KR20160015691A - pain alleviating and treating agent containing a Gastrodiae Rhizoma extract - Google Patents
pain alleviating and treating agent containing a Gastrodiae Rhizoma extract Download PDFInfo
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Abstract
The present invention relates to a composition for alleviating, inhibiting or treating chronic pain comprising an extract of Chimpanzee or a compound isolated therefrom as an active ingredient, and a method for preparing the same, wherein the Chimma extract according to the present invention is effective for alleviating, May be used as a pharmaceutical composition or a functional food composition useful for treatment.
Description
The present invention relates to a composition for alleviating, inhibiting or treating chronic pain comprising an extract of Chimpanzee or a compound isolated therefrom as an active ingredient, and a method for preparing the same, wherein the Chimma extract according to the present invention is effective for alleviating, May be used as pharmaceutical compositions useful for treatment.
The pain felt by humans can be divided into acute pain and chronic pain. According to the International Pain Research Society, pain is defined as "an unpleasant sensory and emotional experience with actual or potential tissue damage", and the pain symptoms can be classified into acute and chronic pain by classifying them as features and duration.
Acute pain is a pain caused by an invasive stimulation caused by a disease or traumatic tissue injury. It usually occurs within 3 to 6 months after birth, pain after surgery, pain after tissue injury, It is effectively treated by drugs (narcotic analgesics, non-steroidal anti-inflammatory analgesics).
Chronic pain is caused by nerve damage and subsequent changes in the nervous system due to various unclear causes. It lasts for longer than the duration of the healing period of the underlying disease or injury, the boundaries of pain are unclear, It is painful, lasts more than 6 months, and the effects of narcotic analgesics and nonsteroidal anti-inflammatory drugs are limited.
For example, there are migraine, rheumatic pain, diabetic pain, and cancer pain, which can dramatically lower the quality of life of the patient and may lead to depression. Narcotic painkillers have moderate effects, but their side effects are so strong that they are difficult to use consistently, and nonsteroidal anti-inflammatory drugs are ineffective. Tricyclic antidepressants and anti-epileptic drugs are currently used clinically but they are known to have little efficacy and thus require the development of new drugs.
As such, acute pain and chronic pain are not only different from each other, but also susceptibility to various drugs is another completely different disease.
Among chronic pain diseases, cancer pain can be divided into the pain caused by the tumor itself, the bone pain caused by the cancer metastasized to the bone, and the treatment related to the treatment, that is, the pain caused by the anticancer agent.
Neuropathic pain caused by nerve damage or an abnormal reaction of the nervous system manifests several symptoms. That is, spontaneous pain that occurs spontaneously without external stimuli, hyperalgesia, which usually feels more pain for pain-inducing stimuli, and weak stimuli that do not cause pain at the normal And allodynia causing severe pain. In addition, such neurogenic pain is also observed in diabetic pain, postherpetic pain, pain after nerve injury, pain after spinal cord injury, and the like.
Recent advances in research have revealed the mechanism of pain. In the pain transmission process, the harmful stimuli applied to the periphery are transmitted to the olfactory cells of the spinal cord via the primary afferent fibers, which go through the spinal cord to the thalamus and then to the cerebral cortex. In this process, peripheral sensitization and central sensitization are involved.
Acute pain is mainly involved with peripheral sensitization. Peripheral sensitization is caused by nerve and inflammatory responses in and around damaged tissue. In other words, prostaglandin, bradykinin, potassium ion (K + ) secreted from the damaged tissue stimulate the nociceptor of the nerve endings of the primary afferent fibers in the skin, Sensitive.
In addition, Substance P secreted by damaged nerve axon reflexes secretes histamine and serotonin by inducing vasodilation and degranulation of mast cells. These substances sensitize the peripheral nerves and cause pain. This process is mainly treated effectively by non-steroidal anti-inflammatory drugs.
On the other hand, chronic pain is mainly involved with central sensitization. Central sensitization is a hypersensitive response of neurons in the olfactory cortex, producing a much more amplified signal than the degree of pain transmitted by primary afferent fibers during tissue injury. In other words, stimulation by the primary nerve stimulates the spinal cord olfactory cells continuously to expand the pain reaction area and prolong the reaction period. This leads to hyperalgesia, allodynia, and spontaneous pain. This process is not inhibited by non-steroidal anti-inflammatory drugs effective for acute pain. Currently, antidepressants, anticonvulsants and narcotic analgesics are administered, but the effect is the most moderate.
In conclusion, chronic pain is a warning signal for disease or tissue damage, and it is not only different from the mechanism of acute pain, which is the mechanism of bio-defense, but also is a completely different disease.
In the United States, 1.4 million people were diagnosed with cancer in 2008, and nearly 10 million suffer from cancer pain. In addition, there is a wide range of pain medications that can be used to treat pain, such as taxanes (paclitaxel, docetaxel), vinca alkaloid (vincristine, vinblastine), and platinum (cisplatin) Pain persists for a few months and sometimes lasts for several years.
Among these drugs, paclitaxel (PAC, Taxol®) is a kind of taxanes that are used to treat breast, cervical, ovarian, non-small cell lung, and Kaposi sarcoma (Vyas and Kadow, Prog. Med. Chem. 32: 289-337, 1995; Wall and Wani, Cancer Res. 55: 753-760, 1995). This drug attaches to the β-tubulin of the microtubule of the cell to stabilize the microtubule and promote the polymerization, thereby exhibiting anticancer activity (Carlier and Pantaloni, Biochem. 22: 4814-4822, 1983).
