JP2006306811A - Analgesic composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an analgesic composition which is safe and does not produce a side effect. <P>SOLUTION: Pain can be reduced by administering an amino acid, theanine, passing through a blood-brain gate as such or a dipeptide comprising the theanine and another amino acid and passing through a blood-brain gate. This composition can be added to drinks, foods or medicines. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an analgesic composition comprising as an active ingredient a theanine that is an amino acid that passes through the blood-brain barrier and / or a dipeptide containing theanine. The present invention also relates to a method for producing the analgesic composition.

  Pain is a feeling that the body is painful and causes discomfort, pain, and grief. The pain may be persistent pain or pulsatile pain. It can also be stabbed, tingling, or tightened. No matter how you feel pain, only those who have experienced pain can describe or define pain. Pain is truly something that cannot be assessed by a third party because there are so many individual differences.

  Pain is clinically classified into acute pain and chronic pain (persistent pain). Acute pain occurs due to specific causes such as wounds and inflammation, and all conventional analgesics have been developed using acute pain as a control and applied clinically. Chronic pain, on the other hand, persists for months or years after the wound that caused acute pain has healed. Conventional analgesics are not always effective for chronic pain, and various drugs (anti-anxiety drugs, anticonvulsants, etc.) are used depending on the pathological condition. However, the fact is that there is no drug that is decisive for healing chronic pain (Non-patent Document 1).

Existing analgesics can be divided into two categories. One is narcotic analgesics such as morphine, codeine and dihydrocodeine, and the other is non-steroidal such as aspirin, ibuprofen NSAIDS (non-steroidal anti-inflammatory drugs).
Narcotic analgesics act on receptors in the central nervous system to relieve both mild and severe pain. Used in increasing doses depending on the degree of pain, the analgesic effect is outstanding. However, the effects of narcotic analgesics are practically dose dependent, resulting in tolerance to analgesics. In the worst case, it is known that there are side effects such as a decrease in respiratory and circulatory function, and there are also addictive effects.

Hiroki Takagi, Pharmacology of acute pain and chronic pain, Journal of the Japan Medical Association 104, No. 1, pp. 37-41, 1990

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a safe analgesic composition that does not exhibit dependency and tolerance and has no side effects.

As a result of intensive studies to solve the above problems, the present inventors have found that theanine, which is a kind of amino acid that passes through the blood / brain barrier, and a peptide containing theanine, which is a kind of amino acid that passes through the blood / brain barrier, It has been found that it has an analgesic action, and has basically completed the present invention.
Theanine is an amino acid contained in tea and has an immediate effect in addition to no side effects. The above-described effect relating to the composition of the present invention is a novel effect that the present inventors have found for the first time.

That is, the present invention includes the following (1) to (5).
(1) An analgesic composition comprising as an active ingredient an amino acid that passes through the blood / brain barrier and / or a peptide containing an amino acid that passes through the blood / brain barrier.
(2) The analgesic composition, wherein the amino acid described in (1) is theanine.
(3) The peptide according to (1) is composed of (A) theanine and (B) theanine, glutamine, alanine, asparagine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, An analgesic composition comprising a dipeptide composed of one kind of amino acid selected from serine, threonine, tryptophan, tyrosine, valine, arginine, and cysteine.
(4) Food / beverage products and pharmaceuticals containing the composition according to any of (1) to (3).
(5) A method for producing a tablet containing the composition according to any one of (1) to (3).

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the analgesic composition which does not express dependence and tolerance, and does not have a side effect, the food-drinks, and a pharmaceutical containing this composition.

Next, embodiments of the present invention will be described in detail, but the technical scope of the present invention is not limited by these embodiments, and can be implemented in various forms without changing the gist of the invention. be able to. Further, the technical scope of the present invention extends to an equivalent range.
The blood / brain barrier in the present invention is a mechanism that prevents substances in the blood from passing through the brain at random, such as a barrier between the blood and the brain. Some amino acids selectively pass through the blood-brain barrier, and there are several types of transport systems. The amino acid used in the present invention is an amino acid that passes through the blood-brain barrier, and in particular is an amino acid that is transported via the L system. Amino acids transported via the L system are long-chain neutral amino acids such as phenylalanine, tyrosine, leucine, isoleucine, valine, histidine, methionine, threonine, and theanine.

  The theanine used in the present invention is a glutamic acid derivative contained in tea leaves, which is the main ingredient of the umami of tea and is used as a food additive for the purpose of taste. The theanine used in the present invention includes a method for extracting from tea leaves, a method for obtaining theanine by organic synthesis reaction (Chem. Pharm. Bull., 19 (7) 1301-1307 (1971)), glutamine and ethylamine. A method of obtaining theanine by allowing glutaminase to act on a mixture of the above (Japanese Patent Publication No. 7-55154), culturing a cultured cell group of tea in a medium containing ethylamine, and increasing the amount of theanine accumulated in the cultured cell group There are a method for promoting the growth of the group (Japanese Patent Laid-Open No. 5-123166) and a method for obtaining theanine by replacing ethylamine with an ethylamine derivative such as ethylamine hydrochloride (Japanese Patent Laid-Open No. 2000-026383). Examples of the tea leaves here include green tea, oolong tea, and black tea. Theanine obtained by such a method can be used in any of the L-form, D-form, and DL-form, but the L-form is also recognized as a food additive, economically. In the present invention, the L-form is preferable because it is easy to use.

