WO2010018856A1 - Prophylactic/ameliorating or therapeutic agent for cannabinoid receptor-related disease - Google Patents

Prophylactic/ameliorating or therapeutic agent for cannabinoid receptor-related disease Download PDF

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WO2010018856A1
WO2010018856A1 PCT/JP2009/064292 JP2009064292W WO2010018856A1 WO 2010018856 A1 WO2010018856 A1 WO 2010018856A1 JP 2009064292 W JP2009064292 W JP 2009064292W WO 2010018856 A1 WO2010018856 A1 WO 2010018856A1
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receptor
group
epa
ameliorating
cannabinoid
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PCT/JP2009/064292
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French (fr)
Japanese (ja)
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秀生 兼廣
浩之 河野
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持田製薬株式会社
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Definitions

  • the present invention relates to an agent for preventing / ameliorating or treating a disease involving cannabinoid receptors, and a method for using the same. More particularly, the present invention relates to an agent for preventing / ameliorating or treating a disease particularly involving cannabinoid 1 receptor, and a method for using the same.
  • the present invention relates to a preventive or alleviating agent for side effects caused by a cannabinoid receptor ligand, and a method for using the same. More specifically, the present invention relates to a preventive or alleviating agent for side effects caused by a cannabinoid 1 receptor ligand, and a method for using the same.
  • Cannabinoid (hereinafter referred to as “CB”) is a general term for ⁇ 9 -tetrahydrocannabinol (hereinafter referred to as “ ⁇ 9 -THC”), which is the main active ingredient of cannabis, and its similar compounds (Non-patent Document 1). ).
  • CB is known to cause various effects on mammals such as confusion of time sensation and spatial sensation, euphoria, hallucination, somnolence, increased appetite, decreased pain sensation, immunosuppression, and anti-inflammation (non-) Patent Document 2).
  • Non-patent Document 3 discloses that a receptor for CB exists in 1988, and many of these actions are receptors. It came to be thought that through.
  • CB receptor As a cannabinoid receptor (hereinafter referred to as “CB receptor”), in 1990, Matsuda et al. (Non-patent Document 4) disclosed a cannabinoid 1 receptor (hereinafter referred to as “CB1 receptor”) in 1993. Munro et al. (Non-patent Document 5) have cloned cannabinoid 2 receptors (hereinafter referred to as “CB2 receptors”), respectively, and two subtypes have been identified to date.
  • CB2 receptors cannabinoid 1 receptor
  • CB1 receptor is expressed in most nervous system tissues and is involved in inhibitory control of neurotransmission.
  • the CB2 receptor is hardly expressed in the central nervous system such as the brain, and is expressed in a large amount in tissues and cells mainly involved in inflammatory reaction or immune response such as spleen and tonsils.
  • actions such as confusion of time and space sensation, euphoria, hallucinations, somnolence, and appetite increase are mediated through CB1 receptors in the central nervous system Has been revealed.
  • the actions such as a decrease in pain sensation, immunosuppression, and anti-inflammation are considered to be actions mediated by cells that participate in immune responses or inflammatory reactions expressing CB2 receptors. It has been.
  • dronabinol (trade name: MARINOL (registered trademark), Unimed Pharmaceuticals, Inc., Marietta, GA, USA) which is ⁇ 9 -THC and CB1 receptor Rimonabant (trade name in the European Union (EU) region: ACOMPLIA (registered trademark), Sanofi-Aventis, Paris, France), etc.
  • CB receptor ligands (such as agonists, antagonists or inverse agonists) are being applied as pharmaceuticals.
  • rimonabant (Acompria (registered trademark)
  • Non-patent Document 7 Non-patent Document 7
  • rimonabant side effects of rimonabant include upper respiratory tract infection, sinusitis, gastroenteritis, depressive disorders (such as depression, manic depression, depression), mood swings with depressive symptoms, anxiety, irritation, hypersensitivity, sleep disorders, Insomnia, abnormal insomnia, panic symptoms, anger, dissatisfaction, emotional disorder, suicide attempt, aggression, aggressive behavior, hallucinations, memory loss (amnesia), attention deficit, dizziness, immobility dizziness, hyposensory, sciatica, Dyssensory, lethargy, flushing, hiccups, nausea, diarrhea, vomiting, loss of appetite, loss of appetite, stomach discomfort, thirst, pruritus, excessive sweating, night sweats, tendonitis, muscle spasm, muscle spasm, asthenia /
  • headache, euphoria, fatigue, insomnia and the like as symptoms of fatigue, influenza, falls, bruises, sprains, and overdose Non-patent Document 7).
  • ⁇ 9 -THC is not present in the animal body. Nevertheless, the presence of the CB receptor suggested the presence of an endogenous CB receptor ligand.
  • Non-Patent Document 9 As a result of searching for an endogenous CB receptor ligand, Devane et al. (Non-Patent Document 9) in 1992 introduced arachidonic acid, which is a polyunsaturated fatty acid (hereinafter referred to as “PUFAs”), from porcine brain.
  • Anandamide also known as N-arachidonoylethanolamine
  • Sugiura et al. (Non-Patent Document 10) in 1995 from rat brain and Mechoulam et al.
  • 2-arachidonoylglycerol (hereinafter referred to as “2-AG”) in which arachidonic acid was ester-bonded to position 2 of glycerol from the small intestine of dogs, respectively, and endogenous CB reception. Reported as a body ligand.
  • Non-Patent Documents 12 and 13 show that glycerol in which arachidonic acid of 2-AG is substituted with PUFAs having 20 or more carbon atoms and 3 or more unsaturated bonds also has an agonistic action on CB1 and 2 receptors.
  • In-vitro studies report that icosatrienoic acid, icosapentoic acid (hereinafter referred to as “EPA”) or docosahexaenoic acid (hereinafter referred to as “DHA”) are in the second position of glycerol.
  • EPA icosatrienoic acid
  • DHA docosahexaenoic acid
  • Examples include 2-eicosatrienoylglycerol, 2-eicosapentaenoylglycerol (hereinafter referred to as “2-EG”), 2-docosahexaenoylglycerol (hereinafter referred to as “2-DG”), and the like. ing.
  • PUFA having the first double bond at the third position from the methyl group side is called ⁇ 3 PUFAs, and examples thereof include ⁇ -linolenic acid, EPA and DHA.
  • EPA-E EPA ethyl ester
  • EPADEL EPA ethyl ester
  • DHA-E DHA ethyl ester
  • Soft capsules (trade name: Lovaza (registered trademark), GlaxoSmithKline (London, UK)) containing about 37.5% by mass of active ingredient for treatment of hypertriglyceridemia It is commercially available as an agent in the United States.
  • the present invention relates to prevention / amelioration of CB receptor-related diseases that are highly safe, effective, and easy to use for the prevention / amelioration or treatment of diseases involving CB receptors, particularly CB1 receptors. It is an object to provide a therapeutic agent and a method of using the same.
  • the present invention also relates to a CB receptor ligand, particularly a CB1 receptor ligand, which is highly safe, effective and easy to use for use in the prevention or reduction of side effects caused by a CB receptor ligand, particularly a CB1 receptor ligand. It is an object of the present invention to provide a preventive or alleviating agent for side effects caused by the above and a method for using the same.
  • At least one compound selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof exhibits a neutral antagonist-like action on the CB receptor, particularly the CB1 receptor, and the CB receptor. It has been found that it has a preventive / ameliorating or therapeutic effect on a related disease, and has a preventive or alleviating effect on side effects of CB receptor ligands, particularly CB1 receptor ligands, and has completed the present invention.
  • the agent for preventing / ameliorating or treating CB receptor-related diseases and the agent for preventing or reducing side effects caused by CB receptor ligands provided by the present invention are from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof. It contains at least one selected compound as an active ingredient. Examples of embodiments of the present invention are shown below.
  • a preventive / ameliorating or treating agent for CB receptor-related diseases comprising as an active ingredient at least one selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof.
  • ⁇ 3PUFAs and pharmaceutically acceptable salts and esters thereof are at least one compound selected from the group consisting of EPA, DHA and ⁇ -linolenic acid and pharmaceutically acceptable salts and esters thereof ( The preventive / ameliorating or therapeutic agent according to any one of 1) to (4). (6) The preventive / ameliorating or treating agent according to any one of (1) to (4) above, which contains EPA-E and / or DHA-E as the ⁇ 3PUFAs and pharmaceutically acceptable salts and esters thereof . (7) The preventive / ameliorating or therapeutic agent according to any one of (1) to (4) above, which contains EPA-E as the ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof.
  • An agent for preventing or alleviating side effects caused by a CB receptor ligand comprising as an active ingredient at least one selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof.
  • the CB1 receptor agonist is anandamide, 2-AG, dronabinol, nabinoximol, AZ-599, AZD-1940, GW-1000, KN-38-7271, O-1057, Org-28611, Org-26828, SCH-
  • the prophylactic or alleviating agent according to (9) above which is at least one compound selected from the group consisting of 900111 and SAB-378.
  • the CB1 receptor antagonist or inverse agonist is ⁇ 9 -tetrahydrocannabivaline, drinaban, rimonabant, sulinaban, otenaban, ibipinavan, taranaban, AZD-2207, AZD-1175, CIS-565C, Org-50189, TM-38837,
  • the prophylactic or alleviating agent according to (11) above which is at least one compound selected from the group consisting of V-25343 and ZYO-1.
  • the side effect of the CB1 receptor ligand is at least one selected from the group consisting of nausea, mood swings associated with depressive symptoms, anxiety, immobility, suicide attempts, eating disorders, and drug dependence. Or the preventive or alleviating agent according to any one of (13).
  • the CB receptor ligand is a CB2 receptor ligand.
  • a method for preventing / ameliorating or treating a CB receptor-related disease comprising a step of administering at least one compound selected from the group consisting of ⁇ 3PUFAs and pharmaceutically acceptable salts and esters thereof.
  • the CB receptor-related disease is a CB1 receptor-related disease.
  • the CB receptor-related disease is a CB2 receptor-related disease.
  • (22) A method for preventing or alleviating a side effect caused by a CB receptor ligand, comprising a step of administering at least one compound selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof. (23) The method according to (22) above, further comprising administering a CB receptor ligand. (24) The method according to (23) above, wherein the two administration steps are performed simultaneously. (25) The method according to (23) above, wherein the two administration steps are performed at different times. (26) The method according to any one of (22) to (25) above, wherein the CB receptor ligand is a CB1 receptor antagonist or inverse agonist.
  • the CB1 receptor-related disease is at least one selected from the group consisting of postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorders, and abnormal taste (taste) 30) Use.
  • the CB receptor-related disease is a CB2 receptor-related disease.
  • the use according to (33) above, wherein the CB receptor-related disease is a CB1 receptor agonist.
  • a CB receptor ligand By using at least one compound selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof, a CB receptor ligand, particularly a CB1 receptor, which is highly safe, effective and easy to use.
  • An agent for preventing or alleviating a side effect caused by a ligand, and a method of using the same can be provided.
  • CB receptor ligands can be reduced by the present invention, and treatment can be continued in patients who have failed to administer CB receptor ligands due to these side effects or who have had to be interrupted. it can.
  • CB1 receptor neutral antagonist-like action resulting in excessive CB1 receptor such as postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorder or abnormal taste (taste) It is useful for preventing / ameliorating or treating a syndrome, disorder or disease caused by enhancement or excessive suppression. It is also useful for preventing or reducing side effects caused by CB1 receptor ligand (agonist, antagonist or inverse agonist).
  • EPA-E is expected to prevent / ameliorate or treat nicotine dependence or postoperative cognitive impairment by inhibiting CB1 receptor hyper-enhancement through CB1 receptor neutral antagonist-like action (Animal model test 1 and clinical model test 1).
  • Tic disorders, Tourette's syndrome, refractory hiccups or abnormal taste (taste) are thought to be associated with CB1 receptor suppression (Non-Patent Documents 6 and 7 and Physiology and Behavior, 2007) , 90, p.425-430), EPA-E inhibits CB1 receptor over-suppression through CB1 receptor neutral antagonist-like action, thereby inhibiting tic disorder, Tourette syndrome, refractory hiccups or taste (taste) ) Is expected to be prevented / ameliorated or treated (clinical model test 2 and animal model test 2).
  • the present invention is a preventive / ameliorating or treating agent for CB receptor-related diseases comprising at least one selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof, and a method of using the same.
  • the present invention also relates to a preventive or alleviating agent for side effects caused by a CB receptor ligand comprising at least one selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof, and a method of using the same. .
  • ⁇ 3 PUFAs is used to mean not only ⁇ 3 PUFAs but also ⁇ 3 PUFAs derivatives such as pharmaceutically acceptable salts or esters thereof.
  • ⁇ 3PUFAs is used in the ordinary sense known to those skilled in the art, and among the fatty acids having a plurality of carbon-carbon double bonds in the molecule, the first double is in the third position counted from the methyl group side. It refers to PUFAs that have bonds.
  • Preferred ⁇ 3 PUFAs are exemplified by EPA, DHA and ⁇ -linolenic acid, more preferably EPA and / or DHA.
  • Examples of the pharmaceutically acceptable salt include salts with an inorganic base such as sodium salt or potassium salt, an organic base such as benzylamine salt or diethylamine salt, or a basic amino acid such as arginine salt or lysine salt.
  • an inorganic base such as sodium salt or potassium salt
  • an organic base such as benzylamine salt or diethylamine salt
  • a basic amino acid such as arginine salt or lysine salt.
  • esters examples include alkyl esters with ethyl or ethanolamine, mono-, di- or tri-glycerol esters, or phospholipid esters such as phosphatidylcholine or phosphatidylethanolamine.
  • Preferred ⁇ 3 PUFAs derivatives include EPA-E, DHA-E, 2-EG, 2-DG, N-icosapentaenoylethanolamine, and N-docosahexaenoylethanolamine, more preferably EPA-E. And / or DHA-E is presented.
  • ⁇ 3 PUFAs used in the present invention may be a synthetic product, a semi-synthetic product or a natural product, or may be in the form of a natural oil containing them.
  • the natural product means a product extracted from a natural oil containing ⁇ 3 PUFAs by a known method, a product that has been refined, or a product that has been further refined.
  • Semi-synthetic products include PUFAs produced by microorganisms and the like, and those obtained by subjecting the PUFAs or natural PUFAs to chemical treatment such as esterification or transesterification.
  • ⁇ 3PUFAs one of these can be used alone, or two or more can be used in combination.
  • the purity of ⁇ 3 PUFAs is not particularly limited, but usually, the content of ⁇ 3 PUFAs in the total fatty acids of the composition of the present agent is preferably 25% by mass or more, more preferably 50% by mass or more, still more preferably 70% by mass or more, even more preferably. Is 85% by mass or more, and it is particularly preferable that the present composition is substantially free of other fatty acid components other than ⁇ 3 PUFAs.
  • the composition ratio of EPA-E / DHA-E and the content ratio of EPA-E + DHA-E in all fatty acids are not particularly limited, but a preferred composition ratio is EPA-E.
  • / DHA-E is preferably 0.8 or more, more preferably 1.0 or more, and further preferably 1.2 or more.
  • EPA-E and / or DHA-E are preferably of high purity.
  • the EPA-E and / or DHA-E content ratio in the total fatty acids and derivatives thereof is preferably 40% by mass or more, more preferably 55% by mass or more, further preferably 84% by mass or more, The thing of 96.5 mass% or more is still more preferable.
  • the purity of ⁇ 3 PUFAs in all fatty acids is preferably high, the EPA + DHA purity which is ⁇ 3 PUFAs is more preferable, and the purity of EPA is more preferable.
  • the content of other long chain saturated fatty acids is preferably low.
  • the content of ⁇ 6 long chain unsaturated fatty acids, particularly arachidonic acid is preferably small, more preferably less than 2% by mass, and even more preferably less than 1% by mass.
  • EPA-E and / or DHA-E used in the preventive / ameliorating or therapeutic agent or preventive or alleviating agent of the present invention is more effective against cardiovascular events such as saturated fatty acids and arachidonic acid than fish oil or fish oil concentrate.
  • cardiovascular events such as saturated fatty acids and arachidonic acid than fish oil or fish oil concentrate.
  • vitamin A since it is an ester, it has a higher oxidation stability than fish oil or the like, which is mainly a triglyceride, and a sufficiently stable composition can be obtained by adding a normal antioxidant.
  • the cardiovascular event is used in the ordinary sense known to those skilled in the art and includes cardiovascular death (such as fatal myocardial infarction or sudden cardiac death), non-fatal myocardial infarction, reinfarction, unstable angina.
  • cardiovascular death such as fatal myocardial infarction or sudden cardiac death
  • non-fatal myocardial infarction such as myocardial infarction or sudden cardiac death
  • non-fatal myocardial infarction such as fatal myocardial infarction or sudden cardiac death
  • non-fatal myocardial infarction such as congestive heart failure, stroke, cerebral infarction, or fainting, or treatment such as coronary artery bypass grafting (CABG), percutaneous coronary angioplasty (PTCA), or stent
  • CABG coronary artery bypass grafting
  • PTCA percutaneous coronary angioplasty
  • stent includes illustratively.
  • Epadale for example, Epadale (Mochida Pharmaceutical) available in Japan can be used.
  • the mixture of EPA-E and DHA-E can be obtained by using, for example, Lovaza (registered trademark) (Glaxo SmithKline) commercially available in the United States.