In addition, PACs induce neuropathic pain not only in anti-cancer activity but also in peripheral neuropathy, ranging from relatively mild symptoms such as numbness of arms and legs and sensory depression to burning pain (Dougherty et al., Pain 109: 132-142, 2004). Neuroscience 138: 329-338, 2006; Potter & Higginson, Lung Cancer 43: 247-257, 2005). The use of PACs at a body surface area of more than 200 mg per square meter indicates neuropathic pain in 55% of patients (Cata et al. 2004; Lipton et al., Neurology 39: 368-373, 1989). Concomitant use with other anticancer agents (cisplatin, vincristine) or with diseases that cause peripheral nerve lesions such as diabetes mellitus increases the incidence of neuropathic pain and increases the severity of pain.
The mechanism of paclitaxel-induced neuropathic pain (PINP) is unclear, but the following are identified. PAC may attach to the axon's microtubule and interfere with axonal conduction and cause nerve damage (Tanner et al., J. Comp. Neurol. 395: 481-492, 1998). PACs do not cross the cerebral blood flow barrier and accumulate at high concentrations in the dorsal root ganglion (Cavaletti et al., Neurotoxicology 21: 389-393, 2000). In patients with PINP, nerve conduction studies showed a marked decrease in the function of Aβ nerves and a slight decrease in Aδ nerves, while C-fiber nerves did not decrease function (Dougherty et al., 109: 132-142, 2004). PAC administration in rats increases the spontaneous response of wide dynamic range neurons in spinal cord, increases posterior conduction to invasive stimuli or heat stimuli, and increases wind-up to electrical stimulation of the skin (Cata et al. Neuroscience 138: 329-338, 2006).
PINP is a dose-limiting adverse effect that most drugs used in clinical practice are ineffective or at very high doses. Nonsteroidal antiinflammatory drugs are ineffective or insignificant in animal studies, and opioids are effective only at very high doses. Drugs such as gabapentin and the sodium channel blocker, Mexiletine, have some effects when repeatedly administered (Xiao et al., Neuroscience 144: 714-720, 2007). Therefore, the development of new therapeutic agents for these diseases is urgently required.
Non-steroidal painkillers such as aspirin, tylenol, and ibuprofen, which are currently widely used in clinical practice, have no effect on chronic pain. Therefore, in clinical practice, gabapentin is the only use for the purpose of controlling these chronic pain. Drug analgesics may be used, of course, but there is a pressing need to develop new and potent new drugs due to their well-known dependence and side effects.
Therefore, in order to develop chronic pain relieving, inhibiting or therapeutic agents, the present inventors screened 50 or more herbal medicines and potent medicines potentially effective for chronic pain, and found that Gastrodiae Rhizoma has excellent chronic pain inhibiting activity Respectively.
Accordingly, the object of the present invention is to provide a composition for alleviating, inhibiting, or treating chronic pain comprising an extract of Chunmei as an active ingredient, wherein the Chunmei extract according to the present invention is a composition comprising a solvent extract of Chunmei, a solvent fraction thereof, .
It is another object of the present invention to provide a method for alleviating, suppressing, or treating chronic pain by administering to a subject in need thereof an alleviating, inhibiting or therapeutically effective amount of chronic pain of the extract of Chimpanzee.
Another object of the present invention is the use of Chimpanzee extract for use in the alleviation, inhibition or treatment of chronic pain.
It is a further object of the present invention to provide a composition for alleviating, inhibiting, or treating chronic pain comprising a single compound isolated from Chumam extract as an active ingredient.
It is a further object of the present invention to provide a method for alleviating, inhibiting, or treating chronic pain by administering to a subject in need thereof a mitigating, inhibiting, or therapeutically effective amount of chronic pain.
Another object of the present invention relates to the use of a single compound isolated from Chunmei extract to alleviate, inhibit or treat chronic pain.
The present invention relates to a composition for relieving, inhibiting, or treating chronic pain, comprising an extract of Chimmae as an active ingredient, wherein the Chimma extract according to the present invention comprises a solvent extract of Chunmei, a solvent fraction thereof or a column fraction, The extracts exhibit chronic pain, relief, inhibition and therapeutic activity.
The present inventors identified specific fractions of Chumma extract with significantly elevated chronic pain relieving activity and isolated the active substance.
Hereinafter, the present invention will be described in more detail
Gastrodiae Rhizoma is a tuberous stem of Gastrodia elata Blume (Orchidaceae). It is traditionally used to treat brain diseases such as headache, epilepsy, stroke and dizziness as well as diabetes, disc, cancer, gastric ulcer, And has been known to have effect on a wide range of diseases. Chunma has been widely used as a remedy for hypertension treatment and headache in the private sector, and is reported to be used for the same purposes (dizziness, hypertension, headache).
Recent studies have shown that ethanol extracts from Chunma showed inhibitory effects on mouse acetic acid-induced writhing test, which is a model of acute pain, and its components, 4-hydroxybenzaldehyde (4-hydroxybenzaldehyde), 4-hydroxybenzyl alcohol (4-hydroxybenzyl alcohol), benzyl alcohol, bis (4-hydroxyphenyl) methane, vanillyl alcohol, and vanillin were also inhibited Ahn et al., J. Ethnopharmacol. 110, 476-482, 2007; Lee et al., Arch Pharm Res. 29, 849-858, 2006). Studies on complexes of alcohol-mixed alcoholic beverages have shown that acetic acid-induced writhing tests and hot plate methods are effective in high-volume experiments. However, these documents only demonstrate the effects of acetic acid induced acute pain or acute pain by hot plate.
