WO2016152054A1

WO2016152054A1 - Pain prevention and alleviation effects of ω3 fatty acid glyceride

Info

Publication number: WO2016152054A1
Application number: PCT/JP2016/001259
Authority: WO
Inventors: 忠広対馬; 芳雄清水; 尚吾徳山; 賀寿夫中本
Original assignee: 備前化成株式会社
Priority date: 2015-03-26
Filing date: 2016-03-08
Publication date: 2016-09-29

Abstract

Provided are compositions by which problems of free-type ω3 fatty acids or ethyl ester-type ω3 fatty acids can be overcome. The present invention provides a medicinal composition and an edible composition for preventing and/or treating a pain, each composition comprising ω3 fatty acid glycerides, wherein the ratio of triglycerides in the ω3 fatty acid glycerides being 60 wt% or more. Also provided is a method for preventing and/or treating a pain using the aforesaid medicinal composition or edible composition.

Description

Pain prevention and improvement of omega-3 fatty acid glycerides

The present invention relates to a treatment method for preventing and / or improving pain, a pharmaceutical composition, a composition for eating and drinking, and a method for producing such a composition. The pharmaceutical composition and the food and beverage composition of the present invention contain ω3 fatty acid glycerides as active ingredients.

Ω3 fatty acids such as α-linolenic acid (ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA) contained in fish oil, algae, genetically modified plants, etc. Not only improves cardiovascular disease, improves cranial nerve function, improves immune function, but also exerts a wide range of functions such as prevention and improvement of diseases through oxidative stress suppression, and is also effective in suppressing cancer growth, etc. It is a material that has been expanded in use (Non-Patent Documents 1 and 2, and Patent Document 1).

These ω3 fatty acids are put on the market as food materials, health food materials, cosmetic materials and pharmaceutical materials as glycerides, free fatty acids and ethyl esters, or concentrated and purified. These ω3 fatty acids are generally concentrated by combining a vacuum precision distillation method, a molecular distillation method, a chromatography method, a low-temperature solvent fractional crystallization method, a urea addition method, a silver nitrate complex formation method, and the like in a timely manner.

In particular, the ethyl ester form of EPA (hereinafter referred to as EPA ethyl) has been sold as a therapeutic agent for obstructive arteriosclerosis, hyperlipidemia, etc. as a switch OTC, and the market for pharmaceutical grade EPA ethyl continues to expand.

There are also commercially available glycerides as they are or after concentrating and purifying ω3 fatty acids. For example, when fish oil is used as a starting material, the ω3 fatty acid contained in the glyceride may be concentrated by a low-temperature solvent fractional crystallization method or concentrated by enzymatic treatment such as lipase. Fatty acid purity is limited to 70%.

Generally, glyceride ω3 fatty acids have a higher absorption rate and higher bioavailability than ethyl ester, but the details have not been elucidated (Non-patent Document 3).

In addition, although free fatty acids have a high absorption rate and reactivity, they are said to cause inflammation and ulceration in the gastrointestinal tract and cause hemolysis of red blood cells when ingested for a long time.

On the other hand, it is known that prostaglandins and leukotrienes derived from fatty acids are involved in the induction of pain and the onset and chronicity of neuropathic pain.

However, it has been reported that ingestion of omega-3 fatty acids such as ALA, EPA, DHA reduces pain associated with rheumatoid arthritis and dysmenorrhea, and is also effective for neuropathic pain, which is intractable pain. Yes. In this connection, in particular with regard to DHA, it indirectly causes an anti-nociceptive action through the opioid nervous system, and this anti-nociceptive action involves the endogenous opioid peptide β-endorphin, Furthermore, it has been revealed that GPR40 is involved in β-endorphin release (Non-patent Documents 4 and 5, Patent Document 2).

Special table 2012-53911 gazette JP 2010-515773 gazette

When omega-3 fatty acids are used as active ingredients in pharmaceutical compositions and food and beverage compositions, free fatty acid type ω3 fatty acids or lower fatty acid esters of these fatty acids with ethanol, methanol, etc. are used. The free fatty acid type is generally considered to induce digestive ulcer, inflammation and erythrocyte hemolysis after oral ingestion, and there is a problem that continuous ingestion is medically unsuitable. Furthermore, the lower alcohol esters of these fatty acids with ethanol, methanol, etc. are inferior in absorption when compared with the free fatty acid type, and a large amount of intake is required, and further, bioavailability is inferior when compared with the free fatty acid type. It is said that it has problems such as being.

Therefore, it has been awaited to provide a composition that solves the problems of free fatty acid type ω3 fatty acid and ethyl ester type ω3 fatty acid.

The inventors of the present invention have completed the present invention by providing a glyceride type ω3-fatty acid as an active ingredient of a preventive or therapeutic agent for pain such as pain.