  • Lovaza registered trademark
  • Gaxo SmithKline commercially available in the United States.
  • Refined fish oil can also be used as ⁇ 3 PUFAs.
  • ⁇ 3PUFAs monoglyceride, diglyceride, triglyceride, or a combination thereof is one of the preferred embodiments.
  • Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International plc, England), as well as EPAX6000FA, EPAX5000TG, EPAX4520TG50, EPAX4510T50, EPAX4510T , K85EE and K80EE (Pronova BioPharma ASA, Lysaker, Norway) containing various ⁇ 3 PUFAs or salts or esters thereof are commercially available and can be obtained and used.
  • CB receptor means known CB receptors, CB1 receptor and CB2 receptor, as well as amino acid sequence and structural / functional similarity between those skilled in the art and CB1 receptor or CB2 receptor (7th membrane A receptor capable of recognizing a penetrating type, a G protein-coupled type, and the like, and is used to mean a receptor to which ⁇ 9 -THC or an analog thereof binds.
  • the CB receptor referred to in the present invention is similar to the CB1 receptor or the CB2 receptor, includes a receptor to which ⁇ 9 -THC or a similar compound binds, and is a known CB receptor, the CB1 receptor or the CB2 It is not limited to receptors only. For example, since a CB1 receptor agonistic action is observed in a CB1 receptor knockout mouse, the existence of a new CB receptor is presumed, and such an unidentified CB receptor is also included.
  • analogous compounds of delta 9 -THC compounds having agonist activity to those skilled in the art can recognize structural similarity to delta 9 -THC compounds or CB1 receptor and / or CB2 receptors Any other compound may be used as long as the compound is known to date.
  • the analog of ⁇ 9 -THC referred to in the present invention includes cannabinol, cannabidiol, cannabigerol, cannabicycrol, and other natural cannabinoids and anandamide , 2-AG, 2-arachidonyl glyceryl ether, virodhamine, palmitoic ethanolamide and N-archydonyl-dopamin Cannabinoids (also referred to as “endogenous cannabinoids”), and A-41988 (also known as BW29Y), ajulemic acid (also known as CT-3, HU-239), AM-087, AM-411, AM- 855, AM-905, AM-906, M-919, AM-938, AM-4030, AMG-1, AMG-3, AMG-36, AMG-41, dexanabinol (HU-211), dimethylheptylpyran, HU-210, JWH- 051, JWH-133, JWH-139, L
  • CB receptor-related disease is used to include biological reactions mediated by CB receptors and related syndromes, disorders and diseases.
  • CB receptor-related diseases include eating, obesity, metabolism, diabetes, glaucoma, social or mood, seizures, drug abuse, caused by excessive or excessive suppression of CB1 receptor and / or CB2 receptor, Includes syndromes, disorders and diseases related to learning / cognition or memory, organ contraction, muscle spasm, gastrointestinal tract and viscera, respiratory organs, locomotor activity or exercise, immunity and inflammation, cell proliferation, pain, and neurodegeneration .
  • Syndromes, disorders and diseases related to eating include bulimia, anorexia, obesity, weight loss, weight gain, unregulated appetite, poor appetite in cancer, AIDS, cachexia, and taste (taste). Abnormalities are included.
  • Syndrome, disorders and diseases associated with obesity include heredity, diet, excess food intake, metabolic syndrome, and hypothalamic disorder or disease, and aging, reduced motor activity, abnormal fat mass distribution, and / or Obesity as a result of abnormal fat compartment distribution and the like is included.
  • Metabolic syndromes, disorders and diseases include metabolic syndrome, dyslipidemia (hypercholesterolemia, hypertriglyceridemia, high LDL cholesterolemia, low HDL cholesterolemia), atherosclerosis, fatty liver , Hepatitis (viral, alcoholic, non-alcoholic, drug), hypertension, diabetes, insulin sensitivity or resistance, and hyperinsulinemia.
  • dyslipidemia hypercholesterolemia, hypertriglyceridemia, high LDL cholesterolemia, low HDL cholesterolemia
  • atherosclerosis fatty liver
  • Hepatitis viral, alcoholic, non-alcoholic, drug
  • hypertension diabetes
  • insulin sensitivity or resistance and hyperinsulinemia.
  • Syndrome, disorder and disease related to diabetes include glucose regulation abnormality, insulin resistance, glucose tolerance abnormality, hyperinsulinemia, dyslipidemia, hypertension, obesity and the like.
  • Type II diabetes is associated with persistent plasma hyperglycemia, polyuria, polyposis, bulimia and chronic microvascular complications such as retinopathy, nephropathy and neuropathy, and dyslipidemia and hypertension. Characterized by clinical signs or symptoms such as macrovascular complications. These micro and macrovascular complications can result in blindness, end-stage renal disease, limb amputation and / or myocardial infarction.
  • Metabolic syndrome is the development of type II diabetes including impaired glucose tolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypertension and obesity, and cerebrovascular disorders such as cardiovascular disease, cerebral infarction and cerebral hemorrhage It is an obstacle that presents risk factors.
  • Syndrome, disorder and disease related to glaucoma include increased intraocular pressure, ocular circulation disorder, optic nerve disorder, rainbow vision, decreased visual acuity, eye pain, visual impairment such as visual field, and blindness.
  • Syndrome, disorder and disease related to society or mood include psychosis in general, depression, manic depression, bipolar disorder, anxiety, schizophrenia, mood disorder, delirium, social affective or cognitive impairment, obsession or urgency Neurosis, adult personality disorder, shock behavior disorder, panic disorder, phobia, confusion, neurological stress disorder, post-traumatic stress disorder (PTSD), attention deficit disorder (ADD / ADHD), hyperactivity, autism, speechlessness, Behavioral addiction, arousal disorder, insomnia, intuition, illusion disorder, and reduced motivation are included.
  • Syndrome, disorder and disease related to drug abuse include alcohol, amphetamines (amphetamine, methamphetamine, etc.), barbiturates (barbitur derivatives, benzodiazepine derivatives, etc.), cannabis (marijuana, hashish, etc.), ***e, hallucinogen (LSD , Mescarin, sirocibin, phencyclidine, etc.), carts, opiates (morphine, heroin, codeine, pethidine, fentanyl, etc.) or organic solvents (toluene, thinner, acetone, ether, chloroform, benzene, etc.) ⁇ Withdrawal symptoms and nicotine or tobacco abuse / dependence / withdrawal symptoms are included.
  • Syndrome, disorder and disease related to learning, cognition or memory include memory loss or impairment as a result of aging, disease and / or drug side effects (adverse events), and cognitive impairment, postoperative cognitive decline ( Confusion, delirium, phantom limb, phantom limb pain, etc.), senile / vascular / alzheimer-type dementia symptoms, amnesia, and forgetting.
  • Syndrome, disorder and disease related to muscle spasms include multiple sclerosis, cerebral palsy, tremor, and infantile febrile convulsions.
  • Spontaneous movements or movement-related syndromes, disorders and diseases include seizures, Parkinson's disease, Parkinson's dyskinesia, multiple sclerosis, epilepsy, motor dysfunction such as levodopa-induced movement disorders, catalepsy, Tourette's syndrome, and tic disorders Etc. are included.
  • Gastrointestinal and visceral-related syndromes, disorders and diseases include gastrointestinal ulcers, gastrointestinal inflammation, gastrointestinal dysmotility-related disorders (with or without pain, diarrhea or constipation), hypersensitivity Bowel syndrome (and other forms of intestinal dysfunction), inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), celiac disease, kidney disease such as renal failure, liver fibrosis, cirrhosis, and urinary tract / bladder Functional impairments are included.
  • Respiratory syndromes, disorders and diseases include chronic pulmonary obstructive disease, emphysema, inflammatory pneumonia, pulmonary fibrosis, asthma, bronchitis, airway obstruction, sleep apnea, and refractory hiccups Is included.
  • Syndrome, disorder and disease related to immunity and inflammation include allergy, arthritis, rheumatoid arthritis, dermatitis, autoimmune disease, immunodeficiency and chronic neuropathic pain.
  • Syndromes, disorders and diseases related to cell proliferation include benign or malignant unregulated cell growth (invasive growth), such as pharyngeal cancer, tongue cancer, esophageal cancer, gastric cancer, duodenal cancer, colon cancer, rectal cancer, Lung cancer, liver cancer, pancreatic cancer, kidney cancer, spleen cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, skin cancer, brain tumor, osteosarcoma, leukemia, or lymphoma, and pain caused by cancer or cachexia • Anorexia, weakness, hypercalcemia, and nausea, nausea, and vomiting caused by anticancer drugs are included.
  • invasive growth such as pharyngeal cancer, tongue cancer, esophageal cancer, gastric cancer, duodenal cancer, colon cancer, rectal cancer, Lung cancer, liver cancer, pancreatic cancer, kidney cancer, spleen cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, skin cancer, brain tumor, osteosarcoma,
  • Pain-related syndromes, disorders and diseases include neuropathic pain mediated by central and peripheral pathways, chronic pain, bone and joint pain, migraine-related pain, cancer pain, menstrual pain, labor pain, phantom limb pain , Pruritus, and enhancement of narcotic and non-narcotic analgesics.
  • Syndromes, disorders and diseases associated with neurodegeneration include Parkinson's disease, Huntington's chorea, multiple sclerosis, hemorrhoids, traumatic head or brain ischemia or secondary biochemical damage associated with neuropathy, Includes Guillain-Barre syndrome, head trauma, spinal cord injury, neuroprotection in neurodegenerative diseases, infant brain developmental disorders / excitement, oxygen deprivation and ischemic brain inflammation due to nerve gas damage, eye damage and seizures, etc. .
  • endotoxin shock hemorrhagic shock
  • hypotension hypothermia
  • nausea due to emetics migraine, Raynaud's disease, premenstrual syndrome or late corpus luteum syndrome, infertility, premature birth, miscarriage, male and female sexual dysfunction, infection , Chronic fatigue syndrome, and osteoporosis.
  • the preventive / ameliorating or therapeutic agent of the present invention preferably prevents / improves CB1 receptor-related diseases, more preferably postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorders or abnormal taste (taste) or Used for treatment.
  • CB receptor ligand is used to mean a compound that binds to a CB receptor and causes a biological reaction.
  • the ligands are classified into agonists and antagonists or inverse agonists depending on the reaction expression pattern, and these are included.
  • Both CB1 and CB2 receptor agonists include endocannabinoids such as anandamide and 2-AG, and dronabinol, GW-1000 (trade name: Satibex (registered trademark), GW Pharmaceuticals (GW) Pharmaceuticals plc, Wiltshire, UK)), and O-1057 (Organix Inc., Woburn, MA, USA)).
  • Agonists specific for the CB1 receptor include AZ-599, AZD-1940 (AstraZeneca), KN-38-7271 (Bayer AG), Org-28611, Org-26828, and SCH-900111. (Organon Biosciences Organon BioScience NV, Oss, The Netherlands) and SAB-378 (Novartis Pharma Novartis Pharma AG, Basel, Switzerland).
  • Examples of agonists specific for the CB2 receptor include GW-842166X (GlaxoSmithKline) and S-777469 (Yoshio Shionogi).
  • CB1 and CB2 receptor antagonists or inverse agonists examples include ⁇ 9 -tetrahydrocannabinalin (GW Pharmaceuticals).
  • CB1 receptor specific antagonists or inverse agonists include drinabant, rimonabant and surinabant (Sanofi-aventis), otenabant (Pfizer Pfizer Inc., New York, NY, USA), AZD-2207.
  • CB2 receptor-specific antagonists include AM-630 (University of Connecticut, Storm, CT).
  • the CB receptor ligand referred to in the present invention is not limited to these.
  • a “CB receptor neutral antagonist” does not affect the equilibrium state of the inactive and active forms of the CB receptor, ie it does not affect the CB receptor in any way, but to either a CB receptor agonist or an inverse agonist. However, it is also used to mean an antagonist that competitively antagonizes. Many of the conventional antagonists are inverse agonists that move the equilibrium between the inactive and active forms of the receptor to the inactive side. Symptoms worsen further when antagonists with strong inverse agonist activity are used due to continuous use or drug withdrawal. Rebound phenomenon is likely to occur. On the other hand, a neutral antagonist is considered not to cause inconvenience associated with continuous use in such an inverse agonist.
  • side effect due to CB receptor ligand is used to mean a reaction unfavorable for a living body among biological reactions caused by administration of a CB receptor ligand. Examples include excessive enhancement by CB receptor agonists, excessive suppression by CB receptor antagonists or inverse agonists, and development of tolerance due to long-term use of CB receptor ligands and rebound phenomenon due to discontinuation of use.
  • CB1 receptor ligand examples include upper respiratory tract infection, sinusitis, gastroenteritis, and depressive disorders (depression, manic depression, depression, etc.) reported as side effects of rimonabant, which is an inverse agonist of CB1 receptor.
  • Mood swings with depressive symptoms anxiety, irritation, irritability, sleep disorder, insomnia, abnormal insomnia, panic symptoms, anger, dissatisfaction, euphoria, emotional disorder, suicide attempt, aggressiveness, aggressive behavior, hallucinations, Headache, memory loss (amnesia), attention deficit, dizziness, immobility, hyposensory, sciatica, sensory dysfunction, lethargy, flushing, hiccup, nausea, diarrhea, vomiting, loss of appetite, loss of appetite, stomach discomfort , Dry mouth, pruritus, hyperhidrosis, night sweats, tendonitis, muscle spasms, muscle spasms, asthenia / fatigue, influenza, falls, bruises and sprains.
  • the most frequently reported adverse reactions include upper respiratory tract infection, gastroenteritis, depressive disorder, mood swings with depressive symptoms, anxiety, irritation, irritability, sleep disorder, insomnia, abnormal insomnia, suicide attempt , Memory loss (amnesia), dizziness, hypoxia, sciatica, sensory abnormalities, flushing, nausea, diarrhea, vomiting, itching, hyperhidrosis, tendonitis, muscle spasm, muscle spasm, asthenia / fatigue, falls, Examples include bruises and sprains, and examples of serious side effects include depressive disorder and suicide attempts.
  • dronabinol a CB1 and CB2 receptor agonist
  • lethargy palpitation
  • tachycardia vasodilation / facial flushing
  • conjunctivitis hypotension
  • abdominal pain nausea, vomiting, diarrhea, incontinence
  • amnesia anxiety, nerve
  • nerve Examples include hypersensitivity, ataxia, confusion, depression, dizziness, uplifting, euphoria, hallucinations, paranoia, drowsiness, abnormal thinking, nightmares, language disturbances, tinnitus, drug dependence, flushing, and visual abnormalities.
  • side effects with high incidence include lethargy, palpitation, tachycardia, vasodilation / facial flushing, abdominal pain, nausea, vomiting, amnesia, anxiety, hypersensitivity, ataxia, confusion, depression, dizziness, uplifting feeling Euphoria, hallucinations, paranoia, sleepiness, abnormal thinking, etc.
  • severe side effects include hypotension, confusion, depression, hallucinations, and drug dependence.
  • the preventive or alleviating agent of the present invention is preferably a side effect of CB1 receptor agonist or inverse agonist, more preferably nausea, mood swings associated with depressive symptoms, anxiety, immobility, suicide attempt, eating disorder, memory disorder or drug Used to prevent or reduce side effects such as addiction.
  • the form of the preventive or alleviating agent of the present invention is not particularly limited.
  • a preparation containing ⁇ 3 PUFAs as a single active ingredient (2) a single preparation obtained by co-formulation of ⁇ 3 PUFAs and a CB receptor ligand, (3)
  • the method for preventing or reducing the side effects caused by the CB receptor ligand is not particularly limited, and may include a step of administering ⁇ 3 PUFAs.
  • a method of using a combination of ⁇ 3PUFAs and a CB receptor ligand including a step of administering ⁇ 3PUFAs and a step of administering a CB receptor ligand is also included.
  • ⁇ 3 PUFAs and CB receptor ligands When used in combination, it should be administered as a combination containing both ⁇ 3 PUFAs and CB receptor ligands, and ⁇ 3 PUFAs and CB receptor ligands should be administered separately as separate preparations at the same time or separately at different times. Including.
  • the term “combination” is not necessarily limited to the case where it is simultaneously present in the patient's body, for example, blood, but in the present invention, “combination” means that the action / effect of either one of the drugs is expressed in the patient's body. In this state, the other drug is administered. It is a usage mode in which the prevention or alleviation effect of the CB receptor is obtained using the preventive or alleviating agent of the present invention. Preferably, a usage mode that coexists in the patient's body, for example, in the blood, is desirable, and a usage mode in which the other drug is administered to the patient within 24 hours after the administration of one drug is preferable. .
  • both drugs may be mixed immediately before the administration, may be administered separately, or can be used by shifting the administration time systematically for various purposes.
  • one drug is administered and the other drug is administered and acted at the time when the effect starts to appear or when the effect is fully manifested.
  • one drug particularly CB receptor ligand
  • the other drug particularly ⁇ 3PUFAs
  • both drugs are administered, and the administration of one drug is stopped when the effect starts to appear or when the effect is fully manifested.
  • the dose of the drug may be decreased in stages.
  • the dose and duration of ⁇ 3PUFAs used in the preventive / ameliorating or treating agent for CB receptor-related diseases of the present invention and the preventive or alleviating side effect due to CB receptor ligand are sufficient to exhibit the intended effect and although it is a period, it can be appropriately increased or decreased depending on its dosage form, administration method, number of administrations per day, symptoms and degree of side effects, body weight, age and the like.