Scientific or pharmacological studies have reported that extracts or fractions of Chumama have efficacy for chronic pain such as neuropathic pain, cancer pain and diabetic pain. This is because these chronic pain is completely different from the acute pain described above.
Recently, it has been reported that gastrodine (4-hydroxybenzyl alcohol 4-β-glucopyranoside) is inferior to diabetic pain in rats by intraperitoneal administration (Sun et al., Plos One 7: e39647, 2012). The foreign material is one of the components of Galeola faberi (Lee et al., Yao Xue Xue Bao 28, 766, 1993) or Chunma.
However, this prior art does not disclose the chronic pain of Chumam extract, nor does it describe the solvent fraction according to the present invention and the active ingredient isolated from the column fraction.
The present invention relates to an extract having a chronic pain-inhibiting activity containing an extract of Chunma, wherein the 'extract' is obtained by treating a solvent crude extract or a specific solvent soluble extract (solvent fraction) and a solvent crude extract or a solvent fraction by a column refining method And the chimme extract may be in the form of a solution, a concentrate or a powder.
The Gastrodiae Rhizoma according to the present invention refers to the gut root of Gastrodia elata Blume (Orchidaceae), and it can use all roots, stems, and leaves of the Gastrodiae Rhizoma.
The chimpanzee extract is prepared by dissolving at least one member selected from the group consisting of leaves, stems, and roots of the horse chestnut in an aqueous solution selected from water, a straight chain or branched alcohol having 1 to 4 carbon atoms, ethyl acetate, ether, chloroform, dichloromethane and benzene Or may be a crude extract obtained by extracting with one or more solvents. (V / v), 20 to 99% (v / v), preferably 30 to 99% (v / v) when a mixture of water and alcohol is used as a solvent used for preparing crude extract of horse chestnut (v / v), more preferably about 30 to 95% (v / v) of a linear or branched alcohol having 1 to 4 carbon atoms, preferably an aqueous methanol solution, an aqueous ethanol solution, an aqueous n-propanol solution, May be at least one selected from the group consisting of
The chewing gum extract according to the present invention may be a solvent fraction obtained by fractionating the solvent crude extract with an additional solvent. For example, the solvent crude extract may contain at least one solvent selected from the group consisting of hexane, ethyl acetate, dichloromethane, ≪ / RTI > For example, the solvent crude extract obtained by extracting the above-mentioned Chunmung extract with at least one solvent selected from the group consisting of water and a linear or branched alcohol having 1 to 4 carbon atoms is selected from the group consisting of hexane, ethyl acetate, dichloromethane, and butanol May be a solvent fraction using one or more solvents.
Preferably, the solvent fraction of the chewing gum according to the present invention may comprise said solvent crude extract, preferably the following solvent fraction.
1) Chromium solvent extracts were sequentially washed with hexane; Ethyl acetate; And fractions obtained with a mixture of dichloromethane and butanol,
2) ethyl acetate fraction I obtained by sequentially adding hexane and ethyl acetate to a crude solvent extract of a horse root,
3) butanoxine fractions I, obtained by sequentially adding hexane and butanol to a crude solvent extract of a horse root,
4) Ethyl acetate fraction II obtained by adding ethyl acetate to a crude solvent extract of horse chestnut, and
5) Butanol fraction obtained by adding butanol to crude solvent extract of horse chestnut II.
In particular, the aqueous alcoholic extract, ethyl acetate, and n-butanol fractions of Chunma showed strong analgesic activity in the neuronal pain rat model induced by paclitaxel, which is superior to gabapentin, the comparator drug, Respectively. Accordingly, the present invention provides an extract of Chumma which has the best effect of suppressing chronic pain in pharmacological activity among Chumma extract.
In another aspect, the present invention relates to a method for preparing an extract of Chumma having a chronic pain-inhibiting activity.
In one embodiment of the present invention, the chimpanzee extract comprises at least one member selected from the group consisting of leaves, stems, and roots of the genus Chunmei, with water, a linear or branched alcohol having 1 to 4 carbon atoms, ethyl acetate, ether, chloroform, Dichloromethane, and benzene. The extract may be a crude extract obtained by extraction with at least one solvent selected from the group consisting of dichloromethane and benzene.
The chewing gum extract according to the present invention will be described in more detail as follows: After cutting the chimney and washing it with water to remove the stenosed product, it is dried to about 5 to 20 times by volume, Is subjected to reflux extraction with an extraction solvent of 7 to 15 vol. After extraction, the filtrate is collected by filtration. The extraction temperature is not particularly limited, but it is preferably 40 to 110 占 폚, preferably 55 to 90 占 폚.
The extraction process may be repeated once or several times. In a preferred example of the present invention, a method of re-extraction after the first extraction may be adopted. In the case of mass production of herbal extracts, The loss is generated due to the high water content, so that the extraction efficiency is lowered only by the first extraction. In addition, the extraction efficiency of each step was verified, and it was found that about 80 to 90% of the total extraction amount was extracted by the second extraction.