For example, the present invention provides the following.
(Item 1)
A pharmaceutical composition comprising omega-3 fatty acid glycerides for preventing and / or treating pain, wherein the proportion of triglycerides in the omega-3 fatty acid glycerides is 70 wt% or more.
(Item 2)
The omega-3 fatty acid is selected from the group consisting of α-linolenic acid (ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Item 2. The pharmaceutical composition according to Item 1, comprising a target omega-3 fatty acid, wherein the target omega-3 fatty acid accounts for 90 wt% or more of the total omega-3 fatty acid.
(Item 3)
Item 3. The pharmaceutical composition according to Item 2, wherein the omega-3 fatty acid is docosahexaenoic acid (DHA).
(Item 4)
The omega-3 fatty acid glyceride is obtained by performing a treatment selected from the group consisting of an enzymatic treatment and a chemical treatment on a substance selected from the group consisting of an omega-3 fatty acid and a lower alcohol ester thereof. The pharmaceutical composition according to Item 1.
(Item 5)
Item 1. A pharmaceutical composition according to item 1, which is taken orally.
(Item 6)
2. The pharmaceutical composition according to item 1, which is administered as an infusion.
(Item 7)
The pain is arthritis, osteoarthritis, indirect rheumatism, autoimmune disorders, sudden recurrence of chronic diseases, pain from fever, and secondary pain for pain disorders or other symptoms, dysmenorrhea Pain, fibromyalgia, musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, pain from other neoplastic diseases, pain from COX-2 mediated symptoms, burns Item 2. The pharmaceutical composition according to item 1, selected from the group consisting of pain and pain associated with trauma.
(Item 8)
An eating and drinking composition containing omega-3 fatty acid glycerides for preventing and / or treating pain, wherein the ratio of triglycerides in the omega-3 fatty acid glycerides is 60 wt% or more.
(Item 9)
The omega-3 fatty acid is selected from the group consisting of α-linolenic acid (ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Item 9. The composition for eating and drinking according to Item 8, comprising a target omega-3 fatty acid, wherein the target omega-3 fatty acid accounts for 90 wt% or more of the total omega-3 fatty acid.
(Item 10)
The composition for eating and drinking according to Item 9, wherein the omega-3 fatty acid is docosahexaenoic acid (DHA).
(Item 11)
The omega-3 fatty acid glyceride is obtained by performing a treatment selected from the group consisting of an enzymatic treatment and a chemical treatment on a substance selected from the group consisting of an omega-3 fatty acid and a lower alcohol ester thereof. The composition for eating and drinking according to Item 8.
(Item 12)
The pain is arthritis, osteoarthritis, indirect rheumatism, autoimmune disorders, sudden recurrence of chronic diseases, pain from fever, and secondary pain for pain disorders or other symptoms, dysmenorrhea Pain, fibromyalgia, musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, pain from other neoplastic diseases, pain from COX-2 mediated symptoms, burns Item 9. The composition for eating and drinking according to Item 8, selected from the group consisting of pain and pain associated with trauma.

According to the present invention, there are provided omega-3 fatty acids such as glyceride-type ALA, SDA, EPA, DPA, DHA, and the like, substances for inhibiting and treating pain such as pain, and compositions for eating and drinking.

Hereinafter, the present invention will be described. Throughout this specification, it should be understood that the singular forms also include the plural concept unless specifically stated otherwise. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. In the present specification, “wt%” is used interchangeably with “mass percent concentration”.

(Definition of terms)
Listed below are definitions of terms particularly used in the present specification.

As used herein, the term “pain” refers to all categories of pain, regardless of its nature or cause, including neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, neuralgia. Pain, orofacial pain, burn pain, chronic bone pain, low back pain, neck pain, abdominal pain, oral burning syndrome, somatic pain, visceral pain (including abdomen), fascial pain, toothache, cancer pain, chemistry Therapeutic pain, myofascial pain syndrome, complex local pain syndrome (CRPS), temporomandibular pain, traumatic pain, paroxysmal pain, surgical pain, postoperative pain, labor pain, reflex sympathetic dystrophy, brachial nerve Plexus withdrawal injury, neurogenic bladder, acute pain, musculoskeletal pain, postoperative pain, chronic pain, persistent pain, peripheral mediated pain, central mediated pain, chronic headache, tension headache, cluster headache, migraine , Associated with familial hemiplegic migraine, headache Condition, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, post-stroke pain, thalamic lesions, radiculopathy, HIV pain, postherpetic pain, non-cardiac chest pain, irritable bowel syndrome and bowel disorders It is understood that the pain associated with dyspepsia, as well as combinations thereof, includes but is not limited to.

As used herein, the term “omega-3 fatty acid” refers to an unsaturated fatty acid having a carbon-carbon double bond at the ω3 position. Examples of omega-3 fatty acids include α-linolenic acid (ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). It is not limited to.

As used herein, the term “lower alcohol ester of fatty acid” refers to an ester of a fatty acid and a lower alcohol. Examples of lower alcohols used for the production of lower alcohol esters of fatty acids include, but are not limited to, methanol and ethanol.

As used herein, the term “omega-3 fatty acid glyceride” includes triglycerides, diglycerides, and monoglycerides. Preferably, the “omega-3 fatty acid glyceride” of the present invention is a triglyceride. In the present invention, preferably, the proportion of triglyceride in the omega-3 fatty acid glyceride is 60 wt% or more. More preferably, it is 65% or more, still more preferably 70 wt% or more, and most preferably 80 wt% or more.

In the present invention, the target omega-3 fatty acids include α-linolenic acid (ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Selected from the group consisting of Preferably, the ratio of the target omega-3 fatty acid in all the omega-3 fatty acids (the ratio of the target omega-3 fatty acids in all types of omega-3 fatty acids) is 80 wt% or more. . The weight of the omega-3 fatty acid used in the calculation of this ratio is calculated as the weight of the omega-3 fatty acid in the weight of the omega-3 fatty acid glyceride, for example, in the case of omega-3 fatty acid glycerides.

The desired glyceride having a purity of ω3 fatty acid of 90 wt% or higher is synthesized by using the fatty acid or lower alcohol ester thereof as a starting material at least 90 wt% or higher as an ester with glycerin. The esterification reaction can be generally obtained by a reversible reaction with lipase or a chemical synthesis reaction with acid or alkali. The fatty acid of 90 wt% or higher or a lower alcohol ester thereof can be obtained by a known method (Japanese Patent Laid-Open Nos. 2000-212588 and 11-209786).

In order to industrially produce glyceride type ALA, SDA, EPA, DPA, and / or DHA, it is necessary to use high purity products of each fatty acid as a starting material. Although the purification method itself of fatty acids or their lower alcohol esters is not the subject of the present invention, when using fish oils, algal fats and microbial fats and oils containing these ω3 fatty acids as starting materials, the alkali catalyst method, the acid catalyst method According to conventional methods, for example, ethyl esterification and methyl esterification of the raw oil and fat containing the ω3-fatty acid by enzymatic methods, etc. are achieved (Matsumoto Wataru, hydrolysis, esterification and transesterification, Oil and Fat Chemical Handbook (The Japan Oil Chemists' Society) Ed.), Maruzen (Tokyo), 454-457 (2001)).