  • EPA-E and / or DHA-E is 0.1 to 10 g / day, preferably 0.3 to 6 g / day, more preferably 0.6 to 4 g / day, still more preferably 0.9 to 2.7 g / day is administered in 1 to 3 divided doses, but the entire dose may be administered in one or several divided doses as necessary.
  • the administration time is preferably during or after meals, more preferably immediately after meals (within 30 minutes).
  • it can be administered as an oral liquid preparation such as an emulsion or a bile acid-added preparation without any restriction on the time of medication.
  • the administration period is appropriately determined depending on the degree of symptoms and the degree of improvement, and is not limited, but for example, 1 year or more, preferably 2 years or more, more preferably 3.5 years or more. More preferably, for more than 5 years, the onset and / or recurrence of the CB receptor-related disease is continued while the pathology or biochemical index of the CB receptor-related disease and the side effects due to the CB receptor ligand continue. It is desirable to continue administration while the state of high risk continues and during the state of high risk of side effects and / or recurrence due to CB receptor ligand. Further, for example, it may be administered every other day or administered for 2 to 3 days per week, and in some cases, a drug holiday of about 1 to 3 months, preferably about 1 week to 1 month may be provided. it can.
  • the agent for preventing / ameliorating or treating a CB receptor-related disease of the present invention and the agent for preventing or alleviating side effects caused by a CB receptor ligand include an active ingredient, a compound alone (including other ingredients inevitably contained during purification). In some cases) or suitable commonly used carriers, media, excipients, binders, lubricants, coloring agents, flavoring agents, emulsifying agents, suspending agents (eg Tween 80).
  • Gum arabic solution Gum arabic solution
  • absorption enhancers eg bile acids such as ursodeoxycholic acid
  • isotonic agents pH adjusters, stabilizers, soothing agents, flavoring agents, flavoring agents, preservatives, antiseptics
  • oxidizing agents eg glycerin, propylene glycol
  • solubilizers eg glycerin, propylene glycol
  • additives include lactose, partially pregelatinized starch, hydroxypropylcellulose, macrogol, tocopherol, hydrogenated oil, sucrose fatty acid ester, hydroxypropylmethylcellulose, titanium oxide, talc, dimethylpolysiloxane, silicon dioxide, and / or carnauba wax. Etc. may be contained.
  • ⁇ 3PUFAs are highly unsaturated, so it is desirable to contain an effective amount of an antioxidant.
  • an antioxidant for example, at least one selected from oil-soluble antioxidants such as butylated hydroxytoluene, brechated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin and ⁇ -tocopherol is used as an antioxidant. It is desirable to contain an effective amount.
  • oil-soluble antioxidants such as butylated hydroxytoluene, brechated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin and ⁇ -tocopherol is used as an antioxidant. It is desirable to contain an effective amount.
  • a water-soluble antioxidant and an oil-soluble antioxidant such as ascorbic acid and derivatives thereof, erythorbic acid, nitrite, and citric acid.
  • the dosage form of the preparation is not particularly limited, and may be an oral preparation or a parenteral preparation.
  • oral preparation for example, oral liquid preparations such as tablets, film-coated tablets, capsules, microcapsules, granules, fine granules, powders, emulsions, syrups, jellies, or inhalants are preferable.
  • Parenteral preparations include, for example, ointments, suppositories, injections (emulsification, suspension, non-aqueous), solid injections used when emulsified or suspended, infusion preparations, or transdermal absorption.
  • An external preparation such as an agent is preferred.
  • Oral preparations can be administered to patients by oral administration, and parenteral preparations can be administered to patients intravenously or intraarterially, by inhalation, rectal, vaginal or external.
  • oral administration in capsules such as soft capsules or microcapsules, or in tablets, film-coated tablets, and emulsions is particularly preferable.
  • it may be orally administered as an enteric preparation or sustained-release preparation, and is preferably administered orally as a jelly agent to dialysis patients or patients who have difficulty swallowing.
  • oral administration as an oral liquid preparation such as an emulsion is preferable because absorption of ⁇ 3PUFAs and / or CB receptor ligand is promoted, administration can be performed without any restriction on the dose, and the dose of the drug can be reduced.
  • the emulsion particles have a smaller diameter, preferably an average diameter of 5 ⁇ m or less, more preferably 1 ⁇ m or less, still more preferably 0.5 ⁇ m or less, and still more preferably 0.2 ⁇ m or less.
  • any emulsifier can be used as long as it can be used in pharmaceutical preparations.
  • examples include polyglycerin fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, sorbitan monostearate, sorbitan trioleate, sodium lauryl sulfate, and nonionic surfactant, preferably egg yolk lecithin, soybean lecithin , Polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, sorbitan fatty acid ester and propylene glycol fat Esters il
  • an emulsification aid such as fatty acids having 12 to 22 carbon atoms such as stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid and myristic acid, or salts thereof.
  • the stabilizer include phosphatidic acid, ascorbic acid, glycerin, cetanol, ethyl paraoxybenzoate, propyl paraoxybenzoate, and the like.
  • Surfactants include sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, Examples include polyoxyethylene alkylphenyl ether, polyoxyethylene polyoxypropylene glycol, and polyoxyethylene polyoxypropylene alkyl ether.
  • Antioxidants include butyrated hydroxytoluene, breached hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin and ⁇ -tocopherol, as well as ascorbic acid and its derivatives
  • Water-soluble antioxidants such as erythorbic acid, nitrite and citric acid are exemplified.
  • the content of EPA in the emulsion is preferably 1 to 60% by mass, more preferably 3 to 40% by mass, and further preferably 5 to 30% by mass.
  • the content of the emulsifier is preferably 0.1 to 10% by mass, more preferably 0.2 to 5% by mass, and still more preferably 0.5 to 3% by mass.
  • the emulsion of the present invention is mixed with, for example, an active ingredient, an emulsifier, glycerin, purified water, and other additives such as an antioxidant, if necessary, and heated to form a solution, which is a normal homogenizer, such as a Manton Gorin type homogenizer.
  • a normal homogenizer such as a Manton Gorin type homogenizer.
  • emulsification is preferably performed at a pressure of 50 to 700 kg / cm 2 , preferably about 1 to 50 times, more preferably about 2 to 20 times, or a microfluidizer, a thin film It can be produced by homogenization using a swirl type high-speed mixer, a high-pressure jet flow reversal type emulsifier, an ultrasonic homogenizer, or the like. Prior to this, preliminary emulsification may be performed using a homomixer or the like.
  • EPA-E group received 1000 mg / kg EPA-E, rimonabant group 10 mg / kg rimonabant and the combination group EPA-E 1000 mg / kg and rimonabant 10 mg / kg 5% Arabic It was suspended in an aqueous rubber solution using Hiscotron (Microtech Nithion) and orally administered once a day.
  • the control group was orally administered with a 5% gum arabic aqueous solution once a day.
  • the body weight was measured every day during the breeding period, and the food intake on the last day of the breeding was measured.
  • the amount of food consumed on the last day of breeding in each group and the mean value ⁇ standard error of weight gain during the breeding period were calculated, and Student's t test was performed.
  • EPA-E had no effect on food intake or weight gain when administered alone orally. And nevertheless, when EPA-E is orally administered in combination with rimonabant (combination group), feeding inhibition and mainly via central CB1 receptor over-suppression by rimonabant, a CB1 receptor inverse agonist, and All the suppression of weight gain was restored.
  • rimonabant combination group
  • the EPA glyceride produced by oral administration of EPA-E exhibits a neutral antagonist-like action on the CB1 receptor, and through this neutral antagonist-like action, suppresses excessive inhibition of the CB1 receptor, thereby suppressing feeding and body weight. It is thought that the increase suppression was restored.
  • the preventive / improving or therapeutic agent of the present invention over- or over-suppressed the CB1 receptor. It is useful for the prevention / amelioration or treatment of CB1 receptor-related diseases caused by this.
  • the preventive or alleviating agent for side effects of the present invention is useful for preventing or reducing side effects caused by a CB1 receptor agonist, antagonist or inverse agonist.
  • the preventive / improving or treating agent and the side effect preventing or reducing agent of the present invention do not act on the CB1 receptor in a state where the CB1 receptor is not excessively enhanced or excessively suppressed, there is an advantage that no side effect is exhibited.
  • the prevention / improvement or therapeutic effect of CB1 receptor-related diseases caused by excessive enhancement or excessive suppression of the CB1 receptor of the present invention can be evaluated by the following animal model test or clinical model test.
  • mice in each group are set: a control group, an EPA-E100 group (administered with EPA-E 100 mg / kg), and an EPA-E300 group (administered with EPA-E 300 mg / kg).
  • EPA-E is suspended in a 5% gum arabic aqueous solution using hiscotron and administered orally once a day during the breeding period.
  • the control group is orally administered with a 5% gum arabic aqueous solution once a day.
  • Administration of nicotine and the following conditions are performed from 3 weeks after the breeding.
  • a 121.4 mg / ml nicotine aqueous solution was prepared and injected into an osmotic pump (Alzet 2001 mini-osmotic pump (1 ⁇ l / hour for 7 days)) implanted subcutaneously in the back of the rat, and 10 mg / kg / day.
  • an osmotic pump Alzet 2001 mini-osmotic pump (1 ⁇ l / hour for 7 days) implanted subcutaneously in the back of the rat, and 10 mg / kg / day.
  • nicotine receptor antagonist mecalamine (1 mg / ml) or physiological saline solution was administered subcutaneously and placed in one compartment for 60 minutes, and the opposite of the morning treatment (morning in the morning) Conditioning is performed by the counterbalance method, in which physiological saline is administered to rats administered with mecalamine, and mecalamine is administered to rats administered with physiological saline) and placed in the other compartment for 60 minutes.
  • EPA-E administration is expected to reduce the time withdrawn from the compartment conditioned by subcutaneous administration of mecalamine in a dose-dependent manner and suppress the mecalamine-induced aversive effect.
  • the EPA-E group is expected to have a higher rate of disappearance of phantom limbs and phantom limb pain and a lower incidence than the control group.
  • a hiccup-like reaction is induced by mechanically stimulating the nasopharyngeal head behind the uvula with a cotton swab through this tube.
  • Hiccup-like reaction is confirmed by electrical muscle contraction with electrodes placed on the posterior cricoid cartilage and diaphragm of the larynx.
  • the intracapsular pressure during the hiccup-like reaction is measured with a pressure transducer via a latex balloon placed at 2/3 of the esophagus.
  • the intracapsular pressure at the time of hiccup-like reflexes by 10 stimuli is summed to give the intensity of hiccup-like reflexes (Oshima T., Anthesia and Analgesia, 2004, Vol. 98, 346-352).
  • a compounding agent with EPA-E and a CB receptor ligand is produced.
  • This is emulsified by passing 10 times under a pressure of 120 kg / cm 2 in the first stage and a total pressure of 500 kg / cm 2 using a Manton Gorin type homogenizer. Thereby, an emulsion having an average particle size of 0.2 ⁇ m or less is obtained. 30 ml of this emulsion is dispensed into ampoules to obtain an emulsion containing 1.8 g of EPA-E and 20 mg of rimonabant per ampoule.
  • an emulsion having an average particle diameter of 1 ⁇ m or less is obtained.
  • 40 ml of this emulsion is dispensed into glass bottles to obtain an emulsion containing about 3.36 g as EPA-E + DHA-E and 4 mg as dronabinol per bottle.
  • the prophylactic / ameliorating or treating agent for CB receptor-related diseases of the present invention containing at least one selected from the group consisting of ⁇ 3PUFAs and pharmaceutically acceptable salts and esters thereof as an active ingredient is highly safe, It is expected to show a preventive / improving or therapeutic effect on a syndrome, disorder or disease caused by excessive enhancement and excessive suppression of the CB receptor, particularly the CB1 receptor. In particular, it is expected that patients who exhibit postoperative cognitive decline, nicotine addiction, refractory hiccups, tic disorders or abnormal taste (taste) will have a preventive / improving or therapeutic effect.
  • the preventive or alleviating side effect of a CB receptor ligand containing at least one selected from the group consisting of ⁇ 3PUFAs and pharmaceutically acceptable salts and esters thereof as an active ingredient of the present invention is highly safe and effective. It is expected to exhibit an effect of preventing or reducing side effects caused by administration of a CB receptor ligand, particularly a CB1 receptor antagonist or inverse agonist. In particular, it is expected to show a preventive or alleviating effect on nausea, mood swings associated with depressive symptoms, anxiety, immobility dizziness, suicide attempts, eating disorders, memory disorders or drug dependence.
  • CB receptor ligands can be reduced by the present invention, and treatment can be continued in patients who have failed to administer CB receptor ligands due to these side effects or who have had to be interrupted. it can.

Abstract

Disclosed is a prophylactic/ameliorating or therapeutic agent for CB receptor-related diseases, which comprises at least one member selected from the group consisting of ω3PUFAs and pharmaceutically acceptable salts and esters thereof as an active ingredient.  Also disclosed is a method for utilizing the prophylactic/ameliorating or therapeutic agent.  It becomes possible to provide a safe and highly effective prophylactic/ameliorating or therapeutic agent for CB receptor-related diseases and a method for utilizing the prophylactic/ameliorating or therapeutic agent.

Description

カンナビノイド受容体関連疾患の予防／改善または治療剤Prevention / amelioration or treatment of cannabinoid receptor related diseases
　本発明は、カンナビノイド受容体が関与する疾患の予防／改善または治療剤、およびその使用方法に関する。より詳細には、特にカンナビノイド１受容体が関与する疾患の予防／改善または治療剤、およびその使用方法に関する。 The present invention relates to an agent for preventing / ameliorating or treating a disease involving cannabinoid receptors, and a method for using the same. More particularly, the present invention relates to an agent for preventing / ameliorating or treating a disease particularly involving cannabinoid 1 receptor, and a method for using the same.
　さらに、本発明は、カンナビノイド受容体リガンドによる副作用の予防または軽減剤、およびその使用方法に関する。より詳細には、特にカンナビノイド１受容体リガンドによる副作用の予防または軽減剤、およびその使用方法に関する。 Furthermore, the present invention relates to a preventive or alleviating agent for side effects caused by a cannabinoid receptor ligand, and a method for using the same. More specifically, the present invention relates to a preventive or alleviating agent for side effects caused by a cannabinoid 1 receptor ligand, and a method for using the same.
　カンナビノイド（以下、「ＣＢ」という。）とは***の主要活性成分であるΔ９－テトラヒドロカンナビノール（以下、「Δ９－ＴＨＣ」という。）とその類似化合物の総称である（非特許文献１）。 Cannabinoid (hereinafter referred to as “CB”) is a general term for Δ 9 -tetrahydrocannabinol (hereinafter referred to as “Δ 9 -THC”), which is the main active ingredient of cannabis, and its similar compounds (Non-patent Document 1). ).
　ＣＢは、哺乳類動物に対して、時間感覚・空間感覚の混乱、多幸感、幻覚、傾眠、食欲増進、痛覚の低下、免疫抑制、抗炎症など様々な作用を引き起こすことが知られている（非特許文献２）。 CB is known to cause various effects on mammals such as confusion of time sensation and spatial sensation, euphoria, hallucination, somnolence, increased appetite, decreased pain sensation, immunosuppression, and anti-inflammation (non-) Patent Document 2).
　これらの薬理学的作用のメカニズムは長い間不明であったが、１９８８年にＤｅｖａｎｅら（非特許文献３）によってＣＢに対する受容体が存在することが明らかにされ、これらの作用の多くは受容体を介すると考えられるようになった。 Although the mechanism of these pharmacological actions has not been known for a long time, Devane et al. (Non-patent Document 3) revealed that a receptor for CB exists in 1988, and many of these actions are receptors. It came to be thought that through.
　カンナビノイド受容体（以下、「ＣＢ受容体」という。）として、１９９０年にＭａｔｓｕｄａら（非特許文献４）によって、カンナビノイド１受容体（以下、「ＣＢ１受容体」という。）が、１９９３年にはＭｕｎｒｏら（非特許文献５）によってカンナビノイド２受容体（以下、「ＣＢ２受容体」という。）が、それぞれ遺伝子クローニングされ、現在までに２つのサブタイプが同定されている。 As a cannabinoid receptor (hereinafter referred to as “CB receptor”), in 1990, Matsuda et al. (Non-patent Document 4) disclosed a cannabinoid 1 receptor (hereinafter referred to as “CB1 receptor”) in 1993. Munro et al. (Non-patent Document 5) have cloned cannabinoid 2 receptors (hereinafter referred to as “CB2 receptors”), respectively, and two subtypes have been identified to date.
　ＣＢ１受容体はほとんどの神経系組織で発現しており、神経伝達の抑制的制御に関与している。一方、ＣＢ２受容体は脳など中枢神経ではほとんど発現しておらず、脾臓や扁桃腺など、主に炎症反応または免疫応答に関与する組織や細胞で大量に発現している。 CB1 receptor is expressed in most nervous system tissues and is involved in inhibitory control of neurotransmission. On the other hand, the CB2 receptor is hardly expressed in the central nervous system such as the brain, and is expressed in a large amount in tissues and cells mainly involved in inflammatory reaction or immune response such as spleen and tonsils.