In an embodiment of the present invention, when the extraction step is repeated twice, the obtained residue is subjected to reflux extraction again with an extraction solvent, about 5 to 15 times by volume, preferably 8 to 12 times by volume. After the extraction, the filtrate is combined with the previously obtained filtrate, and the filtrate is concentrated under reduced pressure to prepare a chymoma extract. The extraction efficiency can be increased by mixing the extraction solution obtained after the second extraction and the filtrate obtained after each extraction, but the extract of the present invention is not limited to the extraction number.
If the amount of the solvent used in the preparation of the chewing gum extract is too small, stirring becomes difficult and the solubility of the extract lowers and the extraction efficiency becomes poor. When the amount is too large, the amount of the solvent used in the following purification step is increased, The use amount of the solvent is preferably within the above-mentioned range.
The thus-obtained filtered extract is used at a concentration of about 10 to 30 times, preferably 15 to 25 times, more preferably about 20 times as much as the total amount of the concentrate to control the content of the remaining lower alcohol so as to be suitable for use as a pharmaceutical raw material The concentrate may be concentrated by
The extraction method used in the present invention may be any conventionally used method such as, but not limited to, cold-water extraction, hot water extraction, ultrasonic extraction, or reflux-cooling extraction.
The present invention provides a composition for alleviating, suppressing or treating chronic pain comprising the above-mentioned Chimpanzee extract as an active ingredient. The Chumma extract comprises a solvent extract of Chunmoo, a solvent fraction, and a column fraction, as described above. The chimpanzee extract preferably contains 0.01 to 30% by weight, 0.1 to 30% by weight, or 1 to 30% by weight, preferably 0.01 to 10% by weight, of at least one compound selected from the group consisting of the compounds represented by formulas %.
The present invention also provides a composition for alleviating, inhibiting or treating chronic pain comprising a compound of the following general formulas (1) to (6) as an active ingredient, which is a single compound isolated from Chimpanzee extract.
[Chemical Formula 1]
4-Hydroxybenzaldehyde
(2)
5- (hydroxymethyl) -furfural
(3)
1-furan-2-yl-2- (4-hydroxyphenyl) -ethanone
[Chemical Formula 4]
(4,4'-dihydroxydiphenyl) methane
[Chemical Formula 5]
5- (4-hydroxybenzyloxymethyl) -furan-2-carbaldehyde
[Chemical Formula 6]
5-Hydroxymethyl-2-furoic acid
The chronic pain may be, but is not limited to, neuropathic pain, cancer pain, diabetic pain and the like. Preferably, the chronic pain of the present invention is neuropathic pain.
The content of the extract as an active ingredient in the composition according to the present invention may be appropriately adjusted depending on the mode and purpose of use, patient condition, symptom type, and the like, and may be 0.001 to 99.9% by weight, 0.01 to 10% Or 0.1 to 99.9% by weight, preferably 0.1 to 50% by weight, or 0.1 to 40% by weight.
The compositions according to the present invention can be administered to mammals, including humans, in a variety of routes. The mode of administration may be any conventional manner and may be administered, for example, by oral, skin, intravenous, intramuscular, subcutaneous, and the like routes, preferably orally. The composition of the present invention may be formulated into oral formulations such as powders, granules, tablets, capsules, ointments, suspensions, emulsions, syrups and aerosols, or parenteral formulations such as transdermal preparations, suppositories, And the like.
In addition to the above-mentioned mixed extract, the composition of the present invention may further comprise pharmaceutically acceptable and physiologically acceptable carriers, excipients and diluents. Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are usually used can be used. Solid formulations for oral administration 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. For oral administration, suspensions, solutions, emulsions, syrups, ointments and the like may be used. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, transdermal preparations and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
In embodiments where the compositions of the present invention are applied to humans, the herbal extract compositions of the present invention may be administered alone, but may be administered in combination with a pharmaceutical carrier selected in consideration of the mode of administration and standard phamaceutical practice Can be mixed and administered. For example, the herbal extract-containing composition of the present invention may be in the form of tablets containing starch or lactose, in the form of capsules containing the ingredients alone or as excipients, or as elixirs or suspensions containing chemicals that taste or color It can be administered orally, buccally or sublingually in its form. Such liquid preparations may contain suspending agents (e. G., A mixture of a semisynthetic glyceride such as methylcellulose, witepsol or apricot kernel oil and a PEG-6 ester or a mixture of PEG-8 and caprylic / Glyceride mixture such as a mixture of glycerides).
The dose of the herbal medicine extract-containing composition of the present invention may vary depending on the patient's age, weight, sex, dosage form, health condition and disease severity, and may be once or twice daily It may be administered in divided doses. For example, the daily dose may be 0.1 to 500 mg / kg, preferably 0.5 to 300 mg / kg, based on the active ingredient content. The above-mentioned dosage is an average case, and the dose may be high or low depending on individual differences. If the daily dose of the mixed-extract-containing composition of the present invention is less than the above-mentioned dosage, no significant effect can be obtained. If the daily dose exceeds the above-mentioned range, it is not only economical but also causes an undesirable side effect It may be within the above range.
In another aspect, the present invention provides a health functional food for chronic pain relief, inhibition, or treatment containing the above-mentioned Chamae plum extract. The health functional food may be various foods, beverages, food additives, and the like.
The content of the herbal medicine extract as an active ingredient contained in the health functional food is not particularly limited according to the form of the food and the intended use, and may be, for example, 0.01 to 15% by weight of the total food, Can be added at a ratio of 0.02 to 10 g, preferably 0.3 to 1 g, based on 100 ml.