The theanine used in the present invention may be in any form such as a purified product (theanine content of 98% or more), a crude product (theanine content of 50% to 98%), an extract extract (theanine content of 1% to 50%). .
Theanine used in the present invention is highly safe. For example, in an acute toxicity test using mice, there is no death due to oral administration of 5 g / kg, and no abnormality is observed in the general state and body weight. In particular, theanine is known as a umami component of tea and is also used as a food additive for flavoring purposes, and there is no limit to the amount of addition in the Food Sanitation Law.

  The peptide in the present invention is a compound formed by condensing two or more amino acids by peptide bonds (also called amide bonds). A thing consisting of many amino acids is called a polypeptide, and a protein consists of one or several polypeptides. Hydrolysis of the peptide produces the original amino acid. Dipeptide is a peptide in which two amino acids are peptide-bonded. Although the manufacturing method of a dipeptide is not specifically limited, It can produce | generate by chemical synthesis, enzyme synthesis, and protein hydrolysis.

  The dipeptide in the present invention is theanyl theanine, theanyl glutamine, glutaminyl theanine, theanyl alanine, alanyl theanine, theanyl asparagine, asparaginyl theanine, theanyl glutamic acid, glutamyl theanine, theanyl aspartic acid, aspartyl Theanine, theanyl glycine, glycyl theanine, theanyl histidine, histidyl theanine, theanyl isoleucine, isoleucine theanine, theanyl leucine, leusilyl theanine, theanyl lysine, lysyl theanine, theanyl methionine, methionyl theanine, theanyl Phenylalanine, phenylalanyl theanine, theanyl proline, prolyl theanine, theanyl serine, seryl theanine, theanyl threonine, threonyl theanine, theanyl trypto § down, tryptophanyl theanine, Te Anil tyrosine, thio shea sulfonyl theanine, Teanirubarin, valyl theanine, Te Anil arginine, arginyl theanine, Te Anil cysteine, and the like cysteinyl theanine.

"Pain" So-called pain is an emotional experience (Classification of Chronic Pain, 2nd Edition, IASP) associated with unpleasant perception, actual or potential tissue damage, or a state expressed using words like disability Task Force on Taxonomy, edited by H. Merskey and N. Bogdug, IASP Press, Seattle, 1994, p209).
A typical definition of acute pain is shown in Halpern, 1984, Advances in Pain Research and Therapy, Vol 7, Ed. C. Bendetii et al, page 47, but the invention is not so limited. . For example, types of unpleasant sensations, perceptions, emotional experiences that involve autonomic (reflex) reactions, and types of mental and behavioral responses caused by injury or acute illness. Tissue injury causes a series of nociceptive stimuli that are converted into action potentials that are transmitted to the spinal cord by nociceptors, which are transmitted to the upper nervous system. Examples of acute pain include toothache, postoperative pain, obstetric pain, neuralgia, myalgia and the like. Examples of acute pain that can be prevented or treated by the present compound include toothache, postoperative pain, obstetric pain, neuralgia, myalgia, and menstrual pain. In particular, the compounds of the present application can be administered prior to surgery in order to attenuate acute pain associated with surgical operations including dental surgery and labor.

  A typical definition of chronic pain is that according to Halpern, ibid, 1984, it is considered as persistent pain beyond the normal course of acute disease or pain beyond the normal course of wound healing. The invention is not limited to this. Chronic pain is a typical result of persistent dysfunction of the nociceptive pain system. Examples of chronic pain include trigeminal neuralgia, neuralgia after rash (a form of chronic pain associated with skin changes that occur in the skin following acute herpes), diabetic neuralgia, burning pain, phantom limb pain, headache, partial bias Headache, joint pain, elbow pain, cervical shoulder arm syndrome, benign prostatic hypertrophy, cervical vertebral prolapse, chronic and recurrent cystitis, degenerative arthritis, rheumatoid arthritis, osteoporosis, visceral chronic gastritis, cervical sprain, shoulder joint Examples include peripheral inflammation, osteoarthritis, and pain associated with cancer.

The analgesic composition means foods and medicines used for the prevention or treatment of pain, and includes analgesics, anesthetics, and medicines used for pain management before and after surgery.
The doses of theanine and dipeptide exhibiting analgesic action in the present invention are appropriately determined according to individual cases in consideration of symptoms, age of administration control, sex, etc., but usually 0.1 mg / kg body weight to 1000 mg / kg body weight (5 mg to 50000 mg per adult), preferably 1 mg / kg body weight to 100 mg / kg body weight (50 mg to 5000 mg per adult), 5 mg to 50000 mg per day for an adult, once or twice to 4 The administration may be divided into appropriate times. In the case of intravenous administration or continuous intravenous administration, administration may be performed at 1 to 24 hours per day. As indicated above, the dosage is determined by various conditions. If effective, dosages below the above ranges can be used.