　近年の研究により、Δ９－ＴＨＣの多様な作用のうち、時間感覚・空間感覚の混乱、多幸感、幻覚、傾眠、食欲増進などの作用は中枢神経系のＣＢ１受容体を介する作用であることが明らかになっている。一方、Δ９－ＴＨＣの作用のうち痛覚の低下、免疫抑制、および抗炎症などの作用に関しては、ＣＢ２受容体を発現している免疫応答または炎症反応に関与する細胞を介する作用であると考えられている。 According to recent studies, among the various actions of Δ 9 -THC, actions such as confusion of time and space sensation, euphoria, hallucinations, somnolence, and appetite increase are mediated through CB1 receptors in the central nervous system Has been revealed. On the other hand, among the actions of Δ 9 -THC, the actions such as a decrease in pain sensation, immunosuppression, and anti-inflammation are considered to be actions mediated by cells that participate in immune responses or inflammatory reactions expressing CB2 receptors. It has been.
　このようにＣＢ受容体を介する多種の作用は、生体の恒常性維持のために重要な役割を果たしている反面、ＣＢ受容体の過剰亢進または過剰抑制が生じた場合には、種々の症候群、障害または疾患が生じることになる（非特許文献１、２および６）。 As described above, various actions via the CB receptor play an important role for maintaining the homeostasis of the living body. On the other hand, when excessive enhancement or excessive suppression of the CB receptor occurs, various syndromes and disorders Or a disease will arise (nonpatent literature 1, 2, and 6).
　また、Δ９－ＴＨＣであるドロナビノール（dronabinol：商品名：マリノール（登録商標）（MARINOL（登録商標））、ユニメッド・ファーマシューティカルズ（Unimed Pharmaceuticals, Inc., Marietta, GA, USA））およびＣＢ１受容体のインバースアゴニストであるリモナバン（rimonabant：欧州連合（ＥＵ）域内での商品名：アコンプリア（登録商標）（ACOMPLIA（登録商標））、サノフィ・アベンティス（Sanofi-Aventis, Paris, France））などのようなＣＢ受容体リガンド（アゴニスト、アンタゴニストまたはインバースアゴニストなど）が医薬品として応用されつつある。例えば、リモナバン（アコンプリア（登録商標））は、主に中枢性摂食抑制作用により抗肥満薬として使用されている(非特許文献７)。しかし、これらの医薬品の過量投与や医薬品に対する過敏反応などにより、ＣＢ受容体の過剰亢進または過剰抑制に起因する副作用の発生が懸念される。 In addition, dronabinol (trade name: MARINOL (registered trademark), Unimed Pharmaceuticals, Inc., Marietta, GA, USA) which is Δ 9 -THC and CB1 receptor Rimonabant (trade name in the European Union (EU) region: ACOMPLIA (registered trademark), Sanofi-Aventis, Paris, France), etc. CB receptor ligands (such as agonists, antagonists or inverse agonists) are being applied as pharmaceuticals. For example, rimonabant (Acompria (registered trademark)) is mainly used as an anti-obesity drug due to its central feeding inhibitory action (Non-patent Document 7). However, there is concern over the occurrence of side effects due to excessive enhancement or excessive suppression of CB receptors due to overdose of these drugs and hypersensitivity reactions to drugs.
　実際、リモナバンの副作用として、上気道感染、副鼻腔炎、胃腸炎、うつ病性障害（うつ、躁うつ、抑うつなど）、抑うつ症状を伴う気分変動、不安、いらだち、神経過敏症、睡眠障害、不眠、異常不眠症、パニック症状、怒り、不満感、情緒障害、自殺企図、攻撃性、攻撃行動、幻覚、記憶喪失（健忘）、注意障害、めまい、不動性めまい、感覚減退症、坐骨神経痛、知覚異常症、嗜眠、紅潮、しゃっくり、悪心、下痢、嘔吐、食欲不振、食欲減退、胃部不快感、口渇、掻痒感、発汗過多、寝汗、腱炎、筋痙攣、筋攣縮、無力症／疲労、インフルエンザ、転倒、打ち身および捻挫などが、ならびに過量投与時の症状として、頭痛、多幸感、疲労および不眠などが報告されている（非特許文献７）。 In fact, side effects of rimonabant include upper respiratory tract infection, sinusitis, gastroenteritis, depressive disorders (such as depression, manic depression, depression), mood swings with depressive symptoms, anxiety, irritation, hypersensitivity, sleep disorders, Insomnia, abnormal insomnia, panic symptoms, anger, dissatisfaction, emotional disorder, suicide attempt, aggression, aggressive behavior, hallucinations, memory loss (amnesia), attention deficit, dizziness, immobility dizziness, hyposensory, sciatica, Dyssensory, lethargy, flushing, hiccups, nausea, diarrhea, vomiting, loss of appetite, loss of appetite, stomach discomfort, thirst, pruritus, excessive sweating, night sweats, tendonitis, muscle spasm, muscle spasm, asthenia / There are reports of headache, euphoria, fatigue, insomnia and the like as symptoms of fatigue, influenza, falls, bruises, sprains, and overdose (Non-patent Document 7).
　うつ病性障害または抑うつ症状を伴う気分変動は最高１０％、および自殺企図は最高１％の割合で報告されており、リモナバンの使用にあたっては、大うつ病の患者または抗うつ薬による治療を行っている患者に対してアコンプリア（登録商標）を使用禁忌とすること、各患者においてアコンプリア（登録商標）による治療のベネフィットがリスクを上回る場合を除いて現在自殺企図がある患者または自殺企図もしくはうつ病性障害の既往がある患者に対してアコンプリア（登録商標）を使用しないこと、患者がうつ病を発症した場合はアコンプリア（登録商標）による治療を中止すること、および、うつ病以外に管理不十分な精神疾患がある患者にはアコンプリア（登録商標）による治療は推奨しないことなどの使用上の特別の注意が付されている（非特許文献７）。この副作用のために、米国食品医薬品局（ＦＤＡ）の諮問委員会は、米国内でのリモナバンの販売を承認すべきでないとの結論を出した（非特許文献８）。 Up to 10% of mood swings with depressive disorder or depressive symptoms and up to 1% of suicidal attempts have been reported, and rimonabant is treated with patients with major depression or antidepressants Patients who are currently on suicide attempt or suicide attempt or depression, unless the patient is contraindicated with Accompli®, and the benefit of treatment with Accompli® exceeds the risk in each patient Do not use Accompli® in patients with a history of sexual disorders, discontinue treatment with Accompli® if the patient develops depression, and poor management other than depression Patients with special mental illness have special precautions such as not recommending treatment with Accompria®. Is (7). Because of this side effect, the US Food and Drug Administration (FDA) advisory board has concluded that the sale of rimonabant in the United States should not be approved (8).
　ところで、Δ９－ＴＨＣは動物の体内には存在しない。それにもかかわらず、ＣＢ受容体が存在することは、内在性のＣＢ受容体リガンドの存在を示唆していた。 By the way, Δ 9 -THC is not present in the animal body. Nevertheless, the presence of the CB receptor suggested the presence of an endogenous CB receptor ligand.
　内在性ＣＢ受容体リガンドの探索が行われた結果、１９９２年にＤｅｖａｎｅら（非特許文献９）がブタの脳から、多価不飽和脂肪酸（以下、「ＰＵＦＡｓ」という。）であるアラキドン酸と一級アミンであるエタノールアミンとのカルボン酸アミドであるアナンダミド（別名：N-arachidonoylethanolamine）を、さらに、１９９５年には、Ｓｕｇｉｕｒａら（非特許文献１０）がラットの脳から、およびＭｅｃｈｏｕｌａｍら（非特許文献１１）がイヌの小腸から、グリセロールの２位にアラキドン酸がエステル結合した２－アラキドノイルグリセロール（2-arachidonoylglycerol；以下「２－ＡＧ」という。）を、それぞれ同定し、内在性のＣＢ受容体リガンドとして報告した。 As a result of searching for an endogenous CB receptor ligand, Devane et al. (Non-Patent Document 9) in 1992 introduced arachidonic acid, which is a polyunsaturated fatty acid (hereinafter referred to as “PUFAs”), from porcine brain. Anandamide (also known as N-arachidonoylethanolamine), which is a carboxylic acid amide with ethanolamine, which is the primary amine, and Sugiura et al. (Non-Patent Document 10) in 1995 from rat brain and Mechoulam et al. Reference 11) identified 2-arachidonoylglycerol (hereinafter referred to as “2-AG”) in which arachidonic acid was ester-bonded to position 2 of glycerol from the small intestine of dogs, respectively, and endogenous CB reception. Reported as a body ligand.
　また、Ｓｕｇｉｕｒａら（非特許文献１２および１３）は、２－ＡＧのアラキドン酸が炭素数２０かつ不飽和結合数３以上のＰＵＦＡｓに置換されたグリセロールもＣＢ１および２受容体に対してアゴニスト作用を有していることをｉｎ　ｖｉｔｒｏ試験で報告しており、具体例としてイコサトリエン酸、イコサペント酸（以下、「ＥＰＡ」という。）またはドコサヘキサエン酸（以下、「ＤＨＡ」という。）がグリセロールの２位に結合した２－エイコサトリエノイルグリセロール、２－エイコサペンタエノイルグリセロール（以下、「２－ＥＧ」という。）または２－ドコサヘキサエノイルグリセロール（以下、「２－ＤＧ」という。）などを挙げている。 Sugiura et al. (Non-Patent Documents 12 and 13) show that glycerol in which arachidonic acid of 2-AG is substituted with PUFAs having 20 or more carbon atoms and 3 or more unsaturated bonds also has an agonistic action on CB1 and 2 receptors. In-vitro studies report that icosatrienoic acid, icosapentoic acid (hereinafter referred to as “EPA”) or docosahexaenoic acid (hereinafter referred to as “DHA”) are in the second position of glycerol. Examples include 2-eicosatrienoylglycerol, 2-eicosapentaenoylglycerol (hereinafter referred to as “2-EG”), 2-docosahexaenoylglycerol (hereinafter referred to as “2-DG”), and the like. ing.
　ＰＵＦＡｓの中でメチル基側から数えて３番目の位置に最初の二重結合があるＰＵＦＡをω３ＰＵＦＡｓといい、α－リノレン酸、ＥＰＡおよびＤＨＡなどが例示される。 Among PUFAs, PUFA having the first double bond at the third position from the methyl group side is called ω3 PUFAs, and examples thereof include α-linolenic acid, EPA and DHA.
　ω３ＰＵＦＡｓ製剤として、ＥＰＡエチルエステル体（以下、「ＥＰＡ－Ｅ」という。）を有効成分として９６．５質量％以上含有する軟カプセル剤（商品名：エパデール（EPADEL）、持田製薬）が閉塞性動脈硬化症および高脂血症治療剤として日本で市販されており（非特許文献１４）、また、ＥＰＡ－Ｅ約４６．５質量％、ＤＨＡエチルエステル体（以下、「ＤＨＡ－Ｅ」という。）約３７．５質量％を有効成分として含有する軟カプセル剤（商品名：ロバザ（登録商標）（LOVAZA（登録商標））、グラクソ・スミスクライン（GlaxoSmithKline, London, UK））が高トリグリセリド血症治療剤として米国で市販されている。 As an ω3 PUFAs preparation, a soft capsule containing 96.5% by mass or more of an EPA ethyl ester (hereinafter referred to as “EPA-E”) as an active ingredient (trade name: EPADEL, Mochida Pharmaceutical) is an occlusive artery It is commercially available in Japan as a therapeutic agent for sclerosis and hyperlipidemia (Non-patent Document 14), and also has about 46.5% by mass of EPA-E, DHA ethyl ester (hereinafter referred to as “DHA-E”). Soft capsules (trade name: Lovaza (registered trademark), GlaxoSmithKline (London, UK)) containing about 37.5% by mass of active ingredient for treatment of hypertriglyceridemia It is commercially available as an agent in the United States.
　しかしながら、ω３ＰＵＦＡｓの、ＣＢ受容体関連疾患に対する予防／改善もしくは治療作用またはＣＢ受容体リガンドの副作用に対する予防もしくは軽減作用についての報告はない。 However, there is no report on the preventive / ameliorating or therapeutic effect of ω3PUFAs on CB receptor-related diseases or the preventive or alleviating effect on side effects of CB receptor ligands.
　本発明は、ＣＢ受容体、特にＣＢ１受容体が関与する疾患の予防／改善または治療に用いるための、安全性が高く、有効性に優れ、使いやすい、ＣＢ受容体関連疾患の予防／改善または治療剤、およびその使用方法を提供することを目的とする。 The present invention relates to prevention / amelioration of CB receptor-related diseases that are highly safe, effective, and easy to use for the prevention / amelioration or treatment of diseases involving CB receptors, particularly CB1 receptors. It is an object to provide a therapeutic agent and a method of using the same.
　また、本発明は、ＣＢ受容体リガンド、特にＣＢ１受容体リガンドによる副作用の予防または軽減に用いるための、安全性が高く、有効性に優れ、使いやすい、ＣＢ受容体リガンド、特にＣＢ１受容体リガンドによる副作用の予防または軽減剤、およびその使用方法を提供することを目的とする。 The present invention also relates to a CB receptor ligand, particularly a CB1 receptor ligand, which is highly safe, effective and easy to use for use in the prevention or reduction of side effects caused by a CB receptor ligand, particularly a CB1 receptor ligand. It is an object of the present invention to provide a preventive or alleviating agent for side effects caused by the above and a method for using the same.
　発明者らは、上記課題を解決すべく鋭意研究を行った結果、ＥＰＡ－Ｅは、単独経口投与した場合にはラットの摂餌量および体重増加に影響を与えないが、リモナバンと併用経口投与した場合には、ＣＢ１受容体インバースアゴニストであるリモナバンによるＣＢ１受容体過剰抑制を介した摂食抑制および体重増加抑制のいずれをも回復させることを見出した。 As a result of intensive studies to solve the above problems, the inventors have found that EPA-E does not affect the food intake and body weight gain of rats when administered orally alone, but is administered orally in combination with rimonabant. In this case, it was found that both the suppression of feeding and the suppression of body weight gain through CB1 receptor excessive suppression by rimonabant, a CB1 receptor inverse agonist, were recovered.
　これに基づいて、ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つの化合物がＣＢ受容体、特にＣＢ１受容体に対してニュートラルアンタゴニスト様の作用を示し、ＣＢ受容体関連疾患の予防／改善または治療作用を有すること、およびＣＢ受容体リガンド、特にＣＢ１受容体リガンドの副作用の予防または軽減作用を有することを見出し、本発明を完成した。 Based on this, at least one compound selected from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof exhibits a neutral antagonist-like action on the CB receptor, particularly the CB1 receptor, and the CB receptor. It has been found that it has a preventive / ameliorating or therapeutic effect on a related disease, and has a preventive or alleviating effect on side effects of CB receptor ligands, particularly CB1 receptor ligands, and has completed the present invention.
　すなわち、本発明が提供するＣＢ受容体関連疾患の予防／改善または治療剤、およびＣＢ受容体リガンドによる副作用の予防または軽減剤は、ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つの化合物を有効成分として含む。以下に本発明の態様例を示す。 That is, the agent for preventing / ameliorating or treating CB receptor-related diseases and the agent for preventing or reducing side effects caused by CB receptor ligands provided by the present invention are from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof. It contains at least one selected compound as an active ingredient. Examples of embodiments of the present invention are shown below.
（１）ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つを有効成分として含有する、ＣＢ受容体関連疾患の予防／改善または治療剤。
（２）ＣＢ受容体関連疾患がＣＢ１受容体関連疾患である上記（１）に記載の予防／改善または治療剤。
（３）ＣＢ１受容体関連疾患が術後認知低下、ニコチン依存症、難治性のしゃっくり、チック障害および嗜好（味覚）の異常からなる群から選ばれる少なくとも１つである、上記（１）または（２）に記載の予防／改善または治療剤。
（４）ＣＢ受容体関連疾患がＣＢ２受容体関連疾患である上記（１）に記載の予防／改善または治療剤。 (1) A preventive / ameliorating or treating agent for CB receptor-related diseases, comprising as an active ingredient at least one selected from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof.
(2) The preventive / ameliorating or therapeutic agent according to (1) above, wherein the CB receptor-related disease is a CB1 receptor-related disease.
(3) The above (1) or (1), wherein the CB1 receptor-related disease is at least one selected from the group consisting of postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorders and abnormal taste (taste). The preventive / ameliorating or therapeutic agent according to 2).
(4) The preventive / ameliorating or treating agent according to (1) above, wherein the CB receptor-related disease is a CB2 receptor-related disease.
（５）ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルがＥＰＡ、ＤＨＡおよびα－リノレン酸ならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つの化合物である、上記（１）ないし（４）のいずれかに記載の予防／改善または治療剤。
（６）前記ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルとしてＥＰＡ－Ｅおよび／またはＤＨＡ－Ｅを含有する、上記（１）ないし（４）のいずれかに記載の予防／改善または治療剤。
（７）前記ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルとしてＥＰＡ－Ｅを含有する、上記（１）ないし（４）のいずれかに記載の予防／改善または治療剤。 (5) The above (5), wherein ω3PUFAs and pharmaceutically acceptable salts and esters thereof are at least one compound selected from the group consisting of EPA, DHA and α-linolenic acid and pharmaceutically acceptable salts and esters thereof ( The preventive / ameliorating or therapeutic agent according to any one of 1) to (4).