The health beverage composition of the present invention may contain various flavors or natural carbohydrates such as ordinary beverages as an additional ingredient, as long as it contains the extract as an essential ingredient at the indicated ratio, and there is no particular limitation to the liquid ingredient. Examples of the above-mentioned natural carbohydrates include monosaccharides such as disaccharides such as glucose and fructose such as maltose, sucrose and the like and polysaccharides such as dextrin, cyclodextrin and the like Sugar, and sugar alcohols such as xylitol, sorbitol, and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
In addition to the above-mentioned composition, the composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
In particular, when the herbal composition of the present invention is administered to a human body, there is no worry about side effects in comparison with other synthetic drugs in view of the general characteristics of natural extracts. In fact, toxicity tests on standardized herbal compositions show no effect on the living body .
The present invention relates to a composition for alleviating, suppressing or treating chronic pain comprising an extract of Chimpanzee or a compound isolated therefrom as an active ingredient, and a method for producing the composition. The Chimpanzee extract according to the present invention has an excellent effect on the chronic pain- And may be used as a pharmaceutical composition or functional food composition useful for alleviating, inhibiting and treating various chronic pain.
FIG. 1 is a graph comparing the effect of 100% ethanol extract (a-4) of Ganoderma lucidum and gabapentin against chronic pain in Example 3 of the present invention.
FIG. 2 is a graph showing the effect of the ethyl acetate fraction (c-2) of Chimpanzee extract of Example 4 of the present invention on chronic pain suppression.
FIG. 3 is a graph showing the results of the isolation of the compound (com-1: 4-Hydroxybenzaldehyde, com-2: 5- (hydroxymethyl) -furfural, com-3: 1-furan- - (4-hydroxyphenyl) -ethanone), respectively.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.
Example 1: Preparation of Ganoderma lucidum extract
Chunma was purchased from Dae Kwang Pharmaceutical Company of Chuncheon and Dongbang Pharmaceutical Co., Ltd. of Seoul, and the identification of medicines was made by Professor Kwon Yong Soo of Kangwon University.
1.1. Solvent Crude extract Produce
Each 100 g root of root was extracted by adding 1 L of each solvent by the following method and extracted twice at room temperature. The extract was vacuum-dried, and the amount of the powder obtained after drying was shown in Table 1.
1-2. menstruum The fraction (1) Produce
10,000 g of horse chestnut was extracted with 40 L of 90% ethanol at 80 ° C for 4 hours, refluxed three times, and vacuum dried (870 g). Then, it was dissolved in 4 L of water, and then fractionated successively with the following solvent, followed by vacuum drying.
That is, a crude extract of a 90% aqueous ethanol solution was successively mixed with n-hexane to obtain an n-hexane fraction (c-1), and ethyl acetate was mixed with the remaining water fraction to obtain an ethyl acetate fraction (c-2) , And a fraction (c-3) obtained from a mixed solvent of dichloromethane (50%) and n-butanol (50%) was obtained in the remaining water fraction and the residue was taken as a water residue (c-4) , And the amounts of the dry powders of the solvent fractions, respectively, are shown in [Table 2].
1-3. menstruum The fraction (2) Produce
1,000 g of horse chestnut was extracted with 70% ethanol three times at 80 ° C for 4 hours and vacuum dried (388.8 g). Thereafter, the resultant was dissolved in 1 L of water, followed by fractionation with n-hexane to discard the n-hexane fraction layer. The remaining polar solvent layer was fractionated with ethyl acetate and dried in vacuo to obtain a dried fraction (30.6 g) Respectively.
1-4. menstruum Of fraction (3) Produce
1,000 g of horse chestnut was extracted with 70% ethanol three times at 80 ° C for 4 hours and vacuum dried (362.2 g). Thereafter, the resultant was dissolved in 1 L of water, followed by fractionation with n-hexane to discard the n-hexane fraction layer. The remaining polar solvent layer was fractionated with n-butanol and dried under vacuum to obtain a dried fraction (92.3 g) Respectively.
1-5. menstruum The fraction (4) Produce
10,000 g of horse chestnut was extracted with 35 L of 80% ethanol three times at 80 ° C for four hours and vacuum dried (960 g). 100 g of the solution was dissolved in 1 L of water, followed by fractionation with ethyl acetate and vacuum drying to obtain a dried fraction (18.8 g), which was designated as sample f-1.
In addition, 800 g of the ethanol extract was dissolved in 3 L of water, followed by fractionation with n-butanol and vacuum drying to obtain a dried fraction (233 g), which was designated as sample f-2.
Example 2: Establishment of an animal model of chronic pain: Paclitaxel - induced neuropathic pain ( PINP )
Experimental animals are young Sprague-Dawley male rats (175-500g, Harlan Sprague-Dawley). They are housed in dark and light-conditioned rats at 12-hour intervals. All animals were tested and confirmed that they had no abnormality after 7 days of adaptation period after arrival.
PAC (Taxol®, Sigma, St. Louis, MO, USA) is dissolved in DMSO at a concentration of 50 mg / ml and stored in a freezer at -80 ° C. Before using the solution, mix the same amount of Tween 80 solution and add sterile physiological saline to make the
The susceptibility to mechanical stimuli of the hind paws was then measured using an up-down method (Dixon, Annu. Rev. Pharmacol. 20, 441, 1980; Chaplan et al. J. Neurosci. Methods 53, 55, 1994). The rats were placed on a plastic mesh (8.5 x 28 x 10 cm) with a wire mesh on the floor and adjusted for 15 minutes. The VF filaments were stimulated vertically for 3 to 4 seconds between the foot and the third and fourth toes of the hindpaw Rats are considered positive if they show a rapid avoidance response, immediately flinch as the filaments are removed, or lick their soles.