In addition, the composition of the present invention can be used in combination with herbs, herbs, amino acids, vitamins, minerals, other foods and drinks, and materials and raw materials acceptable for pharmaceuticals. Here, the herbal medicine to be used is not particularly limited, and examples thereof include valerian, toki, glaze, peony, ginseng and the like.
The herbs are not particularly limited, but anise, carrot seed, clove, coriander, cypress, cinnamon, juniper, ginger, sweet orange, pine needle, basil, patchouli, bitter orange, fennel, black pepper, bay, peppermint , Bergamot, Mandarin, Myrrh, Lemongrass, Rosemary, Grapefruit, Cedarwood, Citronella, Sage, Thyme, Tea Tree, Violet Leaf, Vanilla, Hyssop, Eucalyptus, Lime, Lemon, Ylang Ylang, Cardamom, Clarisage, Jasmine, Geranium, Chamomile, Bulgarian rose, rose, olivenum, lavender, chamomile, geranium, sandalwood neroli, verbena, petit gren, vetiver, marjo Arm, Melissa, rosewood, St. John's wort, Thane Tojonzuwato, Kawakawa, and the like.

  Examples of amino acids used include amino acids that pass through the blood-brain barrier. As amino acids transported through the L system, long chain neutral amino acids such as phenylalanine, tyrosine, leucine, isoleucine, valine, histidine, methionine, threonine, theanine, and amino acids transported through the A system, Short chain neutral amino acids such as alanine, glycine, serine, threonine, and amino acids transported via the ASC system include alanine, serine, cysteine, etc., and amino acids transported by other systems include taurine, glutamic acid , Asparagine, lysine and arginine.

The vitamins used include vitamin A, vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, vitamin D, vitamin E, vitamin K, folic acid, nicotinic acid, lipoic acid, pantothenic acid, biotin, Examples include ubiquinone, prostaglandins, and derivatives of these vitamins, but are not limited thereto.
Examples of minerals used include, but are not limited to, calcium, iron, magnesium, copper, zinc, selenium, and potassium.

  In addition, aloe, royal jelly, melatonin, placenta, propolis, isoflavone, soy lecithin, egg yolk lecithin, egg yolk oil, chondroitin, cacao mass, collagen, vinegar, chlorella, spirulina, ginkgo leaves, green tea, Tochu tea, Huangcha tea, oolong tea , Mulberry leaves, camellia tea, banaba tea, unsaturated fatty acids, sugars such as sugar alcohols and oligosaccharides, fungi such as bifidobacteria and sockeye salmon, mushrooms such as agaricus persimmon, princess matsutake, ganoderma, maitake, blueberries, prunes , Grapes, olives, fruits such as ume and citrus, peanuts, almonds, seeds such as sesame and pepper, peppers, chili, leeks, pumpkins, cucumbers, carrots, burdock, morroheia, garlic, perilla, wasabi, tomatoes, raccoon, Leafy vegetables, vegetables such as salmon and beans, seaweeds such as seaweed, and seafood Shishitorikujira meat, etc. can be used cereals, further these extracts, dry products, crudely purified products, purified products, processed products, brewing products can also be used.

  In addition, in order to ingest the composition for analgesia, which is the product of the present invention, in a food or drink or a pharmaceutical product, in the form of a solution, suspension, powder, solid molded product or the like containing the composition of the present invention. There is no particular limitation as long as it is present. More specifically, kneaded products, processed soybean products, seasonings, mousse, jelly, frozen desserts, strawberries, chocolate, gum, crackers, cakes, bread, soup, coffee, cocoa, green tea, oolong tea, black tea, herbal tea , Concentrated fruit juice, concentrated reduced juice, straight juice, fruit mixed juice, fruit juice with fruit juice, fruit juice drink, fruit / vegetable mixed juice, vegetable juice, carbonated drink, soft drink, dairy drink, dairy products, tablets , Capsules, pharmaceuticals, granules and the like.

  Examples of pharmaceutical dosage forms include internal medicines, injections, patches, suppositories, and inhalants. The internal medicine is taken by a conventionally used tablet, capsule, powder, granule, drink or the like. An injection is injected into the body by intramuscular injection, intradermal injection, subcutaneous injection, intravenous injection or the like. A patch is absorbed into the body by mixing with a conventionally used ointment. Suppositories are absorbed in the body by mixing with cocoa butter, glycerogelatin, sodium stearate, propylene glycol monostearate and the like that are conventionally used. An inhaled drug is inhaled by a conventional method and is absorbed into the body from the nostril or oral cavity, for example, by adding the invention product to water vapor or air.