(6) The preventive / ameliorating or treating agent according to any one of (1) to (4) above, which contains EPA-E and / or DHA-E as the ω3PUFAs and pharmaceutically acceptable salts and esters thereof .
(7) The preventive / ameliorating or therapeutic agent according to any one of (1) to (4) above, which contains EPA-E as the ω3 PUFAs and pharmaceutically acceptable salts and esters thereof.
（８）ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つを有効成分として含有する、ＣＢ受容体リガンドによる副作用の予防または軽減剤。
（９）ＣＢ受容体リガンドがＣＢ１受容体アゴニストである上記（８）に記載の予防または軽減剤。
（１０）ＣＢ１受容体アゴニストがアナンダミド、２－ＡＧ、ドロナビノール、ナビキシモルス、ＡＺ－５９９、ＡＺＤ－１９４０、ＧＷ－１０００、ＫＮ－３８－７２７１、Ｏ－１０５７、Ｏｒｇ－２８６１１、Ｏｒｇ－２６８２８、ＳＣＨ－９００１１１およびＳＡＢ－３７８からなる群から選ばれる少なくとも１つの化合物である、上記（９）に記載の予防または軽減剤。
（１１）ＣＢ受容体リガンドがＣＢ１受容体アンタゴニストまたはインバースアゴニストである上記（８）に記載の予防または軽減剤。
（１２）ＣＢ１受容体アンタゴニストまたはインバースアゴニストがΔ９－テトラヒドロカンナビバリン、ドリナバン、リモナバン、スリナバン、オテナバン、イビピナバン、タラナバン、ＡＺＤ－２２０７、ＡＺＤ－１１７５、ＣＩＳ－５６５Ｃ、Ｏｒｇ－５０１８９、ＴＭ－３８８３７、Ｖ－２５３４３、およびＺＹＯ－１からなる群から選ばれる少なくとも１つの化合物である、上記（１１）に記載の予防または軽減剤。
（１３）ＣＢ１受容体アンタゴニストまたはインバースアゴニストがドリナバン、リモナバン、スリナバン、オテナバン、イビピナバン、タラナバン、およびＡＺＤ－２２０７からなる群から選ばれる少なくとも１つの化合物である上記（１１）に記載の予防または軽減剤。
（１４）ＣＢ１受容体リガンドによる副作用が悪心、抑うつ症状に伴う気分変動、不安、不動性めまい、自殺企図、摂食障害および薬物依存性からなる群から選ばれる少なくとも１つである上記（８）ないし（１３）のいずれかに記載の予防または軽減剤。
（１５）ＣＢ受容体リガンドがＣＢ２受容体リガンドである上記（８）に記載の予防または軽減剤。 (8) An agent for preventing or alleviating side effects caused by a CB receptor ligand, comprising as an active ingredient at least one selected from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof.
(9) The preventive or alleviating agent according to (8) above, wherein the CB receptor ligand is a CB1 receptor agonist.
(10) The CB1 receptor agonist is anandamide, 2-AG, dronabinol, nabinoximol, AZ-599, AZD-1940, GW-1000, KN-38-7271, O-1057, Org-28611, Org-26828, SCH- The prophylactic or alleviating agent according to (9) above, which is at least one compound selected from the group consisting of 900111 and SAB-378.
(11) The preventive or alleviating agent according to (8) above, wherein the CB receptor ligand is a CB1 receptor antagonist or inverse agonist.
(12) The CB1 receptor antagonist or inverse agonist is Δ 9 -tetrahydrocannabivaline, drinaban, rimonabant, sulinaban, otenaban, ibipinavan, taranaban, AZD-2207, AZD-1175, CIS-565C, Org-50189, TM-38837, The prophylactic or alleviating agent according to (11) above, which is at least one compound selected from the group consisting of V-25343 and ZYO-1.
(13) The prophylactic or alleviating agent according to (11) above, wherein the CB1 receptor antagonist or inverse agonist is at least one compound selected from the group consisting of drinaban, rimonabant, sulinaban, otenaban, ibipinabane, taranaban, and AZD-2207. .
(14) The above (8), wherein the side effect of the CB1 receptor ligand is at least one selected from the group consisting of nausea, mood swings associated with depressive symptoms, anxiety, immobility, suicide attempts, eating disorders, and drug dependence. Or the preventive or alleviating agent according to any one of (13).
(15) The preventive or alleviating agent according to (8) above, wherein the CB receptor ligand is a CB2 receptor ligand.
（１６）ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルがＥＰＡ、ＤＨＡおよびα－リノレン酸ならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つの化合物である、上記（８）ないし（１５）のいずれかに記載の予防または軽減剤。
（１７）前記ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルとしてＥＰＡ－Ｅおよび／またはＤＨＡ－Ｅを含有する、上記（８）ないし（１５）のいずれかに記載の予防または軽減剤。
（１８）前記ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルとしてＥＰＡ－Ｅを含有する、上記（８）ないし（１５）のいずれかに記載の予防または軽減剤。 (16) The above (3), wherein the ω3 PUFAs and pharmaceutically acceptable salts and esters thereof are at least one compound selected from the group consisting of EPA, DHA and α-linolenic acid and pharmaceutically acceptable salts and esters thereof. The preventive or alleviating agent according to any one of 8) to (15).
(17) The prophylactic or alleviating agent according to any one of (8) to (15) above, which contains EPA-E and / or DHA-E as the ω3 PUFAs and pharmaceutically acceptable salts and esters thereof.
(18) The prophylactic or alleviating agent according to any one of (8) to (15) above, which contains EPA-E as the ω3 PUFAs and pharmaceutically acceptable salts and esters thereof.
（１９）ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つの化合物を投与する工程を含む、ＣＢ受容体関連疾患を予防／改善または治療するための方法。
（２０）ＣＢ受容体関連疾患がＣＢ１受容体関連疾患である、上記（１９）に記載の予防／改善または治療するための方法。
（２１）ＣＢ受容体関連疾患がＣＢ２受容体関連疾患である、上記（１９）に記載の予防／改善または治療するための方法。 (19) A method for preventing / ameliorating or treating a CB receptor-related disease, comprising a step of administering at least one compound selected from the group consisting of ω3PUFAs and pharmaceutically acceptable salts and esters thereof.
(20) The method for prevention / amelioration or treatment according to (19) above, wherein the CB receptor-related disease is a CB1 receptor-related disease.
(21) The method for prevention / amelioration or treatment according to (19) above, wherein the CB receptor-related disease is a CB2 receptor-related disease.
（２２）ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つの化合物を投与する工程を含む、ＣＢ受容体リガンドによる副作用を予防または軽減するための方法。
（２３）さらにＣＢ受容体リガンドを投与する工程を含む、上記（２２）に記載の方法。
（２４）前記２つの投与工程を同時に行う、上記（２３）に記載の方法。
（２５）前記２つの投与工程を別々の時期に行う、上記（２３）に記載の方法。
（２６）ＣＢ受容体リガンドがＣＢ１受容体アンタゴニストまたはインバースアゴニストである、上記（２２）ないし（２５）のいずれかに記載の方法。
（２７）ＣＢ受容体リガンドがＣＢ２受容体アンタゴニストまたはインバースアゴニストである、上記（２２）ないし（２５）のいずれかに記載の方法。
（２８）ＣＢ受容体リガンドがＣＢ１受容体アゴニストおよび／またはＣＢ２受容体アゴニストである、上記（２２）ないし（２５）のいずれかに記載の方法。
（２９）ＣＢ受容体関連疾患の予防／改善または治療剤を製造するためのω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つの使用。
（３０）ＣＢ受容体関連疾患がＣＢ１受容体関連疾患である上記（２９）に記載の使用。
（３１）ＣＢ１受容体関連疾患が術後認知低下、ニコチン依存症、難治性のしゃっくり、チック障害および嗜好（味覚）の異常からなる群から選ばれる少なくとも１つである、上記（２９）または（３０）に記載の使用。
（３２）ＣＢ受容体関連疾患がＣＢ２受容体関連疾患である上記（２９）に記載の使用。
（３３）ＣＢ受容体リガンドによる副作用の予防または軽減剤を製造するための、ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つの使用。
（３４）ＣＢ受容体関連疾患がＣＢ１受容体アゴニストである上記（３３）に記載の使用。
（３５）ＣＢ１受容体リガンドによる副作用が悪心、抑うつ症状に伴う気分変動、不安、不動性めまい、自殺企図、摂食障害および薬物依存性からなる群から選ばれる少なくとも１つである上記（３３）または（３４）に記載の使用。
（３６）ＣＢ受容体リガンドがＣＢ２受容体リガンドである上記（３３）に記載の使用。 (22) A method for preventing or alleviating a side effect caused by a CB receptor ligand, comprising a step of administering at least one compound selected from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof.
(23) The method according to (22) above, further comprising administering a CB receptor ligand.
(24) The method according to (23) above, wherein the two administration steps are performed simultaneously.
(25) The method according to (23) above, wherein the two administration steps are performed at different times.
(26) The method according to any one of (22) to (25) above, wherein the CB receptor ligand is a CB1 receptor antagonist or inverse agonist.
(27) The method according to any one of (22) to (25) above, wherein the CB receptor ligand is a CB2 receptor antagonist or inverse agonist.
(28) The method according to any one of (22) to (25) above, wherein the CB receptor ligand is a CB1 receptor agonist and / or a CB2 receptor agonist.
(29) Use of at least one selected from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof for producing a preventive / ameliorating or therapeutic agent for CB receptor-related diseases.
(30) The use according to the above (29), wherein the CB receptor-related disease is a CB1 receptor-related disease.
(31) The above (29) or (31), wherein the CB1 receptor-related disease is at least one selected from the group consisting of postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorders, and abnormal taste (taste) 30) Use.
(32) The use according to (29) above, wherein the CB receptor-related disease is a CB2 receptor-related disease.
(33) Use of at least one selected from the group consisting of ω3PUFAs and pharmaceutically acceptable salts and esters thereof for producing an agent for preventing or alleviating side effects caused by CB receptor ligands.
(34) The use according to (33) above, wherein the CB receptor-related disease is a CB1 receptor agonist.
(35) The above (33), wherein the side effect of the CB1 receptor ligand is at least one selected from the group consisting of nausea, mood swings associated with depressive symptoms, anxiety, immobility dizziness, suicide attempts, eating disorders, and drug dependence. Or use as described in (34).
(36) The use according to (33) above, wherein the CB receptor ligand is a CB2 receptor ligand.
　ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つの化合物を使用することにより、安全性が高く、有効性に優れ、使いやすい、ＣＢ受容体関連疾患の予防／改善または治療剤、およびその使用方法を提供することができる。 By using at least one compound selected from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof, prevention / improvement of CB receptor-related diseases that are highly safe, highly effective and easy to use Alternatively, therapeutic agents and methods of use thereof can be provided.
　具体的には、ＣＢ受容体、特にＣＢ１受容体の過剰亢進または過剰抑制により生じる後述する症候群、障害または疾患に対する予防／改善または治療効果を示すことが期待される。 Specifically, it is expected to show a preventive / improving or therapeutic effect on a syndrome, disorder or disease described later caused by excessive enhancement or excessive suppression of the CB receptor, particularly the CB1 receptor.
　ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つの化合物を使用することにより、安全性が高く、有効性に優れ、使いやすい、ＣＢ受容体リガンド、特にＣＢ１受容体リガンドによる副作用の予防または軽減剤、およびその使用方法を提供することができる。 By using at least one compound selected from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof, a CB receptor ligand, particularly a CB1 receptor, which is highly safe, effective and easy to use. An agent for preventing or alleviating a side effect caused by a ligand, and a method of using the same can be provided.
　具体的には、ＣＢ受容体リガンド、特にＣＢ１受容体アンタゴニストまたはインバースアゴニスト投与により生じる後述する副作用の予防または軽減効果を示すことが期待される。 Specifically, it is expected to show an effect of preventing or reducing the side effects described later caused by administration of a CB receptor ligand, particularly a CB1 receptor antagonist or inverse agonist.
　また、本発明によりＣＢ受容体リガンドの副作用を軽減することができ、これらの副作用のためにＣＢ受容体リガンド投与を行えなかった患者や中断せざるを得なかった患者において治療を継続することができる。 In addition, the side effects of CB receptor ligands can be reduced by the present invention, and treatment can be continued in patients who have failed to administer CB receptor ligands due to these side effects or who have had to be interrupted. it can.
　以下に本発明を詳細に説明する。
　ＥＰＡ－Ｅを経口投与するとＣＢ１受容体ニュートラルアンタゴニスト様の作用を示すことにより、術後認知低下、ニコチン依存症、難治性のしゃっくり、チック障害または嗜好（味覚）の異常等のＣＢ１受容体の過剰亢進あるいは過剰抑制により生じる症候群、障害もしくは疾患の予防／改善または治療に有用である。また、ＣＢ１受容体リガンド（アゴニスト、アンタゴニストまたはインバースアゴニスト）による副作用の予防または軽減に有用である。 The present invention is described in detail below.
Oral administration of EPA-E exhibits CB1 receptor neutral antagonist-like action, resulting in excessive CB1 receptor such as postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorder or abnormal taste (taste) It is useful for preventing / ameliorating or treating a syndrome, disorder or disease caused by enhancement or excessive suppression. It is also useful for preventing or reducing side effects caused by CB1 receptor ligand (agonist, antagonist or inverse agonist).
　摂食抑制および体重増加抑制は主に中枢性のＣＢ１受容体抑制が関与していると考えられ（非特許文献２および７）、ＥＰＡ－Ｅの経口投与により生じるＥＰＡのグリセリドのニュートラルアンタゴニスト様作用を介してＣＢ１受容体過剰抑制を抑制して摂食抑制および体重増加抑制を回復させる。また、ＣＢ１受容体インバースアゴニストによる摂食抑制および体重増加抑制の副作用を予防または軽減させる（実験例１）。 Inhibition of food intake and suppression of body weight gain are thought to be mainly related to central CB1 receptor inhibition (Non-patent Documents 2 and 7). Neutral antagonist-like action of glycerides of EPA caused by oral administration of EPA-E CB1 receptor over-suppression is suppressed through, and feeding suppression and weight gain suppression are restored. In addition, side effects of suppression of feeding and suppression of weight gain by CB1 receptor inverse agonist are prevented or reduced (Experimental Example 1).
　ニコチン依存性および退薬時の嫌悪効果、ならびに手術後の錯乱、せん妄、幻肢、および幻肢痛などの術後認知障害はＣＢ１受容体活性化が関連していると考えられ（国際公開２００４／０９４４２９号パンフレット）、ＥＰＡ－ＥはＣＢ１受容体ニュートラルアンタゴニスト様作用を介してＣＢ１受容体過剰亢進を抑制することによりニコチン依存性あるいは術後認知障害を予防／改善または治療することが予測される（動物モデル試験１および臨床モデル試験１）。 Postoperative cognitive deficits such as nicotine dependence and aversive effects at withdrawal and postoperative confusion, delirium, phantom limbs, and phantom limb pain are thought to be associated with CB1 receptor activation (International Publication 2004) EPA-E is expected to prevent / ameliorate or treat nicotine dependence or postoperative cognitive impairment by inhibiting CB1 receptor hyper-enhancement through CB1 receptor neutral antagonist-like action (Animal model test 1 and clinical model test 1).
　チック障害、ツレット症候群、難治性のしゃっくりまたは嗜好（味覚）の異常はＣＢ１受容体抑制が関連していると考えられ（非特許文献６、７およびフィジオロジー　アンド　ビヘイビア（Ｐｈｙｓｉｏｌｏｇｙ　ａｎｄ　Ｂｅｈａｖｉｏｒ）、２００７年、第９０巻、ｐ．４２５－４３０）、ＥＰＡ－ＥはＣＢ１受容体ニュートラルアンタゴニスト様作用を介してＣＢ１受容体過剰抑制を抑制することによりチック障害、ツレット症候群、難治性のしゃっくりまたは嗜好（味覚）の異常を予防／改善または治療することが予測される（臨床モデル試験２および動物モデル試験２）。 Tic disorders, Tourette's syndrome, refractory hiccups or abnormal taste (taste) are thought to be associated with CB1 receptor suppression (Non-Patent Documents 6 and 7 and Physiology and Behavior, 2007) , 90, p.425-430), EPA-E inhibits CB1 receptor over-suppression through CB1 receptor neutral antagonist-like action, thereby inhibiting tic disorder, Tourette syndrome, refractory hiccups or taste (taste) ) Is expected to be prevented / ameliorated or treated (clinical model test 2 and animal model test 2).
　本発明は、ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つを有効成分とするＣＢ受容体関連疾患の予防／改善または治療剤、およびその使用方法である。 The present invention is a preventive / ameliorating or treating agent for CB receptor-related diseases comprising at least one selected from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof, and a method of using the same.
　また、本発明は、ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つを有効成分とするＣＢ受容体リガンドによる副作用の予防または軽減剤、およびその使用方法である。 The present invention also relates to a preventive or alleviating agent for side effects caused by a CB receptor ligand comprising at least one selected from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof, and a method of using the same. .
　本発明では、特に断らない限り、「ω３ＰＵＦＡｓ」は、ω３ＰＵＦＡｓだけではなく、その製薬学上許容される塩またはエステルなどのω３ＰＵＦＡｓ誘導体をも含む意味で使用される。 In the present invention, unless otherwise specified, “ω3 PUFAs” is used to mean not only ω3 PUFAs but also ω3 PUFAs derivatives such as pharmaceutically acceptable salts or esters thereof.