A total of 8 VF filaments are used (corresponding to filament strengths of 3.65, 3.87, 4.10, 4.31, 4.52, 4.74, 4.92, 5.16 and corresponding to 0.45, 0.76, 1.26, 2.04, 3.31, 5.50, 8.32, 14.45 grams). Start with 4.31 filaments. If positive, show weaker filaments. If negative, show stronger filaments. Test six times and record the response. Using these reactions, a 50% threshold is calculated (50% threshold = 10 (X + kd) / 104, where X is the log unit of the last applied filament and k is the value shown in the positive / negative response pattern table , And d represents the mean value (= 0.22) of the difference between the stimuli). The graph shows the threshold for the mechanical stimulus in grams. The measurement of pain was blind because it varied according to the person who performed it.
In addition, in order to determine the sedation induction of the test drug, the posture and the reflection of the rat were determined on the basis of each time after administration (Devor and Zalkind, Pain 94, 101, 2001; Kim et al. 116, 2004).
Five categories through posture:
0 - routine posture and parenting, hair trim;
1-Appropriate anxiety and mobility loss, weight bearing but not moving;
2 - weight bearing but extreme mobility missing;
3 - maintain muscle weight that is unsupportive for weight and can make some object-oriented movements;
4 - No movement and no movement without exercise.
Correction Five categories of reflection:
0 - resisting the rats to stand upright to build up the defenses immediately, quickly and powerfully correct posture;
1 - Standing aside the head to moderate posture, fast but weak posture to correct;
2 - If you put your sideways on the side, you can not resist.
3 - unable to establish the charge immediately;
4 - Can not move.
Immediately after the pain is measured in all the experiments, the sedation of the substance is measured
Example 3: Assessment of Chronic Pain Control Ability of Chunma Extracts
Paclitaxel repeated ip injections (2 mg / kg, 0, 2, 4 and 6 days; total 8 mg / kg) resulted in a 50% mechanical threshold of the rats at the normal (pain threshold of 18.7 grams, 6-8 days) (Kim et al., 2010), which slowly reduced to 0.8 grams on days 12-14, resulting in hyperalgesia and allodynia, which were maintained for at least two and a half months. Because the pain threshold value is proportional to the log scale as compared with the degree of pain in the clinical patient, the y-axis of the chart is represented by a logarithmic scale.
The activity of reducing pain after single oral administration of each crude extract of Example 1 to 200 mg / kg was compared and the results are shown in [Table 3].
The 100% ethanol extract (a-4) showed the strongest activity. The threshold values were 6.1, 10.5, 5.9 and 3.3 grams after 1, 1.5, 2, and 3 hours after oral administration and statistically And significantly decreased pain (Fig. 2).
Threshold values were not significantly changed after 0.5, 1, 1.5, 2, and 3 hours after oral administration of the control drug gabapentin at 100 mg / kg (maximum dose without sedation) compared to the solvent administration group (FIG. 2) . After 3 days of oral administration, the threshold value was significantly increased up to 3.7 grams.
n = 3 to 6, *: P < 0.05, significant difference from the control group
These results indicate that the water-soluble alcohol extract of Chunma exhibits strong activity against single administration, and the ethanol extract has the highest activity. On the other hand, the activity of gabapentin was weak.
Example 4: Charm Of fractions Test of chronic pain control
The activity of reducing the pain after single oral administration of the fractions of Chumma obtained in Examples 1-2 to 1-5 at 100 mg / kg was compared, and the results are shown in Table 4. (C-2, 100 mg / kg) showed the most potent activity. The threshold values of 0.5, 1, 1.5, 2, and 3 hours after oral administration were 3.4, 4.8, 9.5, 8.2, 3.2 grams , Indicating a significant increase in analgesic activity compared to the solvent-treated group (Figure 3).
n = 3 to 6, *: P < 0.05, significant difference from the control group
(C-2, d, f-1) and the n-butanol fraction (e, f-2) exhibited analgesic activity Showed strong chronic pain-inhibiting activity.
In addition, if the sedation is induced, the animal is in a state of no movement and lying, almost similar to anesthesia, so that when sedation is induced in the patient, it is impossible to perform daily activities while lying asleep. (A-4) and ethyl acetate extract (c-2) of the present invention have a "0" value in the movement and the reflex degree in the administration dose, "Showed no sedation. Therefore, the increase in the threshold value of extract was considered to be analgesic action, and gabapentin, the reference drug, did not show any sedative effect.
Example 5: Separation of active substances and determination of structure
According to the activity test result of Example 4, the material was separated from the sample c-2 ethyl acetate fraction obtained in Example 1-2 using a silica gel column. Specifically, 37 g of the EtOAc soluble fraction was added to a silica gel column (500 g, Merck, 63-200 μm, 7 x 50 cm) to separate the active material from the ethyl acetate fraction, and n-hexane: EtOAc (3: 2) To obtain 7 fractions, respectively.