Since these lower alcohol esters are a mixture of multiple types of fatty acid esters, generally one or more methods such as vacuum precision distillation method, molecular distillation method, chromatographic method, urea addition method, silver nitrate complex method, low-temperature solvent fractional crystallization method, etc. A mixture containing at least 90 wt% of the target ω3 fatty acid can be obtained by purification in combination. As a matter of course, these purification methods are merely examples and not the object of the present invention, and it is obvious that the esterification method and the concentration purification method itself are not limited.

The glyceride ω3 fatty acid used in the present invention is assumed to be, for example, trieicosapentaenoyl glyceride in which three molecules of EPA are bound to one molecule of glycerin. Is the same. That is, preferably, the “omega-3 fatty acid glyceride of the present invention” means a triglyceride in which only one ω3 fatty acid is bonded to one molecule of glycerin.

In general, ALA, SDA, EPA, DPA, and DHA contained in each glyceride are required to be at least 90 wt% as a pharmaceutical product. Each glyceride is a mixture composed of triglyceride, diglyceride, and monoglyceride. However, in view of the fact that triglyceride is present as a main component in the living body, the proportion of triglyceride in the total glyceride is preferably 60 wt. % Or more, more preferably 70 wt% or more, and most preferably 80 wt% or more. In one aspect, in the present invention, ω3 fatty acid glyceride refers to a composition comprising monoglyceride, diglyceride and at least 60 wt% triglyceride.

In the present invention, for example, when trieicosapentaenoyl glyceride is chemically or enzymatically synthesized from ethyl eicosapentaenoate, unreacted ethyl eicosapentaenoate, monoeicosapentaenoyl glyceride or dieicosa is synthesized. When pentaenoyl glyceride is present in the product, the proportion of trieicosapentaenoyl glyceride in the total glyceride is preferably at least 60 wt%. The same applies to other ω3 fatty acid glycerides. The same applies when a free ω3 fatty acid is used as a starting material.

Thus, trieicosapentaenoyl glyceride can be chemically or enzymatically synthesized by a known method. The synthesis of each other fatty acid glyceride is the same (Yukihisa Tanaka, Tadashi Funada and Jiro Hirano, ester synthesis reaction by lipase, synthesis of triacylglycerol of EPA and DHA, oil chemistry, 41 (3), 563-567 (1992). And JP-A-8-40981).

The acid value (AV) of the trieicosapentaenoyl glyceride synthesized in this way is 5.0 or less, preferably 4.0 or less, more preferably 3.0 or less, still more preferably 2.0 or less, Preferably it is 1.0 or less. In the present invention, the peroxide value (POV) is 10.0 or less, preferably 8.0 or less, more preferably 6.0 or less, still more preferably 4.0 or less, and most preferably 3.0 or less. Specifically, unpurified trieicosapentaenoyl glyceride mixture is treated by physical treatment such as adsorbent treatment such as activated clay, acid clay, activated carbon, silicic acid, activated alumina, pyrolysis treatment, molecular distillation treatment, etc. Can be reached. The resulting product is added with antioxidants such as vitamin E and ascorbyl palmitate to help maintain quality.

As described above, ω3 fatty acids have been confirmed to be effective for pain (Non-Patent Documents 4 and 5). When using omega-3 fatty acids, it is possible to ingest or ingest as an infusion.

Generally, when a free fatty acid is ingested orally, the absorption rate is high, but inflammation and ulceration in the gastrointestinal tract and hemolysis of red blood cells occur. Ethyl ester fatty acids are said to have a lower absorption rate than free fatty acids and glyceride fatty acids (Non-patent Document 3).

However, to date, the pharmacological function of a composition in which the proportion of the target omega-3 fatty acid is an omega-3 fatty acid glyceride of 90 wt% or more, of which 60 wt% or more is triglyceride is empirically demonstrated. It is not known, and the medical superiority when compared with lower fatty acid esters of ω3 fatty acids and free fatty acids has not been in the range of speculation.

The present inventors have solved the problems of free fatty acids and ester-type ω3 fatty acids in the prior art by providing omega-3 fatty acid glycerides in which the ratio of the target omega-3 fatty acids is 90 wt% or more. The present inventors have found that it exhibits pharmacological superiority and superiority as a composition for eating and drinking, and has completed the present invention.

The following details the effectiveness for pain, taking tridocosahexaenoylglyceride as an example.

(Cause of pain)
Pain is an early warning system necessary to protect the body from disability and noxious stimuli. In contrast to the fact that physiological pain is a necessary system for protecting the living body, chronic pain is a state in which pain is felt despite the healing of the disorder. In this case, the pain does not serve as a warning, and quality. It only reduces the of life (QOL). In general, pain is roughly classified into nociceptive pain, neuropathic pain, cancer pain, and the like regardless of the type of disease. It can also be divided into acute pain and chronic pain according to the duration of pain. Acute pain is a symptom of pain associated with trauma and disease caused by transient excitement of nociceptors by noxious stimuli and disappears in a few days. On the other hand, chronic pain is regarded as substantial pain that seems to be the cause of early pain, and is caused by abnormalities in pain transmission, control, and cognitive mechanisms (Reference 1).

Currently, the use of analgesics used for pain treatment is limited because of the long-term use that causes side effects. Non-steroidal anti-inflammatory drugs (NSAIDs) are known to have side effects such as gastrointestinal disorders and narcotic analgesics such as nausea / vomiting, drowsiness, constipation and respiratory depression. Serious cardiovascular adverse events have also been reported for cycloxygenase (COX) -2 inhibitors. Furthermore, neuropathic pain, which is one of chronic pain, is known to be difficult to succeed with existing therapeutic agents such as NSAIDs and narcotic analgesics, and appropriate treatment from the point that the pathogenesis of pain is unknown This is a situation where it has not been possible to perform (Reference Documents 2 and 3). Thus, the effectiveness and safety of existing analgesics for pain treatment are insufficient, and development of new analgesics and further elucidation of pain control mechanisms are regarded as social issues.

