

Isomerized sugar 10 g

Mannitol 5 g

Purified water Proper quantity Solutions are prepared by adding each of the components into the purified water, applying a proper quantity of lemon flavor to the mixture, mixing the components, adding purified water to the mixture, controlling a total of 100 iα£, filling them in a brown bottle, and sterilizing the bottle.

<Preparation Example 6> Preparation of health food

Curcumin 1000 mg

Vitamin mixture Proper quantity

Vitamin A acetate 70 mg Vitamin E 1.0 mg Vitamin Bl 0.13 mg

Vitamin B2 0.15 mg

Vitamin B6 0.5 mg

Vitamin B12 0.2 μg Vitamin C 10 nig

Biotin 10 μg

Nicotinic acid amide 1.7 mg

Folic acid 50 μg

Calcium pantothenate 0.5 mg Mineral mixture Proper quantity

Ferrous sulfate 1.75 mg

Zinc oxide 0.82 mg

Magnesium carbonate 25.3 mg

Mono potassium phosphate 15 mg Calcium phosphate dibasic 55 mg

Potassium citrate 90 mg

Calcium carbonate 100 mg

Magnesium chloride 24.8 mg The composition ratios of the vitamins and mineral mixtures are produced by mixing and preparing relatively appropriate components for health food in a preferred embodiment. However, the ratios may be changed randomly. The components may be mixed according to a common method of preparing health foods . Granules may be prepared and used in the production of a health food composition according to a common method.

<Preparation Example 7> Preparation of health beverages Curcumin 1000 nig

Citric acid 1000 rag

Oligosaccharide 100 g

Japanese apricot concentrate 2 g Taurine 1 g Purified water Total 900 mi

The components are mixed according to a conventional health beverage production method, and the mixture is heated with stirring at 85 ^°C for one hour. The solution was filtered and stored in a sterilized 2 1 container which is sealed and sterilized. The container was then stored in a refrigerator for further use as a health beverage composition.

The composition of the beverage followed the preferable combination of each component but not always limited thereto and may be modified considering demand class, demand country, purpose of use, local and national preference, etc.

Preparation Example 8> Preparation of functional toothpastes Deionized water 37.578 % Glycerin 25 %

Silicon dioxide 21.5 %

Hexa meta phosphate (HMP) 6.0 %

Synthetic silica 3.0 % Sodium lauryl sulfate 1.2 %

Flavors 1.0 %

Curcumin 1.0 % Sodium hydroxide (50 % solution) 1.0 %

Xanthan gum 1.0 % Sodium benzoate 0.5 %

Titanium dioxide 0.5 %

Sodium saccharin 0.3 %

Sodium fluoride 0.242 %

The composition is mixed according to a conventional method. A toothpaste for dental use is prepared, put into a container, and prepared as a functional toothpaste.

Claims

[CLAIMS]

[Claim 1]

A composition for prevention and treatment of pain containing a therapeutically effective amount of curcumin or pharmaceutically acceptable salts thereof, the curcumin being represented by the following chemical formula 1:

[Claim 2]

The composition as set forth in claim 1, wherein the curcumin is separated and purified from Curcuma longa L..

[Claim 3]

The composition as set forth in claim 1, wherein the curcumin inhibits the activation of vanilloid receptors which mediate pain.

[Claim 4]

The composition as set forth in claim 1, wherein the curcumin inhibits electric signals generated by the vanilloid sub-type 1 (TRPVl) of transient receptor potential channels which mediates pain.

[Claim 5]

The composition as set forth in claim 1, wherein the pain is acute pain, neuropathic pain, postoperative pain, migraine, arthralgia or dentalgia.

[Claim 6]

The composition as set forth in claim 1, wherein an amount of the curcumin ranges from 0.1% to 50% by weight based on a total weight of the composition.

[Claim 7]

Λ functional toothpaste for prevention and improvement of pain containing a therapeutically effective amount of curcumin or pharmaceutically acceptable salts thereof, the curcumin being represented by the following chemical formula 1: <Chemical Formula 1>

[Claim 8]

A functional food for prevention and improvement of pain containing a therapeutically effective amount of curcυmin or pharmaceutically acceptable salts thereof, the curcumin being represented by the fo Llowi ng chemical formula 1 : <Chemical Formula 1>

H)

[Cla im 9] The functional food as set forth in claim 8, wherein the functional food is beverages, gums, vitamin complexes or health supplement food.

[Claim 10]

A method for prevention and treatment of pain, comprising administering a therapeutically effective amount of curcumin or pharmaceutically acceptable salts thereof to a patient, the curcumin being represented by the following chemical formula 1: <Chemical Formula 1>

[Claim 11] The method as set forth in claim 10, wherein the pain is acute pain, neuropathic pain, postoperative pain, migraine, arthralgia or dentalgia.

[Claim 12] A use of curcumin or pharmaceutically acceptable saLts thereof in the manufacture of medicines for prevention and treatment of pain, the curcumin being represented by the following chemical formula 1:

[Claim 13) The use as set forth in claim 12, wherein the pain is acute pain, neuropathic pain, postoperative pain, migraine, arthralgia or dentalg±a.