The tablet production method in the present invention is not particularly limited, and examples thereof include a method of directly compressing tablets after mixing the raw materials and a method of compressing the raw materials after wet granulation or dry granulation. Moreover, excipient | fillers, such as crystalline cellulose and saccharides, can also be mix | blended as needed. Furthermore, in order to improve tableting characteristics, lubricants such as sugar esters and polyglutamic acid esters can be used in combination. Generally, it can contain a taste-masking agent used in foods and drinks, pharmaceuticals and the like. Various flavors can be used as such a flavoring agent, and examples include lemon flavor, orange flavor, grapefruit flavor, chocolate flavor, dl-menthol, and l-menthol.
EXAMPLES Hereinafter, although an Example and a test example demonstrate this invention in detail, this invention is not limited to the said Example and test example.

Example 1 Production of Theanine by Enzymatic Method 0.3 M glutamine and 1.5 M ethylamine hydrochloride in 0.05 M borate buffer (pH 11) in the presence of 0.3 U glutaminase (commercial product) at 30 ° C. The reaction was performed for 22 hours to obtain 225 nmol of L-theanine. Subsequently, the reaction solution was subjected to Dowex 50 × 8 and Dowex 1 × 2 column chromatography (both manufactured by Muromachi Chemical Co., Ltd.), and this was treated with ethanol to isolate the target substance from the reaction solution.

  The isolated substance was subjected to an amino acid analyzer (manufactured by Hitachi, Ltd.) and paper chromatography, and confirmed to be L-theanine by showing the same behavior as the standard substance. Hydrolysis with hydrochloric acid or glutaminase produced glutamic acid and ethylamine in a 1: 1 ratio. Thus, since the isolated substance was hydrolyzed by glutaminase, it was shown that ethylamine was bound to the γ-position of glutamic acid. Moreover, it was confirmed by glutamate dehydrogenase that glutamic acid generated by hydrolysis was in the L form. From the above, 8.5 g of L-theanine was obtained.

<Example 2> Extraction of theanine from tea leaves 10 kg of tea (Camellia sinensis) leaves were extracted with hot water, passed through a cation exchange resin (Muromachi Chemical Co., Ltd., Dowex HCR W-2) and eluted with 1N NaOH. did. The eluted fraction was passed through activated carbon (Nimura Kagaku Kogyo Co., Ltd., Taiho activated carbon SG), and the eluted fraction with 15% ethanol was concentrated using an RO membrane (Nitto Denko Corporation, NTR729HF) and subjected to column chromatography. Then, recrystallization was carried out to produce 24.8 g of L-theanine.
In addition, L-theanine [trade name: Suntheanine, manufactured by Taiyo Kagaku Co., Ltd.] was used for each test and production of each composition described below.

すなわち、上記配合に従って各原料を混合し、造粒後に、１粒あたり０.７５ｇとなるように打錠した。 <Example 3> Production of theanine-blended tablets As an example of a tablet containing the theanine-blended analgesic composition, the raw materials shown in Table 1 below were mixed and then tableted to produce theanine-blended tablets.

That is, each raw material was mixed according to the said mixing | blending, and it tableted so that it might become 0.75g per 1 grain after granulation.

<Example 4> Production of theanyl theanine In the presence of 0.3 U glutaminase (commercial product) in 0.05 M borate buffer (pH 11), 0.32 M L-theanine was reacted at 30 ° C. for 22 hours to give 150 nmon. Of theanyl theanine was obtained. Next, the reaction solution was subjected to Dowex 50 × 8 and Dowex 1 × 2 column chromatography (both manufactured by Muromachi Chemical Co., Ltd.), and the target substance was isolated from the reaction solution.

すなわち、上記配合に従って各原料を混合し、造粒後に、１粒あたり０.７５ｇとなるように打錠した。 <Example 5> Manufacture of a tablet containing theanyl theanine As an example of a tablet containing a composition for analgesia containing theanyl theanine, the raw materials shown in Table 2 below were mixed and then tableted to produce a tablet containing theanyl theanine. .

That is, each raw material was mixed according to the said mixing | blending, and it tableted so that it might become 0.75g per 1 grain after granulation.

<Example 6> Preparation of a mixture of theanylglutamine and glutaminyltheanine 0.4 M L-theanine and 0.4 M L-glutamine in 0.05 M borate buffer (pH 11), 0.3 U glutaminase (commercially available) is present Under the condition, the mixture was reacted at 30 ° C. for 22 hours to obtain a mixture of 120 nmol of theanyl theanine and glutaminyl theanine. Next, the reaction solution was subjected to Dowex 50 × 8 and Dowex 1 × 2 column chromatography (both manufactured by Muromachi Chemical Co., Ltd.), and the target substance was isolated from the reaction solution. Theanylglutamine and glutaminyltheanine were confirmed by mass spectral analysis and structural analysis by NMR.