(Efficacy and mechanism of DHA ethyl for pain)
So far, Nakamoto and Tokuyama, who are the inventors of the present study, have reported that oral administration of DHA ethyl ester exhibits an anti-nociceptive (analgesic) effect on various pain tests. Its mechanism of action has been suggested to increase the production of β-endorphin in the hypothalamic arcuate nucleus region. Furthermore, recent studies have shown that the long-chain fatty acid receptor GPR40, which has been reported as a receptor on which DHA acts, plays an important role in the mechanism of pain control via DHA. The possibility of a new pain control mechanism via / GPR40 signal has been proposed (References 4 to 7). In addition, Lu et al. (Reference 8) shows that DHA is effective in intrathecal administration for carrageenin-induced inflammatory pain and neuroinflammation, and this mechanism involves inflammation derived from microglia via activation of p38 MAPK. It is reported that suppression of sex cytokines is involved.

(Problems of ethyl ester)
There has been research that has been conducted on the absorption efficiency of DHA. After human fish oil was administered once in the form of triglycerides, free fatty acids, and ethyl esters, the ability of DHA to take up plasma triglycerides was examined. The absorption efficiency of DHA was 95% or more for free fatty acids and 57 for triglycerides. % And ethyl ester was reported to be 21% (Reference 9). Thus, the digestive tract absorption of DHA is greatly influenced by its administration form. In particular, the absorption efficiency of ethyl ester is poor.

(Possibility of glyceride body and superiority of EPA-TG)
Since the glyceride form has been reported to have better absorption efficiency than the ethyl ester form, it is expected that the EPA and DHA content in the tissue can be efficiently increased by ingesting these.

Recent studies have revealed that EPA and DHA are converted to resolvins and protectins, which have strong anti-inflammatory effects, respectively, when metabolized by cyclooxygenase and lipoxygenase (Reference 10). Schwab et al. (Reference 11) report that oxidative metabolites of EPA and DHA, resolvin E1 and protectin D1, activate the repair process of inflammation. Furthermore, it was also shown that intrathecal administration (0.3-20 ng) of EPA-derived resolvin E1 and DHA-derived resolvin D1 suppresses inflammatory pain (Reference Document 12). This is because Resolvin E1 (RvE1) and Resolvin D1 (RvD1) act on chemR23 (identified as a receptor for Resolvin) that is expressed in the spinal cord. It is supposed to suppress excitatory action via D aspartic acid (NMDA). Resolvin D precursor 17 (R) -hydroxy-docosahexaenoic acid (17 (R) HDoHE) and aspirin-induced resolvin D1 (AT-RvD1) are very low doses of 1 mg / kg Reported that inflammatory pain can be suppressed in arthritis model mice. Furthermore, subcutaneous footprinting of RvD1 inhibits inflammatory pain by inhibiting the activation of TRP channels such as transient receptor potential channel (TRP) A1, TRPV3 and TRPV4, and spinal cord of RvD1. Intracavitary administration has been reported to be effective in preventing postoperative pain and subsequent relief of symptoms. Interestingly, the anti-nociceptive effects of 17 (R) HDoHE, RvD1 and AT-RvD1 show significant effectiveness against mechanical stimulation rather than thermal stimulation. These action mechanisms are thought to involve activation of signal pathways via GPCRs such as GPR32 and ALX / FPR2. The possibility of involvement of other metabolites such as AT-RvD2,3,4,5 has also been suggested (reference documents 13 to 14). Recently, neuroprotectin / protectin D1 also suppresses neuropathic pain by inhibiting the activation of neuropathy-induced glial cells after nerve trauma and the accompanying inflammatory response (Reference 15). Currently, lipid mediators such as those described above are expected to be new therapeutic agents for inflammatory pain associated with arthritis and back pain inflammatory bowel disease.

From such a background, by administering or ingesting EPA-TG, it is possible to accumulate EPA and the like in the tissue more efficiently than the ethyl ester type, and an action via these lipid mediators can also be expected.

The pharmaceutical composition and the food and beverage composition of the present invention contain ω3 fatty acids such as glyceride-type ALA, SDA, EPA, DPA, DHA as active ingredients. The pharmaceutical composition and the edible composition of the present invention desirably have an active ingredient content of 10% by weight or more, more preferably 30% by weight or more. Other known components or raw materials may be used in combination as appropriate as long as they do not interfere with the desired effects of the present invention. Examples of these include ascorbic acid, amino acids, peptides, proteins and degradation products thereof, various sugars, starches and degradation products thereof, minerals, vitamin E, tocopherol, phytosterols, polyphenols such as catechin, guava leaves, etc. and derivatives thereof Although not limited to these, it is not limited to these.

When these concomitant substances are oil-soluble, such as ascorbyl palmitate, phytosterol, vitamin E, etc., they are mixed with the omega-3 fatty acid or derivative thereof according to the present invention to form a uniform state, and ascorbic acid, amino acid, In the case of water solubility or water dispersibility such as mineral, protein, etc., for example, the dry powder is kneaded with the ω3 fat according to the present invention or a derivative thereof, or an oil containing the same to form a dispersed state, or water and appropriately In addition, a surfactant can be coexisted in an emulsified state.

In the present invention, as described above, a edible composition / pharmaceutical composition comprising ω3 fat or a derivative thereof as an active ingredient is provided. Furthermore, as an aspect of the composition of the present invention, a pharmaceutical composition and a composition for eating and drinking are suitable.

(Formulation of pharmaceutical composition)
The present invention also provides a method of treating and / or preventing a disease or disorder (eg, ulcerative colitis, nephritis, osteoporosis) that can be treated and / or prevented by administration of an effective amount of a therapeutic agent to a subject. . By therapeutic agent is meant a composition of the invention in combination with a pharmaceutically acceptable carrier type (eg, a sterile carrier).

The therapeutic agent is considered to be a medical practice standard (GMP = good) taking into account the clinical condition of the individual patient (especially the side effects of the therapeutic agent alone treatment), the site of delivery, the method of administration, the dosage regimen and other factors known to those skilled in the art. Formulate and administer in a manner that complies with medical practice. Therefore, the target “effective amount” in the present specification is determined by taking such consideration into consideration.