Fraction 3 (2.5 g) was further passed through a silica gel column (200 g, Merck, 63-200 袖 m, 5 x 50 cm) and subjected to column chromatography using n-hexane: EtOAc (3: Respectively. The fraction 3-2 (0.3 g) was further subjected to column chromatography on a silica gel column (30 g, Merck, 40-63 탆, 3 x 20 cm) and CHCl 3 : MeOH (34: 1) as a solvent to give Compound 1 (215 mg, 4-hydroxybenzaldehyde). The fractions 3-4 (1.1 g) were again placed in a silica gel column (150 g, Merck, 40-63 μm, 3 x 50 cm) and column chromatographed with CHCl 3 : MeOH (34: 1) Four fractions were obtained from 3-4-1 to 3-4-4. A small fraction of 3-4-2 (0.15 g) was placed in an ODS column (30 g, YMC-Gel ODS-A, s-150 탆, 3 x 20 cm) and MeOH: H 2 O (50:50) (95 mg, 1-furan-2-yl-2- (4-hydroxyphenyl) -ethanone) was obtained by column chromatography on an ODS column (440 mg, YMC-Gel ODS-A, s-150 m, 3 x 50 cm) and column chromatography with MeOH: H 2 O (50:50) -dihydroxydiphenyl-methane).
Fraction 4 (3.5 g) was added to a silica gel column (200 g, Merck, 63-200 μm, 5 x 50 cm) and column chromatography with CHCl 3 : MeOH (34: And divided into five small fractions from 4-5. Column chromatography of the small fraction 4-4 (1.6 g) was carried out on an ODS column (70 g, YMC-Gel ODS-A, s-150 μm and 3 x 50 cm) -hydroxybenzyloxymethyl) -furan-2-carbaldehyde).
Fraction 5 (9.8 g) was loaded on a silica gel column (300 g, Merck, 63-200 μm, 7 x 50 cm) and column chromatographed with n-hexane: EtOAc (3: 2) as solvent to give 5 small fractions (2.5 g) was added to a silica gel column (150 g, Merck, 40-63 μm, 5 x 50 cm), and column chromatography with n-hexane: EtOAc (3: 1) Compound 2 (980 mg, 5- (hydroxymethyl) -furfural) was obtained.
Fraction 6 (7.3 g) was loaded on an ODS flash column (130 g, RediSep®, Teledyne Isco) and subjected to column chromatography using MeOH: H 2 O (30:70) as a solvent to give 5 And divided into small fractions. The small fraction 6-2 (0.8 g) was loaded on an ODS flash column (130 g, RediSep®, Teledyne Isco) and subjected to column chromatography using MeOH: H 2 O (10:90) as a solvent to obtain 6-2-1 to 6 And divided into 6 small fractions. The fraction 6-2-2 (0.4 g) was added to a sephadex LH20 column (30 g, 3 x 50 cm) and purified by using a solvent of MeOH: H 2 O (40:60) to obtain Compound 6 (130 mg, 5-hydroxymethyl- -furoic acid.
These structures were determined by comparing the following instrumental analyzes with previously reported literature values (Compound 1: Xiao et al., China Journal of Chinese Materia Medica, 27, 35-36, 2002; Compound 2: Shen and Mu, Planta Medica, Phar. Bull., 29, 55-62, 1981, Fisher et al., Magnetic. ≪ RTI ID = 0.0 > Lee et al., Planta Medica, 73, 1287-1291, 2007; Compound 6: Yang et al., Pharmaceutical Biology, 48, 589-594, 2010).
The structural formulas of each of the compounds isolated in the above examples are specifically described below.
Compound 1 (4-Hydroxybenzaldehyde)
[Chemical Formula 1]
1 H-NMR (600 MHz, CD 3 OD, ppm)
(2H, d, J = 8.8 Hz, H-3, H-5)
13 C-NMR (150 MHz, CD 3 OD, ppm)
C-6), 130.95 (C-1), 116.89 (C-3, C-5)
Compound 2 (5- (hydroxymethyl) -furfural)
(2)
1 H-NMR (600 MHz, CD 3 OD, ppm)
(1H, d, J = 3.6 Hz, H-4), 4.68 (2H, s, CH 2 OH )
13 C-NMR (150 MHz, CD 3 OD, ppm)
(C-3), 110.02 (C-4), 57.43 (CH 2 OH), 177.82 (CHO), 161.01
Compound 3 (1-furan-2-yl-2- (4-hydroxyphenyl) -ethanone)
(3)
1 H-NMR (600 MHz, CD 3 OD, ppm)
D, J = 8.4 Hz, H-2 ', H-3), 7.76 (1H, d, J = 1.0 Hz, (2H, s), 6.76 (2H, d, J = 8.4 Hz, H-3 ', H- 7-CH 2 )
13 C-NMR (150 MHz, CD 3 OD, ppm)
C-6 '), 125.03 (C-4), 152.08 (C-2), 147.47 1 '), 118.75 (C- 3), 115.04 (C-3', C-5 '), 112.21 (C-4), 33.23 (C-7, CH 2)
Compound 4 (4, 4'-dihydroxydiphenyl) methane
[Chemical Formula 4]
1 H-NMR (600 MHz, CD 3 OD, ppm)
H-6 '), 6.71 (4H, d, J = 8.5 Hz, H-3, H-5 / H -3 ', H-5') , 3.51 (2H, s, CH 2)
13 C-NMR (150 MHz, CD 3 OD, ppm)
C-1 ', 115.42 (C-3 / C-4'), 130.53 (C-2, C-6 / C- C-5 / C-3 ' , C-5'), 34.77 (CH 2)
Compound 5 (5- (4-hydroxybenzyloxymethyl) -furan-2-carbaldehyde)
[Chemical Formula 5]
1 H-NMR (600 MHz, CD 3 OD, ppm)
(2H, d, J = 8.4 Hz, H-2 ', H-6'), 6.76 (2H, , d, J = 8.4Hz, H -3 ', H-5'), 6.56 (1H, d, J = 3.7Hz, H-4), 4.48 (2H, s, 7-
13 C-NMR (150 MHz, CD 3 OD, ppm)
(C-6), 158.81 (C-5), 157.05 (C-4 '), 152.70 (C-2), 129.64 C-3), 114.85 (C-3 ', C-5'), 111.37 (C-4), 72.21