すなわち、上記配合に従って各原料を混合し、造粒後に、１粒あたり０.７５ｇとなるように打錠した。 <Example 7> Manufacture of tablets containing theanylglutamine and glutaminyltheanine mixture Tablets as an example of an analgesic composition containing theanylglutamine and glutaminyltheanine mixture and mixing the raw materials shown in Table 3 below, followed by tableting Then, tablets containing theanyl theanine and glutaminyl theanine were produced.

That is, each raw material was mixed according to the said mixing | blending, and it tableted so that it might become 0.75g per 1 grain after granulation.

<Test Example 1>
Effect of theanine in the acute pain test (tail flick test) The method for carrying out the acute pain test (tail flick test) was as follows. The test was conducted on male SD rats (1 group: 7 animals each) weighing about 200 g. As a test group, L-theanine was dissolved in distilled water and orally administered at 0.01 mg / kg body weight to 1000 mg / kg body weight. As a control group, only distilled water was administered. Rats after administration of theanine or distilled water were placed in a transparent plastic cylindrical cage, and the tail was extended backward along the groove provided. Nociceptive stimulation (thermal stimulation) was applied by irradiating high-intensity light (Tail Flick Analgesia Meter 0570-001L, Columbus Instruments International Co, Ltd., Columbus, Ohio, USA) at a position 2 to 3 cm from the tip of the tail. The time from the start of thermal stimulation to the jumping of the tail was measured to determine the reaction latency. In order to prevent tissue damage, thermal stimulation was set to a maximum of 14 seconds even when there was no response (cut-off time). Response latencies were measured before administration, 10, 30, 60, 90, 120 minutes after drug administration and at 1 hour intervals (up to 360 minutes) until the reaction time returned to baseline.

<Data analysis and statistics>
The response latency of the tail flick test was converted to% MPE (maximum response effect) according to the following formula.
% MPE = [(response latency after administration−response latency before administration) / (cutoff time−response latency before administration)] × 100 (cutoff time was 14 seconds)
The difference between the administration groups was subjected to a significant difference test by Student's t-test. A P value of 0.05 or less was considered statistically significant.

<Result>
The response latency of the tail flick test baseline (before administration) was 3.1 ± 0.1 seconds (mean ± standard deviation). Oral administration of theanine prolonged the tail flick response latency in a dose-dependent manner (FIG. 1). As shown in Table 4, in the group administered with theanine, it was found that the reaction latency was significantly prolonged at 0.1 mg / kg to 1000 mg / kg compared to the control group.

<Test Example 2>
Effect of theanyl theanine in the acute pain model (tail flick test) In Test Example 1, the same test (tail flick test) as in Test Example 1 was conducted except that theanyl theanine of Example 4 was used instead of theanine. Carried out.
<Data analysis and statistics>
% MPE (maximum reaction effect) described in Test Example 1 was determined. The difference between the administration groups was a significant difference test by Student's t-test. A P value of 0.05 or less was considered statistically significant.

<Result>
The response latency of the tail flick test baseline (before administration) was 3.1 ± 0.1 seconds (mean ± standard deviation). Oral administration of theanyl theanine prolonged the tail flick response latency in a dose-dependent manner (FIG. 2). As shown in Table 5, it was found that in the group administered with theanyl theanine, the response latency was significantly prolonged at 10 mg / kg to 1000 mg / kg compared to the control group.

<Test Example 3>
Effect of Theanylglutamine and Glutaminyl Theanine Mixture in Acute Pain Model (tail flick test) In Test Example 1, except for using theanylglutamine and glutamyltheanine mixture of Example 6 instead of theanine, A similar test (tail flick test) was performed.

<Data analysis and statistics>
% MPE (maximum reaction effect) described in Test Example 1 was determined. The difference between the administration groups was a significant difference test by Student's t-test. A P value of 0.05 or less was considered statistically significant.

<Result>
The response latency of the tail flick test baseline (before administration) was 3.0 ± 0.1 seconds (mean ± standard deviation). As shown in Table 6, it was found that in the group administered with theanylglutamine and glutamyltheanine, the response latency was significantly prolonged at 10 mg / kg compared with the control group. On the other hand, at 1000 mg / kg, there was no significant increase in the response latency with the control group.

<Test Example 4>
Effect of theanine on rat acute and chronic pain models The formalin test was performed as follows. Theanine was orally administered to rats, and after 10 minutes, anesthesia was performed with 3% halothane. After confirming that self-issued movement disappeared, the rats were removed from the anesthesia box. 50 μl of 5% formalin was subcutaneously administered to the back of the right hind limb with a 30G needle, and the rats were placed in a Plexiglas chamber and observed for 60 minutes. Pain response is measured by measuring the frequency of flinch and shaking the injected foot every 5 minutes after 1-2 minutes, 5-6 minutes, and 10 minutes after administration. Quantified. The formalin-stimulated pain response was expressed in a biphasic manner as described in J. Pharmacol. Exp. Ther. 263: 136-146, 1992. That is, Phase 1 (Phase 1) was observed 0-6 minutes after formalin administration, and Phase 2 (Phase 2) was observed after about 10 minutes after administration.