As a general suggestion, the total pharmaceutically effective amount of orally administered therapeutic agent per dose is in the range of about 2 μg / kg / day to 1000 mg / kg / day of patient body weight, as described above. This is left to therapeutic discretion. More preferably, for the extracts of the present invention, this dose is at least 10 mg / kg / day, most preferably between about 20 mg / kg / day and about 1000 mg / kg / day for humans. Also, as a general proposition, the total pharmaceutically effective amount of the therapeutic agent administered parenterally per dose is in the range of about 0.2 μg / kg / day to 250 mg / kg / day of patient weight. As noted above, this is left to therapeutic discretion. More preferably, for the extract of the invention, this dose is at least 1 mg / kg / day, most preferably between about 5 mg / kg / day and about 25 mg / kg / day for humans.

The therapeutic agent can be oral, rectal, parenteral, intracisternally, intravaginally, intraperitoneally, topically (such as by powder, ointment, gel, instillation, or transdermal patch), oral or oral or It can be administered as a nasal spray. A typical route of administration of the pharmaceutical composition of the present invention is oral administration.

“Pharmaceutically acceptable carrier” refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulant or any type of formulation aid.

The therapeutic agent of the present invention is also appropriately administered by a sustained release system. Suitable examples of sustained release therapeutic agents are oral, rectal, parenteral, intracisternally, intravaginally, intraperitoneally, topically (powder, ointment, gel, infusion, or transdermal patch) Etc.), or as an oral or nasal spray. “Pharmaceutically acceptable carrier” refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulant or any type of formulation adjuvant. The term “parenteral” as used herein refers to modes of administration including intravenous and intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injections and infusions.

The therapeutic agent of the present invention is also appropriately administered by a sustained release system. Suitable examples of sustained release therapeutic agents include suitable polymer materials (eg, semipermeable polymer matrices in the form of molded articles (eg, films or microcapsules)), suitable hydrophobic materials (eg, in acceptable quality oils). Or an ion exchange resin, and poorly soluble derivatives (eg, poorly soluble salts).

Sustained release matrices include polylactide (US Pat. No. 3,773,919, EP 58,481), a copolymer of L-glutamic acid and γ-ethyl-L-glutamate (Sidman et al., Biopolymers 22: 547-556 (1983)). ), Poly (2-hydroxyethyl methacrylate) (Langer et al., J. Biomed. Mater. Res. 15: 167-277 (1981), and Langer, Chem. Tech. 12: 98-105 (1982)), ethylene vinyl Acetate (Langer et al., Ibid) or poly-D-(-)-3-hydroxybutyric acid (EP133,988).

Sustained release therapeutic agents also include the therapeutic agents of the present invention entrapped in liposomes (generally, Langer, Science 249: 1527-1533 (1990); Treat et al., Liposomes in the Therapeutic Diseases and Cancers, Cancer -See Berstein and Fiddler (eds.), Liss, New York, pages 317-327 and 353-365 (1989)). Liposomes containing therapeutic agents can be prepared by methods known per se: DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. USA 82: 3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA 77: 4030-4034 (1980); EP52,322; EP36,676; EP88,046; EP143,949; EP142,641; Japanese Patent Application No. 83-118008; US Patent 4,485,045 And 4,544,545 and EP 102,324. Usually, liposomes are small (about 200-800 cm) unilamellar type, where the lipid content is greater than about 30 mol% cholesterol and the selected proportion is adjusted for optimal therapeutic agents.

In still further embodiments, the therapeutics of the invention can be delivered by a pump (Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgary 88: 507 ( 1980); Saudek et al., N. Engl. J. Med. 321: 574 (1989)).

Other controlled release systems are discussed in the review by Langer (Science 249: 1527-1533 (1990)).

For parenteral administration, in one embodiment, in general, the therapeutic agent is toxic to the recipient in the desired degree of purity, in a pharmaceutically acceptable carrier, i.e. the dosage and concentration used. It is formulated by mixing in a unit dosage injectable form (solution, suspension or emulsion) with one that is not and compatible with the other ingredients of the formulation. For example, the formulation preferably does not include oxidation and other compounds known to be harmful to therapeutic agents.

Generally, a formulation is prepared by contacting the therapeutic agent uniformly and intimately with a liquid carrier or a finely divided solid carrier or both. Next, if necessary, the product is shaped into the desired formulation. Preferably, the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Nonaqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as are liposomes.

The carrier suitably contains trace amounts of additives such as substances that enhance isotonicity and chemical stability. Such substances are not toxic to the recipient at the dosages and concentrations used, such as phosphate, citrate, succinate, acetic acid and other organic acids or their salts. Buffering agents; antioxidants such as ascorbic acid; low molecular weight (less than about 10 residues) polypeptides (eg, polyarginine or tripeptides); proteins such as serum albumin, gelatin or immunoglobulins; polyvinylpyrrolidone Hydrophilic polymers such as: amino acids such as glycine, glutamic acid, aspartic acid or arginine; monosaccharides, disaccharides and other carbohydrates including cellulose or derivatives thereof, glucose, mannose or dextrin; chelating agents such as EDTA Sugar sugars such as mannitol or sorbitol Lumpur; counterions such as sodium; and / or polysorbate include nonionic surfactants such as poloxamers or PEG.

The therapeutic agent is typically formulated in such a vehicle at a pH of about 6-9 at a concentration of about 10 mg / ml to 1000 mg / ml, preferably 50-1000 mg / ml. It is understood that by using the specific excipients, carriers or stabilizers described above, salts are formed.

Any drug to be used for therapeutic administration may be in a state that does not contain a living organism / virus other than the virus as an active ingredient, that is, in a sterile state. Aseptic conditions are easily achieved by filtration through sterile filtration membranes (eg, 0.2 micron membranes). In general, the therapeutic agent is placed in a container having a sterile access port, for example, an intravenous solution bag or vial with a stopper puncturable with a hypodermic needle.

Treatment agents are usually stored in unit dose or multi-dose containers, such as sealed ampoules or vials, as aqueous solutions or lyophilized formulations for reconstitution. As an example of a lyophilized formulation, a 10 ml vial is filled with 5 ml of a sterile filtered 5% (w / v) aqueous therapeutic agent and the resulting mixture is lyophilized. The lyophilized therapeutic agent is reconstituted with bacteriostatic water for injection to prepare an infusion solution.