Compound 6 (5-Hydroxymethyl-2-furoic acid)
[Chemical Formula 6]
1 H-NMR (600 MHz, CD 3 OD, ppm)
7.15 (1H, d, J = 3.4Hz, H-3), 6.45 (1H, d, J = 3.4Hz, H-4), 4.56 (2H, s,
13 C-NMR (150 MHz, CD 3 OD, ppm)
160.42 (C = O), 159.29 (C-2), 144.34 (C-5), 118.54 (C-3), 108.81 (C-4), 56.13 (
Example 6: Content analysis of the extract of Chunmei
(4-hydroxyphenyl) methane, 1-furan-2-yl-2 (4-hydroxyphenyl) -ethanone, 5-hydroxymethyl-2-furoic acid, The ethyl acetate fraction (c-2, d, f-1) showing strong anticholinergic activity in Example 4 was found to be contained in the chumma extract and fractions, and 5- (4-hydroxybenzyloxymethyl) ) And n-butanol fraction (e, f-2) were subjected to a physico-chemical analysis test using HPLC as follows.
High performance liquid chromatography was measured using a PDA (Waters Alliance Model 2695). The column used was a Waters Symmetry C18 250 x 4.6 mm, 5 탆, and the sample temperature was maintained at 25 캜 and the column temperature was maintained at 40 캜. The concentration of the sample was 10 mg / ml, 10 μl was injected, and the flow rate was 1.0 ml / min. The standard substances were purchased from commercial sources such as 5- (hydroxymethyl) -furfural, 4-hydroxybenzaldehyde and bis (4-hydroxyphenyl) methane, and 1-furan-2-yl-2- (4-hydroxyphenyl) -hydroxymethyl-2-furoic acid, 5- (4-hydroxybenzyloxymethyl) -furan-2-carbaldehyde was isolated and purified from chymase. The mobile phase was prepared by dissolving 6.5 g of Ammonium Formate in 1 L of water. The solution was adjusted to pH 4.5 ± 0.05 with formic acid and 95: 5 with methanol (solvent A) and methanol (solvent B) (A: B = 94: 6 to 94: 6), 10 to 30 minutes (A: B = 94: 6 to 60:40), 30 to 40 minutes ), 40 to 50 minutes (A: B = 60:40 to 10:90), 50 to 55 minutes (A: B = 10:90 to 10:90), 55 to 56 minutes (A: ~ 94: 6) and 56 ~ 65 minutes (A: B = 94: 6 ~ 94: 6). The results are shown in the following Table 5. The calculation of the active ingredient content in the extract was expressed by the weight percentage of the respective standard substances, that is, the weight of the single compound as a percentage of the total weight of the extract to be analyzed as a percentage By weight.
Example 7: Test of inhibition of chronic pain of isolates
As a result of Examples 3 and 4, in order to test the activity of the isolates obtained by the method of Example 2 in order to find the active substance from the most active fraction c-2, the pain was completely caused On the 25th day, 30 mg / kg or 100 mg / kg of test substance were orally administered, respectively, and pain thresholds were then measured at 0.5, 1, 1.5, 2, 3 and 4 hours. The results are shown in the following [Table 6] and [Figure 3].
n = 6, *: P <0.05, significant difference from the control group
As shown in the table above, the isolated materials 5- (hydroxymethyl) -furfural, 4-hydroxybenzaldehyde, Bis (4-hydroxyphenyl) methane, 1-furan- (4-hydroxybenzyloxymethyl) -furan-2-carbaldehyde and 5-hydroxymethyl-2-furoic acid significantly increased the threshold value as compared with the untreated control group and showed strong analgesic action. Substance.
Example 8. Acute toxic black
To test for acute toxicity, sample a-4, sample c-2, and sample e were used. 4 and c-2 were orally administered at 500 mg / kg, 1 g / kg and 2 g / kg to ICR mice (6 weeks of age, purchased from Nara Biotech, SPF) There were no abnormal behaviors or dead individuals. Therefore, these compositions may be used safely.
As a result of the above examples, the water-soluble alcohol extract, ethyl acetate and n-butanol fraction of Chunma showed strong analgesic action in the neuropathic rat model induced by paclitaxel, and this efficacy has a stronger analgesic effect than the comparative drug gabapentin .
Particularly, the fraction containing the isolated compound as a main component It can be used as a powerful chronic pain remedy. These results, as the first invention, confirm that the potency of the activity as a therapeutic agent for chronic pain is much more effective than the therapeutic agents so far.
Claims (18)
Wherein the solvent fraction is a solvent fraction using at least one solvent selected from the group consisting of hexane, ethyl acetate, dichloromethane and butanol.
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