<Result>
In both Phase 1 (1-6 minutes) and phase 2 (10-60 minutes), the number of flinch decreased as the theanine dose increased (FIG. 3). Further, as shown in Table 7, the number of flinch was significantly suppressed in the theanine 0.1 mg / kg administration group as compared with the control group. This effect was observed up to the 1000 mg / kg administration group, with the theanine 10 mg / kg administration group being the maximum effect.

<Test Example 5>
Effect of theanyl theanine in rat acute and chronic pain models In Test Example 4, a formalin test was carried out in the same manner as in Test Example 4 except that theanyl theanine was administered instead of theanine.
<Result>
As shown in Table 8, the number of flinch in phase 2 (10-60 minutes) is significantly greater in the 10 mg / kg theanyl theanine administration group than in the control group. Was suppressed. This effect was observed up to the 1000 mg / kg administration group, with the theanyl theanine 10 mg / kg administration group being the maximum effect.

<Test Example 6>
Effect of theanylglutamine and glutaminyltheanine mixture in rat acute and chronic pain models In Test Example 4, a formalin test was conducted in the same manner as in Test Example 4, except that theanylglutamine and glutamyltheanine were administered instead of theanine. Carried out.
<Result>
As shown in Table 9, the number of flinch in phase 2 (10-60 minutes) is significantly more in the 10 mg / kg theanyl theanine administration group than in the control group. Was suppressed. This effect was observed up to the 1000 mg / kg administration group, with the theanyl theanine 10 mg / kg administration group being the maximum effect.

Below, the results of taking are shown by experience examples.
1. Initial MO 55-year-old woman, weight 54 kg
Chief complaint: Finger joint pain and edema From mid-February 2003, pain and swelling of all finger joints in the left hand began to be observed. As a result of the serum test, systemic lupus erythematosus (SLE) was diagnosed, and from April 2003, 6 tablets of the above-mentioned Example 3 theanine combination tablet were administered daily as a pain countermeasure. No concomitant medications. Pain was alleviated from the second day after administration, and disappearance of pain was observed on the fifth day. The administration of the above-mentioned Example 3 theanine-containing tablet was reduced from the fifth day to 2 tablets per day, and no tolerance for analgesic effect was observed. Administration continued until October 2004, but there was no recurrence of the disease and no side effects. In the middle of June 2004, there was a period when she stopped taking it for a month, and the pain recurred during that period.

2. Initial J. O. 48-year-old male weight 65 kg
Chief complaint: Bilateral knee arthritis Since both knee joint pains persisted from around November 2000, rheumatoid arthritis (RA) was suspected and various tests were conducted. As a result, since the antinuclear antibody was 35 times positive, the tablet of the above example was changed to the tablet containing theanyl theanine of Example 5 from May 2001 under the diagnosis of systemic lupus erythematosus (SLE). The administration of 7 tablets per day was started. Thereafter, the symptoms gradually improved, and the symptoms disappeared completely at the time of the medical examination on December 1 of the same year. Thereafter, arthralgia recurred for 2 weeks after discontinuation of tablet administration, but there was no dependence. Symptoms improved when administration was started again. Since then, no pain has been observed until today.

3. Initial F. F. 58-year-old male weight 76kg
The chief complaint: low back pain, both knee joint pain In August 1999, I visited an orthopedic surgeon for low back pain and was diagnosed with lumbar disc herniation. Because of the addition of both knee joint pain and general malaise in October, the patient visited the internal medicine department in October of the same year. As a result of various examinations, multiple rheumatoid arthritis was diagnosed. From December 15 of the same year, theanylglutamine of Example 7 was used. Only 8 tablets of glutaminyltheanine mixture-containing tablet were administered per day. The joint pain had disappeared at the time of visit 2 weeks later, but as a precaution, administration of 3 tablets per day was continued. Until October 2000, there was no recurrence of joint pain and no side effects.

4). Initial AK 25-year-old woman weight 46 kg
Chief complaint: Bilateral knee joint pain, precordial pain Since June 2000, both knee joint pain has been observed. He received electrotherapy at the Osteopathic Clinic from August of the same year, but it did not improve. He visited an orthopedic surgeon in April 2001 and was temporarily relieved after receiving external medicine. From around December 2002, I had both knee joint pain and anterior chest pain, and I visited the internal medicine department. Tender pain was recognized on the anterior sternum, and as a result of various examinations, SLE was diagnosed. From February 13, 2001, 12 theanine-containing tablets of Example 3 were administered daily. As of December 2001, The joint pain has almost disappeared. Since January 2002, 4 tablets have been administered every other day, but no dependence on the dosing period has been confirmed.