The present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more components of the therapeutic agent of the present invention. A notice of the form prescribed by a government agency that regulates the manufacture, use or sale of a medicinal product or biological product may be attached to such a container, and this notice may be attached to the government regarding the manufacture, use or sale for human administration. Represents institutional approval. In addition, the therapeutic agent may be used in combination with other therapeutic compounds.

The therapeutic agent of the present invention can be administered alone or in combination with other therapeutic agents. The combinations can be administered, for example, either simultaneously as a mixture; simultaneously or concurrently but separately; or over time. This includes the presentation that the combined agents are administered together as a therapeutic mixture, and also the procedure where the combined agents are administered separately but simultaneously, eg, through separate intravenous lines to the same individual . Administration in combination further includes separate administration of one of the compounds or agents given first, followed by the second.

In the preparation of the omega-3 fatty acid or derivative thereof of the present invention, the above-mentioned extract may be used as it is, but this is further fractionated to obtain a fraction containing an active ingredient at a higher concentration. It may be used.

(Manufacture of composition for eating and drinking)
The suitable aspect of this invention is a composition for eating and drinking. That is, a pharmaceutical composition or a composition for eating or drinking containing an omega-3 fatty acid or a derivative thereof obtained as described above as an active ingredient is used as it is as a liquid, gel or solid food, for example, juice, soft drink , Coffee, tea, Japanese tea, oolong tea, vegetable juice, natural fruit juice, milk drink, milk, soy milk, sports drink, near-water drink, nutritional drink, coffee drink, cocoa, soup, dressing, mousse, jelly, yogurt, Pudding, sprinkles, infant formula, processed milk, sports drink, energy drink, cake mix, bread, pizza, pie, crackers, biscuits, cake, cookies, spaghetti, macaroni, pasta, udon, buckwheat, ramen, candy, soft candy , Gum, chocolate, rice cake, potato chips Powdered or liquid dairy products such as snacks, snacks, ice cream, sorbets, creams, cheese, powdered milk, condensed milk, milk drinks, buns, oysters, rice cakes, soy sauce, sauce, noodle soup, sauces, dashi stock, Stew, soup, mixed seasoning, curry, mayonnaise, ketchup, retort curry, retort stew, retort soup, canned, ham, hamburger, meatballs, croquette, dumplings, pilaf, rice balls, frozen Add to foods and refrigerated foods, chikuwa, rice cakes, bento rice, sushi, baby milk, baby food, baby food, sports food, dietary supplements, supplements, health foods, etc., dextrin, lactose, starch as required It is processed into pellets, tablets, granules, etc. together with excipients such as excipients, fragrances, pigments, etc. Coated with available molding to as a health food or dietary supplements such as capsules or the like. The blending amount of the omega-3 fatty acid of the present invention or a derivative thereof in these foods or food-drinking compositions is difficult to define uniformly depending on the type and state of the food or composition, but is about 0.01 to 50 % By weight, more preferably 0.1 to 30% by weight. If the blending amount is less than 0.01% by weight, the desired effect by oral intake is small, and if it exceeds 50% by weight, the flavor may be impaired or the food may not be prepared depending on the type of food. In addition, the omega-3 fatty acid or derivative thereof of the present invention may be used for food as it is.

Hereinafter, the present invention will be described in detail with reference to examples and the like, but the present invention is not limited thereto.

Embodiments of the present invention will be described in detail. As a raw material, a desired ω3 fatty acid ester, glycerin, and a hydroxide of an alkali metal or alkaline earth metal are prepared. The ω3-fatty acid ester of the substrate is an ester condensation compound of ALA, SDA, EPA, DPA, DHA, a compound obtained by ester condensation of a carboxyl group substituted with these fatty acids, and ethanol is used as the alcohol to be condensed. Although preferable, it is not limited thereto. As hydroxides with alkali metals and alkaline earth metals, calcium hydroxide, sodium hydroxide, potassium hydroxide, etc., potassium hydroxide is preferred.

These fatty acid esters, glycerin, and potassium hydroxide are heated and stirred. In this case, the heating device is set to a range of 110 ° C. to 130 ° C. using an oil bath, for example, and further, a decompression device such as a vacuum pump is used to reduce the pressure to 5 mmHg or less. Pressure is preferred.

After cooling the reaction product after the heating and stirring treatment to room temperature, water and an organic solvent, preferably hexane and ethanol, are added and separated into two layers by liquid-liquid distribution. The lower aqueous phase is discarded and unreacted hydroxylation is performed. Remove potassium and glycerin. In addition, the kind of organic solvent will not be ask | required if this hydroxide and this unreacted glycerol can be removed.

The upper organic phase in which the reactant is dissolved is recovered and the solvent is distilled off using a rotary evaporator. The pressure in the reduced pressure is preferably 150 mmHg or less, but may be higher if the solvent can be distilled off. The temperature at the time of distilling off the solvent is in a range where the oxidation of the reaction product does not proceed extremely, and is 20 ° C. to 40 ° C., preferably 30 ° C.
After distilling off the solvent, the reaction product is purified by various purification methods such as column chromatography to obtain the desired tridocosahexaenoyl glyceride.

(Example 1: Synthesis of ω3 fatty acid glyceride from ethyl ester)
Specific examples for the preparation of tridocosahexaenoyl glyceride using DHA ethyl ester as a starting material are shown below:
45 g (0.126 mol) of DHA ethyl ester (purity: 97%), 4.0 g (0.043 mol) of glycerin, and 0.6 g (0.011 mol) of potassium hydroxide were placed in a reaction vessel. The triglyceride synthesis reaction was carried out by reducing the pressure to 5 mmHg by means of a vacuum pump in an oil bath and stirring for 24 hours.

After the heat-treated reaction product is cooled to room temperature, it is transferred to a separatory funnel, and water, hexane, and ethanol are added to separate it into two layers by liquid-liquid distribution. Glycerin and potassium hydroxide were removed.