　ここで、ω３ＰＵＦＡｓとは、当業者が知る通常の意味で使われ、分子内に複数の炭素－炭素二重結合を有する脂肪酸のうち、メチル基側から数えて３番目の位置に最初の二重結合があるＰＵＦＡｓをいう。 Here, ω3PUFAs is used in the ordinary sense known to those skilled in the art, and among the fatty acids having a plurality of carbon-carbon double bonds in the molecule, the first double is in the third position counted from the methyl group side. It refers to PUFAs that have bonds.
　好ましいω３ＰＵＦＡｓとして、ＥＰＡ、ＤＨＡおよびαリノレン酸が例示され、より好ましくはＥＰＡおよび／またはＤＨＡが提示される。 Preferred ω3 PUFAs are exemplified by EPA, DHA and α-linolenic acid, more preferably EPA and / or DHA.
　製薬学上許容しうる塩としては、ナトリウム塩もしくはカリウム塩などの無機塩基、ベンジルアミン塩もしくはジエチルアミン塩などの有機塩基、またはアルギニン塩もしくはリジン塩などの塩基性アミノ酸との塩が例示される。 Examples of the pharmaceutically acceptable salt include salts with an inorganic base such as sodium salt or potassium salt, an organic base such as benzylamine salt or diethylamine salt, or a basic amino acid such as arginine salt or lysine salt.
　製薬学上許容しうるエステルとしては、エチルもしくはエタノールアミン等とのアルキルエステル、モノ－、ジ－もしくはトリ－グリセロールエステル、またはフォスファチジルコリンもしくはフォスファチジルエタノールアミン等のリン脂質エステルが例示される。 Examples of pharmaceutically acceptable esters include alkyl esters with ethyl or ethanolamine, mono-, di- or tri-glycerol esters, or phospholipid esters such as phosphatidylcholine or phosphatidylethanolamine. The
　好ましいω３ＰＵＦＡｓ誘導体としては、ＥＰＡ－Ｅ、ＤＨＡ－Ｅ、２－ＥＧ、２－ＤＧ、Ｎ－イコサペンタエノイルエタノールアミン、Ｎ－ドコサヘキサエノイルエタノールアミンが例示され、より好ましくはＥＰＡ－Ｅおよび／またはＤＨＡ－Ｅが提示される。 Preferred ω3 PUFAs derivatives include EPA-E, DHA-E, 2-EG, 2-DG, N-icosapentaenoylethanolamine, and N-docosahexaenoylethanolamine, more preferably EPA-E. And / or DHA-E is presented.
　本発明で用いられるω３ＰＵＦＡｓは、合成品、半合成品または天然品のいずれでもよく、これらを含有する天然油の形態でもよい。ここで、天然品とは、ω３ＰＵＦＡｓを含有する天然油から公知の方法によって抽出されたもの、粗精製されたもの、またはそれらを更に高度に精製したものを意味する。半合成品は、微生物などにより産生されたＰＵＦＡｓを含み、そのＰＵＦＡｓまたは天然のＰＵＦＡｓにエステル化またはエステル交換等の化学処理を施したものも含む。本発明では、ω３ＰＵＦＡｓとして、これらのうちの１種を単独で、または２種以上を組み合わせて用いることができる。 Ω3 PUFAs used in the present invention may be a synthetic product, a semi-synthetic product or a natural product, or may be in the form of a natural oil containing them. Here, the natural product means a product extracted from a natural oil containing ω3 PUFAs by a known method, a product that has been refined, or a product that has been further refined. Semi-synthetic products include PUFAs produced by microorganisms and the like, and those obtained by subjecting the PUFAs or natural PUFAs to chemical treatment such as esterification or transesterification. In the present invention, as ω3PUFAs, one of these can be used alone, or two or more can be used in combination.
　ω３ＰＵＦＡｓの純度は特に限定されないが、通常、本剤組成物の全脂肪酸中のω３ＰＵＦＡｓの含量として、好ましくは２５質量％以上、より好ましくは５０質量％以上、さらに好ましくは７０質量％以上、いっそう好ましくは８５質量％以上であり、とりわけ好ましくは本剤組成物がω３ＰＵＦＡｓ以外の他の脂肪酸成分を実質的に含まない態様である。 The purity of ω3 PUFAs is not particularly limited, but usually, the content of ω3 PUFAs in the total fatty acids of the composition of the present agent is preferably 25% by mass or more, more preferably 50% by mass or more, still more preferably 70% by mass or more, even more preferably. Is 85% by mass or more, and it is particularly preferable that the present composition is substantially free of other fatty acid components other than ω3 PUFAs.
　例えば、ＥＰＡ－ＥおよびＤＨＡ－Ｅを用いる場合、ＥＰＡ－Ｅ／ＤＨＡ－Ｅの組成比および全脂肪酸中のＥＰＡ－Ｅ＋ＤＨＡ－Ｅの含量比は特に問わないが、好ましい組成比として、ＥＰＡ－Ｅ／ＤＨＡ－Ｅは、好ましくは０．８以上、より好ましくは１．０以上、さらに好ましくは１．２以上である。 For example, when EPA-E and DHA-E are used, the composition ratio of EPA-E / DHA-E and the content ratio of EPA-E + DHA-E in all fatty acids are not particularly limited, but a preferred composition ratio is EPA-E. / DHA-E is preferably 0.8 or more, more preferably 1.0 or more, and further preferably 1.2 or more.
　ＥＰＡ－Ｅおよび／またはＤＨＡ－Ｅは高純度のものが好ましい。例えば、全脂肪酸およびその誘導体中のＥＰＡ－Ｅおよび／またはＤＨＡ－Ｅ含量比が４０質量％以上のものが好ましく、５５質量％以上のものがより好ましく、８４質量％以上のものがさらに好ましく、９６．５質量％以上のものがいっそう好ましい。 EPA-E and / or DHA-E are preferably of high purity. For example, the EPA-E and / or DHA-E content ratio in the total fatty acids and derivatives thereof is preferably 40% by mass or more, more preferably 55% by mass or more, further preferably 84% by mass or more, The thing of 96.5 mass% or more is still more preferable.
　すなわち、全脂肪酸中のω３ＰＵＦＡｓ純度が高いことが好ましく、ω３ＰＵＦＡｓであるＥＰＡ＋ＤＨＡ純度が高いことが更に好ましく、ＥＰＡの純度が高いことがより好ましい。他の長鎖飽和脂肪酸含量は少ないことが好ましい。ω３ＰＵＦＡｓ以外の長鎖不飽和脂肪酸含量については、ω６系長鎖不飽和脂肪酸、特にアラキドン酸含量は少ないことが好ましく、より好ましくは２質量％未満であり、さらに好ましくは１質量％未満である。 That is, the purity of ω3 PUFAs in all fatty acids is preferably high, the EPA + DHA purity which is ω3 PUFAs is more preferable, and the purity of EPA is more preferable. The content of other long chain saturated fatty acids is preferably low. Regarding the content of long chain unsaturated fatty acids other than ω3 PUFAs, the content of ω6 long chain unsaturated fatty acids, particularly arachidonic acid, is preferably small, more preferably less than 2% by mass, and even more preferably less than 1% by mass.
　本発明の予防／改善もしくは治療剤または予防もしくは軽減剤に用いられるＥＰＡ－Ｅおよび／またはＤＨＡ－Ｅは、魚油または魚油の濃縮物に比べ、飽和脂肪酸やアラキドン酸等の心血管イベントに対して好ましくない不純物が少なく、栄養過多やビタミンＡ過剰摂取の問題もなく作用効果を発揮することが可能である。また、エステル体のため主にトリグリセリド体である魚油等に比べて酸化安定性が高く、通常の酸化防止剤添加により十分安定な組成物を得ることが可能である。なお、ここでいう心血管イベントとは、当業者が知る通常の意味で使われ、心血管死（致死性心筋梗塞または突然心臓死等）、非致死性心筋梗塞、再梗塞、不安定狭心症、一過性虚血発作、鬱血性心不全、脳卒中、脳梗塞、もしくは失神等の病態、または、冠動脈バイパス術（ＣＡＢＧ）、経皮的冠血管形成術（ＰＴＣＡ）、もしくはステント等の処置を例示的に含む。 EPA-E and / or DHA-E used in the preventive / ameliorating or therapeutic agent or preventive or alleviating agent of the present invention is more effective against cardiovascular events such as saturated fatty acids and arachidonic acid than fish oil or fish oil concentrate. There are few undesirable impurities, and it is possible to exert the effect without problems of overnutrition and excessive intake of vitamin A. Further, since it is an ester, it has a higher oxidation stability than fish oil or the like, which is mainly a triglyceride, and a sufficiently stable composition can be obtained by adding a normal antioxidant. The cardiovascular event is used in the ordinary sense known to those skilled in the art and includes cardiovascular death (such as fatal myocardial infarction or sudden cardiac death), non-fatal myocardial infarction, reinfarction, unstable angina. Disease, transient ischemic attack, congestive heart failure, stroke, cerebral infarction, or fainting, or treatment such as coronary artery bypass grafting (CABG), percutaneous coronary angioplasty (PTCA), or stent Includes illustratively.
　このＥＰＡ－Ｅは、たとえば、日本国内において入手可能なエパデール（持田製薬）を用いることができる。 For this EPA-E, for example, Epadale (Mochida Pharmaceutical) available in Japan can be used.
　また、ＥＰＡ－ＥとＤＨＡ－Ｅの混合物は、たとえば、米国で市販されているロバザ（登録商標）（グラクソ・スミスクライン）を入手して使用することもできる。 Also, the mixture of EPA-E and DHA-E can be obtained by using, for example, Lovaza (registered trademark) (Glaxo SmithKline) commercially available in the United States.
　ω３ＰＵＦＡｓとして、精製魚油も使用できる。また、ω３ＰＵＦＡｓのモノグリセリド、ジグリセリドもしくはトリグリセリドまたはこれらの組合せなども好ましい態様の一つである。 Refined fish oil can also be used as ω3 PUFAs. Also, ω3PUFAs monoglyceride, diglyceride, triglyceride, or a combination thereof is one of the preferred embodiments.
　例えば、インクロメガ（lncromega）Ｆ２２５０、Ｆ２６２８、Ｅ２２５１、Ｆ２５７３、ＴＧ２１６２、ＴＧ２７７９、ＴＧ２９２８、ＴＧ３５２５およびＥ５０１５（クローダ・インターナショナル（Croda International plc, Yorkshire, UK））、ならびにＥＰＡＸ６０００ＦＡ、ＥＰＡＸ５０００ＴＧ、ＥＰＡＸ４５１０ＴＧ、ＥＰＡＸ２０５０ＴＧ、ＥＰＡＸ７０１０ＥＥ、Ｋ８５ＴＧ、Ｋ８５ＥＥおよびＫ８０ＥＥ（プロノバ・バイオファーマ（Pronova BioPharma ASA, Lysaker, Norway））などの種々のω３ＰＵＦＡｓまたはその塩もしくはエステルを含有する製品が市販されており、これらを入手して使用することもできる。 For example, Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International plc, Yorkshire, UK), as well as EPAX6000FA, EPAX5000TG, EPAX4520TG50, EPAX4510T50, EPAX4510T , K85EE and K80EE (Pronova BioPharma ASA, Lysaker, Norway) containing various ω3 PUFAs or salts or esters thereof are commercially available and can be obtained and used.
　「ＣＢ受容体」とは、既知のＣＢ受容体であるＣＢ１受容体およびＣＢ２受容体、ならびに当業者がＣＢ１受容体またはＣＢ２受容体とのアミノ酸配列および構造・機能上の類似性（７回膜貫通型、Ｇタンパク質共役型など）を認識できる受容体であり、Δ９－ＴＨＣまたはその類似化合物が結合する受容体の意味で使用される。 “CB receptor” means known CB receptors, CB1 receptor and CB2 receptor, as well as amino acid sequence and structural / functional similarity between those skilled in the art and CB1 receptor or CB2 receptor (7th membrane A receptor capable of recognizing a penetrating type, a G protein-coupled type, and the like, and is used to mean a receptor to which Δ 9 -THC or an analog thereof binds.
　すなわち、本発明でいうＣＢ受容体は、ＣＢ１受容体またはＣＢ２受容体に類似し、Δ９－ＴＨＣまたはその類似化合物が結合する受容体を含み、既知のＣＢ受容体であるＣＢ１受容体またはＣＢ２受容体のみに限定されない。例えば、ＣＢ１受容体ノックアウトマウスでＣＢ１受容体アゴニスト作用が観察されることから、新たなＣＢ受容体の存在が推測されており、このような未同定のＣＢ受容体も包含される。 That is, the CB receptor referred to in the present invention is similar to the CB1 receptor or the CB2 receptor, includes a receptor to which Δ 9 -THC or a similar compound binds, and is a known CB receptor, the CB1 receptor or the CB2 It is not limited to receptors only. For example, since a CB1 receptor agonistic action is observed in a CB1 receptor knockout mouse, the existence of a new CB receptor is presumed, and such an unidentified CB receptor is also included.
　ここで、Δ９－ＴＨＣの類似化合物とは、当業者がΔ９－ＴＨＣとの構造上の類似性を認識できる化合物、またはＣＢ１受容体および／もしくはＣＢ２受容体に対してアゴニスト活性を有する化合物であればよく、現在までに知られている化合物のみに限定されない。すなわち、本発明でいうΔ９－ＴＨＣの類似化合物は、カンナビノール（cannabinol）、カンナビジオール（cannabidiol）、カンナビゲロール（cannabigerol）およびカンナビシクロール（cannabicycrol）などに例示される天然カンナビノイド、ならびにアナンダミド、２－ＡＧ、２－アラキドニルグリセリルエーテル（2-arachidonyl glyceryl ether）、ビロダミン（virodhamine）、パルミトイルエタノールアミド（palmitic ethanolamide）およびＮ－アラキドニルドーパミン（N-archydonyl-dopamin）などに例示されるエンドカンナビノイド（「内因性カンナビノイド」ともいう。）、ならびにＡ－４１９８８（別名：ＢＷ２９Ｙ）、アジュレム酸（ajulemic acid）（別名：ＣＴ－３、ＨＵ－２３９）、ＡＭ－０８７、ＡＭ－４１１、ＡＭ－８５５、ＡＭ－９０５、ＡＭ－９０６、ＡＭ－９１９、ＡＭ－９３８、ＡＭ－４０３０、ＡＭＧ－１、ＡＭＧ－３、ＡＭＧ－３６、ＡＭＧ－４１、デキサナビノール（ＨＵ－２１１）、ジメチルヘプチルピラン（dimethylheptylpyran）、ＨＵ－２１０、ＪＷＨ－０５１、ＪＷＨ－１３３、ＪＷＨ－１３９、Ｌ－７５９６３３、Ｌ－７５９６５６、レボナントラドール（levonantradol）、ナビロン（nabilone）、ナビタン（nabitan）、Ｏ－８０６、Ｏ－８２３、Ｏ－１０５７、Ｏ－１１２５、Ｏ－１２３８、Ｏ－２５４５、Ｏ－２６９４、パラヘキシル（parahexyl）、ＴＨＣ－Ｏ－酢酸（THC-O-acetate）、ＴＨＣ－Ｏ－リン酸（THC-O-phosphate）、ＣＰ　４７４９７、ＣＰ　５５２４４、ＣＰ　５５９４０、ＨＵ－３０８、２－イソプロピル－５－メチル－１－（２，６－ジヒドロキシ－４－ノニルフェニル）シクロへクス－１－エン（2-isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene）、ＡＭ－６３０、ＡＭ－１２４１、Ｌ－７６８２４２、ＪＷＨ－０１５、ＪＷＨ－０１８、ＪＷＨ－０７３、ＪＷＨ－０８１、ＪＷＨ－２００、プラバドリン（pravadoline）、ＷＩＮ　５５２１２－２、ＪＷＨ－０３０、ＪＷＨ－１４７、ＪＷＨ－３０７、ＡＭ－８８３、アラキドニル－２´－クロロエチルアミド（arachidonyl-2'-chloroethylamide）、アラキドニルシクロプロピルアミド（arachidonylcyclopropylamide）、メタナンダミド（methanandamide）、Ｏ－５８５、Ｏ－６８９、Ｏ－１８１２、Ｏ－１８６０、Ｏ－１８６１、ＢＡＹ　３８－７２７１、ＢＡＹ　５９－３０７４、ＧＷ　８４２１６６Ｘ、ＪＷＨ－１７１、およびＯ－２２２０などに例示される合成カンナビノイド、ならびに当業者がこれらとの構造上の類似性を認識することができる化合物が含まれる。 Here, the analogous compounds of delta 9 -THC, compounds having agonist activity to those skilled in the art can recognize structural similarity to delta 9 -THC compounds or CB1 receptor and / or CB2 receptors Any other compound may be used as long as the compound is known to date. That is, the analog of Δ 9 -THC referred to in the present invention includes cannabinol, cannabidiol, cannabigerol, cannabicycrol, and other natural cannabinoids and anandamide , 2-AG, 2-arachidonyl glyceryl ether, virodhamine, palmitoic ethanolamide and N-archydonyl-dopamin Cannabinoids (also referred to as “endogenous cannabinoids”), and A-41988 (also known as BW29Y), ajulemic acid (also known as CT-3, HU-239), AM-087, AM-411, AM- 855, AM-905, AM-906, M-919, AM-938, AM-4030, AMG-1, AMG-3, AMG-36, AMG-41, dexanabinol (HU-211), dimethylheptylpyran, HU-210, JWH- 051, JWH-133, JWH-139, L-759633, L-759656, levonantradol, nabilone, nabitan, O-806, O-823, O-1057, O-1125 , O-1238, O-2545, O-2694, parahexyl, THC-O-acetate, THC-O-phosphate, CP 47497, CP 55244 CP 55940, HU-308, 2-isopropyl-5-methyl-1- (2,6-dihydroxy-4-nonylphenyl) cycl Rohex-1-ene (2-isopropyl-5-methyl-1- (2,6-dihydroxy-4-nonylphenyl) cyclohex-1-ene), AM-630, AM-1241, L-768242, JWH- 015, JWH-018, JWH-073, JWH-081, JWH-200, pravadoline, WIN 55212-2, JWH-030, JWH-147, JWH-307, AM-883, arachidonyl-2'-chloro Ethylamide (arachidonyl-2'-chloroethylamide), arachidonylcyclopropylamide, methanandamide, O-585, O-689, O-1812, O-1860, O-1861, BAY 38-7271, Synthetic cannabinoids exemplified by BAY 59-3074, GW 842166X, JWH-171, and O-2220, and the like Skilled in the art include compounds capable of recognizing a structural similarity with these.