5. Initial N. F. 66 years old woman weight 63kg
Chief complaint: Chronic low back pain From the age of 50, back pain was so severe that I sometimes fell asleep. The pharmacy was seeking painkillers and herbal medicines, but when it was cold or tired, the pain became worse and I had a hard time. In May 2001, I visited an orthopedic surgeon after receiving an indication that there was a concern about osteoporosis. As a result of the X-ray examination, there was no worry about osteoporosis, and the theanyl theanine-containing tablets of Example 5 were administered 5 tablets a day. On the 10th day after administration, the pain suddenly disappeared and I was surprised. The pain recurred one day after discontinuing administration because the pain disappeared. When I start taking it again, my pain disappears and I fear relapse.

6). Initial M. I. 49-year-old woman 49kg
The chief complaint: peri-arthritis of the shoulder. The shoulder was stiff, and I felt severe pain when I moved it. Since the pain was severe, 10 tablets each day of the tablet containing a mixture of theanylglutamine and glutaminyltheanine of Example 7 were taken from July 2004. The pain decreased sharply on the 7th day after taking the medicine, but he continued taking it to prevent recurrence and complete healing.

<Example 8> Manufacture of a theanine combination candy As an example of a food or drink or a medicine containing a theanine combination analgesic composition, a theanine combination candy was manufactured using the raw materials shown in Table 10 below.

While dissolving 64 kg of granulated sugar in 20 kg of water, the mixture was heated to 110 ° C., the remaining 10 kg of water in which theanine was dissolved and chickenpox were added, and the temperature was raised to 145 ° C. The fire was turned off and 50% tartaric acid was added and mixed. It cooled to 75-80 degreeC, and it shape | molded with the shaping | molding roller, and prepared theanine compounding candy.
As a result of measuring the theanine content in the candy, the content was 89.6 mg / g per piece (1.2 g).

<Example 9> Manufacture of a theanine-blended blueberry beverage As an example of a food or drink or a medicine containing a theanine-blended analgesic composition, a theanine-blended beverage was produced using the raw materials shown in Table 11 below.

  Fructose glucose, blueberry concentrated juice, 1/5 transparent lemon juice, Na citrate and theanine were added to water and dissolved by stirring. Adjust the pH of the solution to 3.1 using 50% Na citrate (crystal), raise the temperature to 95 ° C, add fragrance, fill the container 100 mL at a time and cool to produce a theanine-containing blueberry beverage did. In addition, as a result of quantifying theanine in blueberry juice, the content was 98.3 mg / 100 mL.

<Example 10> Manufacture of a grapefruit beverage containing theanyl theanine As an example of a food or drink or pharmaceutical containing the analgesic composition containing theanyl theanine, a beverage containing theanyl theanine was produced using the raw materials shown in Table 12 below. .

Fructose dextrose solution, theanyl theanine, ferric pyrophosphate, placenta extract and 100% grapefruit juice were added to water and dissolved with stirring. Using Na citrate, the pH of the solution was adjusted to 3.1, and after raising the temperature to 95 ° C., a flavor was added, and 100 mL each was filled into a container and cooled to produce a grapefruit beverage containing theanyl theanine. In addition, as a result of quantifying theanyl theanine in grapefruit juice, the content was 96.4 mg / 100 mL.
As described above, according to this example, it was possible to provide a safe analgesic composition that does not exhibit dependency and tolerance and has no side effects, and foods and beverages and pharmaceuticals containing this composition.

Examples of embodiments according to the present invention are as follows.
(1) An analgesic composition containing theanyl theanine as an active ingredient.
(2) An analgesic composition containing theanylglutamine as an active ingredient.
(3) An analgesic composition containing glutaminyltheanine as an active ingredient.
(4) An analgesic composition containing theanylalanine as an active ingredient.
(5) An analgesic composition containing alanyl theanine as an active ingredient.
(6) An analgesic composition containing theanyl asparagine as an active ingredient.
(7) An analgesic composition containing asparaginyl theanine as an active ingredient.
(8) An analgesic composition containing theanyl glutamic acid as an active ingredient.
(9) An analgesic composition containing glutamyl theanine as an active ingredient.
(10) An analgesic composition containing theanylglycine as an active ingredient.
(11) An analgesic composition containing glycyltheanine as an active ingredient.
(12) An analgesic composition containing theanyl histidine as an active ingredient.
(13) An analgesic composition containing histidyltheanine as an active ingredient.
(14) An analgesic composition containing theanyl isoleucine as an active ingredient.
(15) An analgesic composition containing isoleucyltheanine as an active ingredient.
(16) An analgesic composition containing theanyl leucine as an active ingredient.
(17) An analgesic composition comprising leusilyltheanine as an active ingredient.
(18) An analgesic composition containing theanyl lysine as an active ingredient.
(19) An analgesic composition containing lysyl theanine as an active ingredient.
(20) An analgesic composition containing theanylmethionine as an active ingredient.