After recovering the upper hexane phase in which tridocosahexaenoylglyceride is dissolved, the solvent is distilled off at a pressure of 150 mmHg and a temperature of 30 ° C. using a rotary evaporator to obtain 34.5 g of the reaction product (tridocosahexahexa Enoyl glyceride: 20.7 g, diglyceride: 9.3 g, monoglyceride: 3.4 g, free fatty acid: 0.7 g, unreacted DHA ethyl ester: 0.03 g). The reaction product was purified by tridocosahexaenoyl glyceride by silica gel column chromatography using a hexane-diethyl ether mixture as a mobile phase, added with activated carbon, stirred, and filtered to give an acid value of 1 or less and a peroxide value of 3 Hereinafter, an omega-3 fatty acid glyceride having 65% by weight of tridocosahexaenoyl glyceride and a DHA composition ratio (ratio of DHA in the whole omega-3 fatty acid) of 96% was obtained.

(Example 2: Synthesis of ω3 fatty acid glyceride from methyl ester)
45 g (0.131 mol) of DHA methyl ester (purity: 97%) and glycerin 4.0
g (0.043 mol) and 0.6 g (0.011 mol) of potassium hydroxide in a reaction vessel, and reduced in pressure to 5 mmHg by a vacuum pump in an oil bath at 120 ° C. and stirred for 24 hours to obtain triglyceride. The synthesis reaction was performed.

The reaction product after the heat treatment is cooled to room temperature, then transferred to a separatory funnel, water and hexane are added, and ethanol is further separated into two layers by liquid-liquid distribution. Glycerol and potassium hydroxide were removed.

After recovering the upper hexane phase in which tridocosahexaenoylglyceride is dissolved, the solvent is distilled off at a pressure of 150 mmHg and a temperature of 30 ° C. using a rotary evaporator to obtain 34.5 g of the reaction product (tridocosahexahexa Enoyl glyceride: 21.1 g, diglyceride: 8.3 g, monoglyceride: 4.1 g, free fatty acid: 0.8 g, unreacted DHA methyl ester: 0.03 g). The reaction product was purified by tridocosahexaenoyl glyceride by silica gel column chromatography using a hexane-diethyl ether mixture as a mobile phase, added with activated clay, stirred and filtered to give an acid value of 1 or less and a peroxide value of 3 Hereinafter, omega-3 fatty acid glycerides having 78% by weight of tridocosahexaenoyl glyceride and 98% DHA composition ratio (ratio of DHA in the whole omega-3 fatty acids) were obtained.

(Example 3: Synthesis of ω3 fatty acid glyceride from fatty acid)
45 g (0.137 mol) of DHA (purity: 97%), 4.5 g (0.049 mol) of glycerin, and 2.25 g of Lipozyme RMIM (Novo Nordisk A / S Corp. Denmark) were placed in a reaction vessel at 60 ° C. A triglyceride synthesis reaction was performed by reducing the pressure to 5 mmHg with a vacuum pump in a hot water bath and shaking for 48 hours.

The reaction product after the shaking reaction was transferred to a separatory funnel, a diethyl ether-ethanol (1: 1) solution was added, and the reaction mixture was separated into two layers by liquid-liquid distribution to stop the reaction. Unreacted glycerin was removed by discarding the lower aqueous phase.

After collecting the upper hexane phase in which tridocosahexaenoylglyceride was dissolved, the solvent was distilled off at a pressure of 150 mmHg and a temperature of 30 ° C. using a rotary evaporator to obtain the reaction product. The reaction product contains 81% of tridocosahexaenoyl glyceride and 19% of diglyceride, and this was purified by tridocosahexaenoyl glyceride by silica gel column chromatography using a hexane-diethyl ether mixture as a mobile phase. By adding acid clay and stirring and filtering, acid value = 1 or less, peroxide value = 3 or less, tridocosahexaenoyl glyceride is 88 wt%, DHA composition ratio (DHA in all omega-3 fatty acids) An omega-3 fatty acid glyceride having a ratio of 97% was obtained.

(Example 4: tail flick test)
The anti-nociceptive effect of DHA on heat stimulation was tested. Anti-nociceptive action against heat stimulation was evaluated by tail-flick test. Mice were placed on a tail-flick type analgesic effect measuring device (MK-330B, Muromachi Kikai, Tokyo, Japan), radiant heat was applied to the dorsal side of the tail, and the latency until the tail was moved was measured. The intensity of the thermal stimulation was adjusted so that the tail was moved between 2.5 and 3 seconds after the heat was applied, and was used as a reference value for the response latency (baseline latency). Response latencies were measured 30, 60, and 120 minutes after DHA administration. In order to prevent damage to the stimulation site, thermal stimulation was performed up to 10 seconds (cut-off time). Response latency is expressed as [(each latency−reference value of reaction latency) / (10−reference value of reaction latency)] as a percentage of the maximum possible effect (% of maximum possible effect (% MPE)). did. The area under the curve (AUC) of the MPE-time curve was calculated to evaluate the anti-nociceptive effect.

Administration of tridocosahexaenoyl glyceride prepared in Example 1 increased the response latency in a dose-dependent manner, and a peak of action was observed 60 minutes after administration. Similarly, the curve area of the tridocosahexaenoyl glyceride administration group was significantly increased compared to the control group and the DHA ethyl group. Compared to DHA ethyl, its action was stronger.

(Example 5: Acetic acid rising test)
Mice were transferred from home cages to new cages one by one and allowed to acclimate for 1 hour, followed by intraperitoneal injection of 0.6% (v / v) acetic acid (Wako, 10 mg / kg) for 30 minutes The number of times was measured.

In the control group, 55 ± 9 rising times were observed by acetic acid administration. In contrast, oral administration of tridocosahexaenoyl glyceride prepared in Example 2 dose-dependently and significantly reduced the number of rising, and its effect was stronger compared to DHA ethyl.