　「ＣＢ受容体関連疾患」とは、ＣＢ受容体により媒介される生物学的反応ならびにそれに関連する症候群、障害および疾患を含む意味で使用される。 “CB receptor-related disease” is used to include biological reactions mediated by CB receptors and related syndromes, disorders and diseases.
　ＣＢ受容体関連疾患の具体例としては、ＣＢ１受容体および／またはＣＢ２受容体の過剰亢進または過剰抑制により生じる、摂食、肥満、代謝、糖尿病、緑内障、社会性または気分、発作、薬物乱用、学習・認知または記憶、臓器収縮、筋痙攣、消化管および内臓、呼吸器、自発運動または運動、免疫および炎症、細胞増殖、疼痛、ならびに神経変性などに関連する症候群、障害および疾患が包含される。 Specific examples of CB receptor-related diseases include eating, obesity, metabolism, diabetes, glaucoma, social or mood, seizures, drug abuse, caused by excessive or excessive suppression of CB1 receptor and / or CB2 receptor, Includes syndromes, disorders and diseases related to learning / cognition or memory, organ contraction, muscle spasm, gastrointestinal tract and viscera, respiratory organs, locomotor activity or exercise, immunity and inflammation, cell proliferation, pain, and neurodegeneration .
　摂食に関連する症候群、障害および疾患には、過食症、拒食症、肥満症、体重低下、体重増加、無調節な食欲、癌・ＡＩＤＳ・悪液質における食欲不振、および嗜好（味覚）の異常などが包含される。 Syndromes, disorders and diseases related to eating include bulimia, anorexia, obesity, weight loss, weight gain, unregulated appetite, poor appetite in cancer, AIDS, cachexia, and taste (taste). Abnormalities are included.
　肥満に関連する症候群、障害および疾患には、遺伝、食事、食料摂取容量過剰、メタボリック症候群、および視床下部障害もしくは疾患、ならびに、加齢、低下した運動活性、異常な脂肪量分布、および／または異常な脂肪区画分布などの結果としての肥満などが包含される。 Syndrome, disorders and diseases associated with obesity include heredity, diet, excess food intake, metabolic syndrome, and hypothalamic disorder or disease, and aging, reduced motor activity, abnormal fat mass distribution, and / or Obesity as a result of abnormal fat compartment distribution and the like is included.
　代謝に関連する症候群、障害および疾患には、メタボリック症候群、脂質異常症（高コレステロール血症、高トリグリセリド血症、高ＬＤＬコレステロール血症、低ＨＤＬコレステロール血症）、アテローム性動脈硬化症、脂肪肝、肝炎（ウイルス性、アルコール性、非アルコール性、薬物性）、高血圧、糖尿病、インシュリン感受性もしくは抵抗性、および高インシュリン血症などが包含される。 Metabolic syndromes, disorders and diseases include metabolic syndrome, dyslipidemia (hypercholesterolemia, hypertriglyceridemia, high LDL cholesterolemia, low HDL cholesterolemia), atherosclerosis, fatty liver , Hepatitis (viral, alcoholic, non-alcoholic, drug), hypertension, diabetes, insulin sensitivity or resistance, and hyperinsulinemia.
　糖尿病に関連する症候群、障害および疾患には、グルコース調節異常、インシュリン抵抗性、耐糖能異常、高インシュリン血症、異常脂質血症、高血圧症、および肥満症などが包含される。 Syndrome, disorder and disease related to diabetes include glucose regulation abnormality, insulin resistance, glucose tolerance abnormality, hyperinsulinemia, dyslipidemia, hypertension, obesity and the like.
　ＩＩ型糖尿病は、持続的な血漿高血糖、多尿症、多渇症、多食症、ならびに網膜症、腎症および神経障害のような慢性微小血管合併症、ならびに脂質異常症および高血圧症のような大血管合併症などの臨床的徴候または症状を特徴とする。これらの微小および大血管合併症は、失明、末期腎臓病、肢の切断および／または心筋梗塞をもたらし得る。 Type II diabetes is associated with persistent plasma hyperglycemia, polyuria, polyposis, bulimia and chronic microvascular complications such as retinopathy, nephropathy and neuropathy, and dyslipidemia and hypertension. Characterized by clinical signs or symptoms such as macrovascular complications. These micro and macrovascular complications can result in blindness, end-stage renal disease, limb amputation and / or myocardial infarction.
　メタボリック症候群は、耐糖能異常、高インシュリン血症、インシュリン抵抗性、異常脂質血症、高血圧症および肥満症を包含するＩＩ型糖尿病、ならびに心臓血管疾患、脳梗塞および脳出血などの脳血管障害の発症の危険因子を提示する障害である。 Metabolic syndrome is the development of type II diabetes including impaired glucose tolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypertension and obesity, and cerebrovascular disorders such as cardiovascular disease, cerebral infarction and cerebral hemorrhage It is an obstacle that presents risk factors.
　緑内障に関連する症候群、障害および疾患には、眼圧上昇、眼循環障害、視神経の障害、虹視、視力低下、眼痛、視野などの視機能障害、および失明などが包含される。 Syndrome, disorder and disease related to glaucoma include increased intraocular pressure, ocular circulation disorder, optic nerve disorder, rainbow vision, decreased visual acuity, eye pain, visual impairment such as visual field, and blindness.
　社会または気分に関連する症候群、障害および疾患には、精神病一般、うつ病、躁うつ病、双極性障害、不安症、統合失調症、気分障害、せん妄、社会情動障害もしくは認識障害、強迫または切迫神経症、成人人格障害、衝撃行動障害、パニック障害、恐怖症、錯乱、神経性ストレス症、外傷後ストレス障害（ＰＴＳＤ）、注意不足障害（ＡＤＤ／ＡＤＨＤ）、多動症、自閉症、無言症、行動嗜癖、覚醒障害、不眠、直情性、錯覚障害、および意欲減退などが包含される。 Syndrome, disorder and disease related to society or mood include psychosis in general, depression, manic depression, bipolar disorder, anxiety, schizophrenia, mood disorder, delirium, social affective or cognitive impairment, obsession or urgency Neurosis, adult personality disorder, shock behavior disorder, panic disorder, phobia, confusion, neurological stress disorder, post-traumatic stress disorder (PTSD), attention deficit disorder (ADD / ADHD), hyperactivity, autism, speechlessness, Behavioral addiction, arousal disorder, insomnia, intuition, illusion disorder, and reduced motivation are included.
　薬物乱用に関連する症候群、障害および疾患には、アルコール、アンフェタミン類（アンフェタミン、メタンフェタミンなど）、バルビツレート類（バルビツール誘導体、ベンゾジアゼピン誘導体など）、***（マリファナ、ハシシュなど）、コカイン、幻覚剤（ＬＳＤ、メスカリン、シロシビン、フェンシクリジンなど）、カート、オピエート（モルヒネ、ヘロイン、コデイン、ペチジン、フェンタニルなど）または有機溶剤（トルエン、シンナー、アセトン、エーテル、クロロホルム、ベンゼンなど）などの薬物乱用・依存症・離脱症状、およびニコチンまたはタバコ乱用・依存症・離脱症状などが包含される。 Syndrome, disorder and disease related to drug abuse include alcohol, amphetamines (amphetamine, methamphetamine, etc.), barbiturates (barbitur derivatives, benzodiazepine derivatives, etc.), cannabis (marijuana, hashish, etc.), ***e, hallucinogen (LSD , Mescarin, sirocibin, phencyclidine, etc.), carts, opiates (morphine, heroin, codeine, pethidine, fentanyl, etc.) or organic solvents (toluene, thinner, acetone, ether, chloroform, benzene, etc.)・ Withdrawal symptoms and nicotine or tobacco abuse / dependence / withdrawal symptoms are included.
　学習、認知または記憶に関連する症候群、障害および疾患には、加齢、疾患および／または薬剤の副作用（有害事象）などの結果としての記憶喪失または障害、ならびに、認知障害、術後認知低下（錯乱、せん妄、幻肢、幻肢痛など）、老人性・血管性・アルツハイマー型痴呆症の諸症状、健忘症、および忘却などが包含される。 Syndrome, disorder and disease related to learning, cognition or memory include memory loss or impairment as a result of aging, disease and / or drug side effects (adverse events), and cognitive impairment, postoperative cognitive decline ( Confusion, delirium, phantom limb, phantom limb pain, etc.), senile / vascular / alzheimer-type dementia symptoms, amnesia, and forgetting.
　筋痙攣に関連する症候群、障害および疾患には、多発性硬化症、脳性麻痺、振戦、および乳児期の熱性痙攣などが包含される。 Syndrome, disorder and disease related to muscle spasms include multiple sclerosis, cerebral palsy, tremor, and infantile febrile convulsions.
　自発運動または運動に関連する症候群、障害および疾患には、発作、パーキンソン病、パーキンソン病のジスキネジア、多発性硬化症、癲癇、レボドパ惹起運動障害等の運動機能障害、カタレプシー、ツレット症候群、およびチック障害などが包含される。 Spontaneous movements or movement-related syndromes, disorders and diseases include seizures, Parkinson's disease, Parkinson's dyskinesia, multiple sclerosis, epilepsy, motor dysfunction such as levodopa-induced movement disorders, catalepsy, Tourette's syndrome, and tic disorders Etc. are included.
　消化管および内臓に関連する症候群、障害および疾患には、胃腸潰瘍、胃腸炎症、胃腸運動不全関連障害（疼痛、下痢または便秘を伴うか、またはそのどちらも伴わないかのいずれか）、過敏性腸症候群（および腸運動不全の他の形態など）、炎症性腸疾患（潰瘍性大腸炎、クローン病など）、セリアック病、腎不全などの腎疾患、肝線維症、肝硬変、および尿路・膀胱機能障害などが包含される。 Gastrointestinal and visceral-related syndromes, disorders and diseases include gastrointestinal ulcers, gastrointestinal inflammation, gastrointestinal dysmotility-related disorders (with or without pain, diarrhea or constipation), hypersensitivity Bowel syndrome (and other forms of intestinal dysfunction), inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), celiac disease, kidney disease such as renal failure, liver fibrosis, cirrhosis, and urinary tract / bladder Functional impairments are included.
　呼吸器に関連する症候群、障害および疾患には、慢性肺閉塞性疾患、肺気腫、炎症性肺炎、肺線維症、喘息、気管支炎、気道閉塞、睡眠時無呼吸症、および難治性のしゃっくりなどが包含される。 Respiratory syndromes, disorders and diseases include chronic pulmonary obstructive disease, emphysema, inflammatory pneumonia, pulmonary fibrosis, asthma, bronchitis, airway obstruction, sleep apnea, and refractory hiccups Is included.
　免疫および炎症に関連する症候群、障害および疾患には、アレルギー、関節炎、関節リウマチ、皮膚炎、自己免疫疾患、免疫不全、および慢性神経障害性疼痛などが包含される。 Syndrome, disorder and disease related to immunity and inflammation include allergy, arthritis, rheumatoid arthritis, dermatitis, autoimmune disease, immunodeficiency and chronic neuropathic pain.
　細胞増殖に関連する症候群、障害および疾患には、良性または悪性の無調節な細胞増殖（浸潤性増殖）、例えば、咽頭癌、舌癌、食道癌、胃癌、十二指腸癌、大腸癌、直腸癌、肺癌、肝臓癌、膵臓癌、腎臓癌、脾臓癌、膀胱癌、乳癌、子宮癌、卵巣癌、前立腺癌、皮膚癌、脳腫瘍、骨肉種、白血病、またはリンパ腫等、および癌や悪液質による疼痛・食欲不振・衰弱・高カルシウム血症、および抗癌剤による悪心・吐き気・嘔吐などが包含される。 Syndromes, disorders and diseases related to cell proliferation include benign or malignant unregulated cell growth (invasive growth), such as pharyngeal cancer, tongue cancer, esophageal cancer, gastric cancer, duodenal cancer, colon cancer, rectal cancer, Lung cancer, liver cancer, pancreatic cancer, kidney cancer, spleen cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, skin cancer, brain tumor, osteosarcoma, leukemia, or lymphoma, and pain caused by cancer or cachexia • Anorexia, weakness, hypercalcemia, and nausea, nausea, and vomiting caused by anticancer drugs are included.
　疼痛に関連する症候群、障害および疾患には、中枢および末梢経路に媒介される神経因性疼痛、慢性疼痛、骨および関節痛、片頭痛関連疼痛、癌性疼痛、生理痛、陣痛、幻肢痛、掻痒、ならびに麻薬性・非麻薬性鎮痛薬の増強などが包含される。 Pain-related syndromes, disorders and diseases include neuropathic pain mediated by central and peripheral pathways, chronic pain, bone and joint pain, migraine-related pain, cancer pain, menstrual pain, labor pain, phantom limb pain , Pruritus, and enhancement of narcotic and non-narcotic analgesics.
　神経変性に関連する症候群、障害および疾患には、パーキンソン病、ハンチントン舞踏病、多発性硬化症、癲癇、外傷性頭部または脳損傷に付随する虚血または二次性生化学的損傷、ニューロパシー、ギランバレー症候群、頭部外傷、脊髄損傷、神経変性疾患での神経保護、乳幼児脳の発達障害・過剰興奮、神経ガス損傷による酸欠および虚血脳炎症、眼の損傷ならびに発作などが包含される。 Syndromes, disorders and diseases associated with neurodegeneration include Parkinson's disease, Huntington's chorea, multiple sclerosis, hemorrhoids, traumatic head or brain ischemia or secondary biochemical damage associated with neuropathy, Includes Guillain-Barre syndrome, head trauma, spinal cord injury, neuroprotection in neurodegenerative diseases, infant brain developmental disorders / excitement, oxygen deprivation and ischemic brain inflammation due to nerve gas damage, eye damage and seizures, etc. .
　その他、エンドトキシンショック、出血性ショック、低血圧、低体温、催吐剤による吐き気、偏頭痛、レイノー病、月経前症候群または黄体後期症候群、不妊、早産、流産、男性および女性の性機能不全、感染症、慢性疲労症候群、ならびに骨粗しょう症などが包含される。 Others, endotoxin shock, hemorrhagic shock, hypotension, hypothermia, nausea due to emetics, migraine, Raynaud's disease, premenstrual syndrome or late corpus luteum syndrome, infertility, premature birth, miscarriage, male and female sexual dysfunction, infection , Chronic fatigue syndrome, and osteoporosis.
　本発明の予防／改善または治療剤は、好ましくはＣＢ１受容体関連疾患、より好ましくは術後認知低下、ニコチン依存症、難治性のしゃっくり、チック障害または嗜好（味覚）の異常の予防／改善または治療に使用される。 The preventive / ameliorating or therapeutic agent of the present invention preferably prevents / improves CB1 receptor-related diseases, more preferably postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorders or abnormal taste (taste) or Used for treatment.
　「ＣＢ受容体リガンド」は、ＣＢ受容体に結合して生物学的反応を起こさせる化合物の意味で使用される。リガンドは反応発現様式によりアゴニストおよびアンタゴニストまたはインバースアゴニストなどに分類され、これらが包含される。 “CB receptor ligand” is used to mean a compound that binds to a CB receptor and causes a biological reaction. The ligands are classified into agonists and antagonists or inverse agonists depending on the reaction expression pattern, and these are included.
　ＣＢ１およびＣＢ２両受容体アゴニストとしては、アナンダミドおよび２－ＡＧなどのエンドカンナビノイド、ならびにドロナビノール、ＧＷ－１０００（商品名：サティベックス（登録商標）（Sativex（登録商標））、ＧＷファーマシューティカルズ（GW Pharmaceuticals plc, Wiltshire, UK））、およびＯ－１０５７（オーガニックス（Organix Inc., Woburn, MA, USA））などが例示される。 Both CB1 and CB2 receptor agonists include endocannabinoids such as anandamide and 2-AG, and dronabinol, GW-1000 (trade name: Satibex (registered trademark), GW Pharmaceuticals (GW) Pharmaceuticals plc, Wiltshire, UK)), and O-1057 (Organix Inc., Woburn, MA, USA)).