(21) An analgesic composition containing methionyl theanine as an active ingredient.
(22) An analgesic composition containing theanylphenylalanine as an active ingredient.
(23) An analgesic composition containing phenylalanyl theanine as an active ingredient.
(24) An analgesic composition containing theanylproline as an active ingredient.
(25) An analgesic composition containing prolyl theanine as an active ingredient.
(26) An analgesic composition containing theanylserine as an active ingredient.
(27) An analgesic composition containing seryltheanine as an active ingredient.
(28) An analgesic composition containing theanyl threonine as an active ingredient.
(29) An analgesic composition containing threonyl theanine as an active ingredient.
(30) An analgesic composition containing theanyltryptophan as an active ingredient.
(31) An analgesic composition containing tryptophanyl theanine as an active ingredient.
(32) An analgesic composition containing theanyltyrosine as an active ingredient.
(33) An analgesic composition containing thiosinyl theanine as an active ingredient.
(34) An analgesic composition containing theanyl valine as an active ingredient.
(35) An analgesic composition containing valyltheanine as an active ingredient.
(36) An analgesic composition containing theanyl arginine as an active ingredient.
(37) An analgesic composition containing arginyl theanine as an active ingredient.
(38) An analgesic composition containing theanylcysteine as an active ingredient.
(39) An analgesic composition containing cysteinyl theanine as an active ingredient.
(40) An analgesic composition comprising aspartyl theanine as an active ingredient.

(41) An analgesic composition containing theanyl aspartic acid as an active ingredient.
(42) An analgesic composition containing glutaminylalanine as an active ingredient.
(43) An analgesic composition containing alanylglutamine as an active ingredient.
(44) An analgesic composition containing glutaminyl asparagine as an active ingredient.
(45) An analgesic composition containing asparaginyl glutamine as an active ingredient.
(46) An analgesic composition containing glutaminyl glutamic acid as an active ingredient.
(47) An analgesic composition containing glutaminylglycine as an active ingredient.
(48) An analgesic composition containing glycylglutamine as an active ingredient.
(49) An analgesic composition comprising glutaminylhistidine as an active ingredient.
(50) An analgesic composition containing histidylglutamine as an active ingredient.
(51) An analgesic composition containing glutaminylisoleucine as an active ingredient.
(52) An analgesic composition containing isoleucylglutamine as an active ingredient.
(53) An analgesic composition containing glutaminylleucine as an active ingredient.
(54) An analgesic composition containing leusilylglutamine as an active ingredient.
(55) An analgesic composition containing glutaminyl lysine as an active ingredient.
(56) An analgesic composition containing lysylglutamine as an active ingredient.
(57) An analgesic composition containing glutaminylmethionine as an active ingredient.
(58) An analgesic composition containing methionyl glutamine as an active ingredient.
(59) An analgesic composition containing glutaminylphenylalanine as an active ingredient.
(60) An analgesic composition containing phenylalanyl glutamine as an active ingredient.

(61) An analgesic composition containing glutaminylproline as an active ingredient.
(62) An analgesic composition containing prolyl glutamine as an active ingredient.
(63) An analgesic composition containing glutaminylserine as an active ingredient.
(64) An analgesic composition containing serylglutamine as an active ingredient.
(65) An analgesic composition containing glutaminyl threonine as an active ingredient.
(66) An analgesic composition containing threonyl glutamine as an active ingredient.
(67) An analgesic composition containing glutaminyltryptophan as an active ingredient.
(68) An analgesic composition containing tryptophanyl glutamine as an active ingredient.
(69) An analgesic composition containing glutaminyltyrosine as an active ingredient.
(70) An analgesic composition containing tyrosylglutamine as an active ingredient.
(71) An analgesic composition containing glutaminyl valine as an active ingredient.
(72) An analgesic composition containing valylglutamine as an active ingredient.
(73) An analgesic composition containing glutaminylarginine as an active ingredient.
(74) An analgesic composition containing arginyl glutamine as an active ingredient.
(75) An analgesic composition containing glutaminylcysteine as an active ingredient.
(76) An analgesic composition containing cysteinyl glutamine as an active ingredient.
(77) An analgesic composition containing glutaminyl asparagine as an active ingredient.
(78) An analgesic composition comprising asparaginyl glutamine as an active ingredient.
(79) An analgesic composition containing glutaminyl aspartic acid as an active ingredient.
(80) An analgesic composition containing aspartyl glutamine as an active ingredient.
(81) An analgesic composition containing glutaminyl glutamine as an active ingredient.

It is a graph which shows the effect of theanine in Tail flick test. It is a graph which shows the effect of theanyl theanine in Tail flick test. It is a graph which shows the effect of theanine in Formalin test.

Claims (5)

An analgesic composition comprising an amino acid passing through the blood / brain barrier and / or a peptide containing an amino acid passing through the blood / brain barrier as an active ingredient. 2. The analgesic composition, wherein the amino acid according to claim 1 is theanine. The peptide according to claim 1, wherein (A) theanine and (B) theanine, glutamine, alanine, asparagine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, An analgesic composition comprising a dipeptide composed of one type of amino acid selected from tryptophan, tyrosine, valine, arginine, and cysteine. Food-drinks and a pharmaceutical containing the composition in any one of Claims 1-3. The method to manufacture the tablet containing the composition in any one of Claims 1-3.

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