(Example 6: formalin test)
The mice were transferred one by one from the home cage to a new cage and allowed to acclimate to the environment for 1 hour, and then 10 mL of formalin 5% was administered subcutaneously to the right hind footpad of the mouse. The total time of licking, biting, and flinging of the administration site was measured in seconds and evaluated. Pain behavior was measured for 30 minutes between 0-10 minutes (early phase) and 10-30 minutes (late phase) after formalin was administered.

In the control group, pain behaviors such as licking, biting, and shaking caused by subcutaneous administration of formalin to the footpad were observed in early phase of 147 ± 13 seconds and in late phase of 300 ± 37 seconds. It was. In contrast, the administration of tridocosahexaenoyl glyceride prepared in Example 3 significantly reduced pain behavior in both early and late phases, and this action was significantly suppressed compared to the control group and the DHA ethyl group. It was.

(Example 7: Test in chronic inflammatory pain model mouse)
The chronic inflammatory pain model was prepared by administering 0.5 mg / kg Freund's complete adjuvant (CFA) into the right hind footpad of mice. As a subject group, physiological saline was administered. As a chronic inflammatory pain model, a mouse which was subjected to foot thickening and pain evaluation, and had inflammation of the foot, mechanical allodynia and thermal hyperalgesia from 1 day after CFA administration was used. Digital calipers (Shinwa Measurement, Niigata, Japan) were used for foot thickening.

The mouse was placed on a metal mesh and allowed to adapt for 60 minutes with a transparent plastic case covered. After confirming the disappearance of spontaneous movement, touch test filament (Touch-Test (R) Sensory E)
The test was started with 0.16 g of the filament (Valators) (North Coast Medical Inc, CA, USA). The filament was pressed vertically against the ventral center of the hind limb of the mouse until it was bent slightly, and the escape response to the stimulus for 6 seconds was observed. The operation of applying stimulation with this filament was repeated 10 times, and the number of times of showing an escape reaction was recorded.

The evaluation of escape response to thermal stimulation was performed as follows. The mouse was placed in a plastic case on the glass floor and allowed to adapt for 3 hours. After confirming the disappearance of spontaneous movement, radiant heat is applied from the bottom of the glass floor to the ventral side of the hind limb of the mouse using the planter test (Ugo Basile, Comerio, Italy), and the hind limb is raised. The reaction latency (pWL) until showing an escape response was recorded. In order to prevent tissue damage, the measurement time was set to a maximum of 20 seconds.

Inflammation of the foot was observed from 1 day after the administration of CFA, and inflammation was continuously observed after 3, 5, 7, and 14 days thereafter. Similarly, mechanical allodynia was observed 1 day after CFA administration, and mechanical allodynia was observed until 14 days thereafter. Similarly, thermal hyperalgesia continued until 14 days later. In these mice, single or repeated administration of tridocosahexaenoyl glyceride prepared in Example 3 significantly reduced mechanical allodynia and thermal hyperalgesia, and this effect was compared to the DHA ethyl ester administration group. Was significantly suppressed.

As described above, the present invention has been exemplified using the preferred embodiment of the present invention, but the present invention should not be construed as being limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. It is understood that those skilled in the art can implement an equivalent range based on the description of the present invention and the common general technical knowledge from the description of specific preferred embodiments of the present invention. Patents, patent applications, and documents cited herein should be incorporated by reference in their entirety, as if the contents themselves were specifically described herein. Understood.

The present invention provides a therapeutic method for preventing and / or improving pain, a pharmaceutical composition, a composition for eating and drinking, and a method for producing such a medicine and a composition for eating and drinking.

(References)
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Claims

A pharmaceutical composition containing omega-3 fatty acid glycerides for preventing and / or treating pain, wherein the proportion of triglycerides in the omega-3 fatty acid glycerides is 60 wt% or more.
The omega-3 fatty acid is selected from the group consisting of α-linolenic acid (ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). The pharmaceutical composition according to claim 1, comprising a target omega-3 fatty acid, wherein the target omega-3 fatty acid accounts for 90 wt% or more of the total omega-3 fatty acid.
The pharmaceutical composition according to claim 2, wherein the omega-3 fatty acid is docosahexaenoic acid (DHA).
The omega-3 fatty acid glyceride is obtained by performing a treatment selected from the group consisting of an enzymatic treatment and a chemical treatment on a substance selected from the group consisting of an omega-3 fatty acid and a lower alcohol ester thereof. The pharmaceutical composition according to claim 1.
The pharmaceutical composition according to claim 1, which is taken orally.
The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered as an infusion.
The pain is arthritis, osteoarthritis, indirect rheumatism, autoimmune disorders, sudden recurrence of chronic diseases, pain from fever, and secondary pain for pain disorders or other symptoms, dysmenorrhea Pain, fibromyalgia, musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, pain from other neoplastic diseases, pain from COX-2 mediated symptoms, burns The pharmaceutical composition according to claim 1, selected from the group consisting of pain and pain associated with trauma.
An eating and drinking composition containing omega-3 fatty acid glycerides for preventing and / or treating pain, wherein the ratio of triglycerides in the omega-3 fatty acid glycerides is 60 wt% or more.
The omega-3 fatty acid is selected from the group consisting of α-linolenic acid (ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). The composition for eating and drinking according to claim 8, comprising a target omega-3 fatty acid, wherein the target omega-3 fatty acid accounts for 90 wt% or more of the total omega-3 fatty acid.
The composition for eating and drinking according to claim 9, wherein the omega-3 fatty acid is docosahexaenoic acid (DHA).
The omega-3 fatty acid glyceride is obtained by performing a treatment selected from the group consisting of an enzymatic treatment and a chemical treatment on a substance selected from the group consisting of an omega-3 fatty acid and a lower alcohol ester thereof. The composition for eating and drinking according to claim 8.
The pain is arthritis, osteoarthritis, indirect rheumatism, autoimmune disorders, sudden recurrence of chronic diseases, pain from fever, and secondary pain for pain disorders or other symptoms, dysmenorrhea Pain, fibromyalgia, musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, pain from other neoplastic diseases, pain from COX-2 mediated symptoms, burns The composition for eating and drinking according to claim 8, which is selected from the group consisting of pain and pain associated with trauma.