　ＣＢ１受容体に特異的なアゴニストとしては、ＡＺ－５９９、ＡＺＤ－１９４０（アストラゼネカ、Astra Zeneca)、ＫＮ－３８－７２７１（バイエル、Bayer AG）、Ｏｒｇ－２８６１１、Ｏｒｇ－２６８２８、およびＳＣＨ－９００１１１（オルガノン・バイオサイエンス　Organon BioScience N.V., Oss, The Netherlands）、およびＳＡＢ－３７８（ノバルティスファーマ　Novartis Pharma AG, Basel, Switzerland）などが例示される。ＣＢ２受容体に特異的なアゴニストとしては、ＧＷ－８４２１６６Ｘ（グラクソ・スミスクライン）およびＳ－７７７４６９（塩野義製薬）などが例示される。 Agonists specific for the CB1 receptor include AZ-599, AZD-1940 (AstraZeneca), KN-38-7271 (Bayer AG), Org-28611, Org-26828, and SCH-900111. (Organon Biosciences Organon BioScience NV, Oss, The Netherlands) and SAB-378 (Novartis Pharma Novartis Pharma AG, Basel, Switzerland). Examples of agonists specific for the CB2 receptor include GW-842166X (GlaxoSmithKline) and S-777469 (Yoshio Shionogi).
　ＣＢ１およびＣＢ２両受容体アンタゴニストまたはインバースアゴニストとしては、Δ９－テトラヒドロカンナビバリン（ＧＷファーマシューティカルズ）が例示される。ＣＢ１受容体特異的アンタゴニストまたはインバースアゴニストとしては、ドリナバン（drinabant）、リモナバンおよびスリナバン（surinabant）（サノフィ・アベンティス）、オテナバン（otenabant）（ファイザー　Pfizer Inc., New York, NY, USA）、ＡＺＤ－２２０７およびＡＺＤ－１１７５（アストラゼネカ（AstraZeneca plc, London, UK））、イビピナバン（ibipinabant）（ソルベイファーマシューティカルズ　Solvay Pharmaceuticals, Marietta, GA, USA）、ＣＩＳ－５６５Ｃ（東レ　Toray)、Ｏｒｇ－５０１８９（オルガノンバイオサイエンス）、ＴＭ－３８８３７（ケア　エックス　Care X SA）、Ｖ－２５３４３（バーナリス　Vernalis plc, Winnersh, Berkshire, UK）、ＺＹＯ－１（ザイダス・カディラ（Cadila Pharmaceuticals Ltd., Gujarat, India）、ならびにタラナバン（taranabant）（メルク　Merck & Co., Inc., Whitehouse Station, NJ, USA）などが例示される。ＣＢ２受容体特異的アンタゴニストとしては、ＡＭ－６３０（コネチカット大学　University of Connecticut, Storm, CT）などが例示される。 Examples of both CB1 and CB2 receptor antagonists or inverse agonists include Δ 9 -tetrahydrocannabinalin (GW Pharmaceuticals). CB1 receptor specific antagonists or inverse agonists include drinabant, rimonabant and surinabant (Sanofi-aventis), otenabant (Pfizer Pfizer Inc., New York, NY, USA), AZD-2207. And AZD-1175 (AstraZeneca plc, London, UK), ibipinabant (Solvay Pharmaceuticals, Marietta, GA, USA), CIS-565C (Toray), Org-50189 (Organon Bio) Science), TM-38837 (Care X SA), V-25343 (Vernalis plc, Winnersh, Berkshire, UK), ZYO-1 (Cadila Pharmaceuticals Ltd., Gujarat, India), and Taranavan ( taranabant) (Merck Merck & Co., Inc., Whitehouse Station, NJ, USA, etc. Examples of CB2 receptor-specific antagonists include AM-630 (University of Connecticut, Storm, CT).
　なお、本発明でいうＣＢ受容体リガンドはこれらに限定されるものではない。 The CB receptor ligand referred to in the present invention is not limited to these.
　「ＣＢ受容体ニュートラルアンタゴニスト」は、ＣＢ受容体の不活性型と活性型の平衡状態に影響しない、すなわちそれ自体ではＣＢ受容体になんら影響しないが、ＣＢ受容体アゴニストおよびインバースアゴニストのいずれに対しても同様に競合的に拮抗するアンタゴニストの意味で使用される。従来のアンタゴニストの多くは受容体の不活性型と活性型の平衡状態を不活性側に移動させるインバースアゴニストであり、インバースアゴニスト活性の強いアンタゴニストが連用により薬剤耐性や休薬すると症状がさらに悪化するリバウンド現象などを生じやすい。一方、ニュートラルアンタゴニストは、このようなインバースアゴニストにおける連用に伴う不都合を生じさせないと考えられる。 A “CB receptor neutral antagonist” does not affect the equilibrium state of the inactive and active forms of the CB receptor, ie it does not affect the CB receptor in any way, but to either a CB receptor agonist or an inverse agonist. However, it is also used to mean an antagonist that competitively antagonizes. Many of the conventional antagonists are inverse agonists that move the equilibrium between the inactive and active forms of the receptor to the inactive side. Symptoms worsen further when antagonists with strong inverse agonist activity are used due to continuous use or drug withdrawal. Rebound phenomenon is likely to occur. On the other hand, a neutral antagonist is considered not to cause inconvenience associated with continuous use in such an inverse agonist.
　「ＣＢ受容体リガンドによる副作用」とは、ＣＢ受容体リガンド投与により生じる生物学的反応のうち生体にとって好ましくない反応の意味で使用される。ＣＢ受容体アゴニストによる過剰亢進、ＣＢ受容体アンタゴニストまたはインバースアゴニストによる過剰抑制、およびＣＢ受容体リガンド長期使用による耐性発現や使用中断によるリバウンド現象なども含まれる。 The term “side effect due to CB receptor ligand” is used to mean a reaction unfavorable for a living body among biological reactions caused by administration of a CB receptor ligand. Examples include excessive enhancement by CB receptor agonists, excessive suppression by CB receptor antagonists or inverse agonists, and development of tolerance due to long-term use of CB receptor ligands and rebound phenomenon due to discontinuation of use.
　ＣＢ１受容体リガンドによる副作用としては、例えば、ＣＢ１受容体インバースアゴニストであるリモナバンの副作用として報告されている上気道感染、副鼻腔炎、胃腸炎、うつ病性障害（うつ、躁うつ、抑うつなど）、抑うつ症状を伴う気分変動、不安、いらだち、神経過敏症、睡眠障害、不眠、異常不眠症、パニック症状、怒り、不満感、多幸感、情緒障害、自殺企図、攻撃性、攻撃行動、幻覚、頭痛、記憶喪失（健忘）、注意障害、めまい、不動性めまい、感覚減退症、坐骨神経痛、知覚異常症、嗜眠、紅潮、しゃっくり、悪心、下痢、嘔吐、食欲不振、食欲減退、胃部不快感、口渇、掻痒感、発汗過多、寝汗、腱炎、筋痙攣、筋攣縮、無力症／疲労、インフルエンザ、転倒、打ち身および捻挫などが包含される。これらのうち、発現頻度が高い副作用としては、上気道感染、胃腸炎、うつ病性障害、抑うつ症状を伴う気分変動、不安、いらだち、神経過敏症、睡眠障害、不眠、異常不眠症、自殺企図、記憶喪失（健忘）、めまい、感覚減退症、坐骨神経痛、知覚異常症、紅潮、悪心、下痢、嘔吐、掻痒感、発汗過多、腱炎、筋痙攣、筋攣縮、無力症／疲労、転倒、打ち身および捻挫などが例示され、重篤な副作用としては、うつ病性障害および自殺企図などが例示される。 Examples of side effects caused by CB1 receptor ligand include upper respiratory tract infection, sinusitis, gastroenteritis, and depressive disorders (depression, manic depression, depression, etc.) reported as side effects of rimonabant, which is an inverse agonist of CB1 receptor. , Mood swings with depressive symptoms, anxiety, irritation, irritability, sleep disorder, insomnia, abnormal insomnia, panic symptoms, anger, dissatisfaction, euphoria, emotional disorder, suicide attempt, aggressiveness, aggressive behavior, hallucinations, Headache, memory loss (amnesia), attention deficit, dizziness, immobility, hyposensory, sciatica, sensory dysfunction, lethargy, flushing, hiccup, nausea, diarrhea, vomiting, loss of appetite, loss of appetite, stomach discomfort , Dry mouth, pruritus, hyperhidrosis, night sweats, tendonitis, muscle spasms, muscle spasms, asthenia / fatigue, influenza, falls, bruises and sprains. Among these, the most frequently reported adverse reactions include upper respiratory tract infection, gastroenteritis, depressive disorder, mood swings with depressive symptoms, anxiety, irritation, irritability, sleep disorder, insomnia, abnormal insomnia, suicide attempt , Memory loss (amnesia), dizziness, hypoxia, sciatica, sensory abnormalities, flushing, nausea, diarrhea, vomiting, itching, hyperhidrosis, tendonitis, muscle spasm, muscle spasm, asthenia / fatigue, falls, Examples include bruises and sprains, and examples of serious side effects include depressive disorder and suicide attempts.
　またＣＢ１およびＣＢ２受容体アゴニストであるドロナビノールの副作用として報告されている無気力、動悸、頻脈、血管拡張／顔面紅潮、結膜炎、血圧低下、腹痛、悪心、嘔吐、下痢、失禁、健忘、不安、神経過敏症、運動失調、錯乱、うつ、めまい、高揚感、多幸感、幻覚、パラノイア、眠気、思考異常、悪夢、言語障害、耳鳴り、薬物依存、紅潮、および視覚異常などが包含される。これらのうち、発現頻度が高い副作用としては、無気力、動悸、頻脈、血管拡張／顔面紅潮、腹痛、悪心、嘔吐、健忘、不安、神経過敏症、運動失調、錯乱、うつ、めまい、高揚感、多幸感、幻覚、パラノイア、眠気、および思考異常などが例示され、重篤な副作用としては、血圧低下、錯乱、うつ、幻覚、および薬物依存などが例示される。 Also reported as side effects of dronabinol, a CB1 and CB2 receptor agonist, lethargy, palpitation, tachycardia, vasodilation / facial flushing, conjunctivitis, hypotension, abdominal pain, nausea, vomiting, diarrhea, incontinence, amnesia, anxiety, nerve Examples include hypersensitivity, ataxia, confusion, depression, dizziness, uplifting, euphoria, hallucinations, paranoia, drowsiness, abnormal thinking, nightmares, language disturbances, tinnitus, drug dependence, flushing, and visual abnormalities. Among these, side effects with high incidence include lethargy, palpitation, tachycardia, vasodilation / facial flushing, abdominal pain, nausea, vomiting, amnesia, anxiety, hypersensitivity, ataxia, confusion, depression, dizziness, uplifting feeling Euphoria, hallucinations, paranoia, sleepiness, abnormal thinking, etc., and severe side effects include hypotension, confusion, depression, hallucinations, and drug dependence.
　本発明の予防または軽減剤は、好ましくはＣＢ１受容体アゴニストまたはインバースアゴニストの副作用、より好ましくは悪心、抑うつ症状に伴う気分変動、不安、不動性めまい、自殺企図、摂食障害、記憶障害または薬物依存性などの副作用の予防または軽減に使用される。 The preventive or alleviating agent of the present invention is preferably a side effect of CB1 receptor agonist or inverse agonist, more preferably nausea, mood swings associated with depressive symptoms, anxiety, immobility, suicide attempt, eating disorder, memory disorder or drug Used to prevent or reduce side effects such as addiction.
　本発明の予防または軽減剤の形態は特に限定されず、例えば（１）ω３ＰＵＦＡｓを単独有効成分とする製剤、（２）ω３ＰＵＦＡｓとＣＢ受容体リガンドとを同時製剤化して得られる単一の製剤、（３）ω３ＰＵＦＡｓとＣＢ受容体リガンドとを別々に製剤化して得られる２種類の製剤を組合せてキットとした製剤の形態がある。 The form of the preventive or alleviating agent of the present invention is not particularly limited. For example, (1) a preparation containing ω3 PUFAs as a single active ingredient, (2) a single preparation obtained by co-formulation of ω3 PUFAs and a CB receptor ligand, (3) There is a form of a preparation in which two kinds of preparations obtained by separately preparing ω3 PUFAs and a CB receptor ligand are combined.
　ＣＢ受容体リガンドによる副作用を予防または軽減するための方法は特に限定されず、ω３ＰＵＦＡｓを投与する工程を含めばよい。例えば、ω３ＰＵＦＡｓを投与する工程とＣＢ受容体リガンドを投与する工程を含む、ω３ＰＵＦＡｓとＣＢ受容体リガンドとを組み合わせて用いる方法（以下、「併用」という。）も含まれる。 The method for preventing or reducing the side effects caused by the CB receptor ligand is not particularly limited, and may include a step of administering ω3 PUFAs. For example, a method of using a combination of ω3PUFAs and a CB receptor ligand (hereinafter referred to as “combination”) including a step of administering ω3PUFAs and a step of administering a CB receptor ligand is also included.
　併用する場合、ω３ＰＵＦＡｓおよびＣＢ受容体リガンドを共に含む配合剤として投与すること、および、ω３ＰＵＦＡｓとＣＢ受容体リガンドとがそれぞれ別個の製剤として同時期にもしくは時間差をおいて別々に投与されることを含む。 When used in combination, it should be administered as a combination containing both ω3 PUFAs and CB receptor ligands, and ω3 PUFAs and CB receptor ligands should be administered separately as separate preparations at the same time or separately at different times. Including.
　「別個の製剤として同時期にもしくは時間差をおいて別々に投与される」態様には、（１）ω３ＰＵＦＡｓを投与される患者に、ＣＢ受容体リガンドを有効成分として含有する組成物を投与する態様、および、（２）ＣＢ受容体リガンドを投与される患者に、ω３ＰＵＦＡｓ有効成分として含有する組成物を投与する態様が含まれる。 In the aspect of “administered separately as a separate preparation at the same time or with a time difference”, (1) an aspect in which a composition containing a CB receptor ligand as an active ingredient is administered to a patient receiving ω3 PUFAs And (2) a mode in which a composition containing ω3 PUFAs as an active ingredient is administered to a patient who receives a CB receptor ligand.
　また、「併用」とは必ずしも患者の体内、例えば血中において同時に存在する場合に限られないが、本発明において「併用」とは、いずれか一方の薬剤の作用・効果が患者の体内に発現している状態で他方の薬剤を投与する使用態様をいう。本発明の予防または軽減剤を用いてＣＢ受容体による副作用の予防または軽減効果が得られるような使用態様である。好ましくは、患者の体内、例えば血中において同時に存在する使用態様が望ましく、また好ましくは、患者に対して、一方の薬剤を投与してから２４時間以内に他方の薬剤を投与する使用態様が好ましい。 In addition, the term “combination” is not necessarily limited to the case where it is simultaneously present in the patient's body, for example, blood, but in the present invention, “combination” means that the action / effect of either one of the drugs is expressed in the patient's body. In this state, the other drug is administered. It is a usage mode in which the prevention or alleviation effect of the CB receptor is obtained using the preventive or alleviating agent of the present invention. Preferably, a usage mode that coexists in the patient's body, for example, in the blood, is desirable, and a usage mode in which the other drug is administered to the patient within 24 hours after the administration of one drug is preferable. .
　これらの時間差をおいて投与する場合は、例えば、ω３ＰＵＦＡｓとＣＢ受容体リガンドの順序での投与、または逆の順序での投与がある。同時に投与する場合、投与経路が同一であれば投与直前に両薬剤を混合してもよく、別々に投与しても良い、また種々の目的で計画的に投与時期をずらして用いることができる。 In the case of administration with these time differences, for example, there are administration in the order of ω3 PUFAs and CB receptor ligand, or administration in the reverse order. In the case of simultaneous administration, if the administration route is the same, both drugs may be mixed immediately before the administration, may be administered separately, or can be used by shifting the administration time systematically for various purposes.
　具体的な例としては、一方の薬剤を投与し、その効果が発現し始める時期もしくは十分に発現している間に、他方の薬剤を投与して作用させる方法がある。また、一方の薬剤、特にＣＢ受容体リガンドを徐放化して１日１回投与とし、他方の薬剤、特にω３ＰＵＦＡｓを１日複数回、例えば２ないし３回投与としてもよいし、同様に１日１回投与としてもよい。両薬ともに１日１回投与、さらには１日１回同時投与あるいは配合剤とすれば、患者の服薬の負担を軽減し、服薬コンプライアンスが向上して副作用の予防または軽減効果も増すことが期待され、好ましい。 As a specific example, there is a method in which one drug is administered and the other drug is administered and acted at the time when the effect starts to appear or when the effect is fully manifested. Alternatively, one drug, particularly CB receptor ligand, can be sustainedly released and administered once a day, and the other drug, particularly ω3PUFAs, can be administered multiple times a day, for example, 2 to 3 times a day. It may be a single dose. If both drugs are administered once a day, or if they are administered simultaneously or once a day as a combination drug, it is expected to reduce the burden of patient compliance, improve compliance, and prevent or reduce side effects. And preferred.
　また、例えば、両薬剤を投与し、その効果が発現し始める時期もしくは十分発現している時期に、一方の薬剤の投薬を中止する方法がある。薬剤の投薬を中止する場合には、段階的に薬剤の用量を減量してもよい。また、例えば、一方の薬剤の休薬期間に他方の薬剤を投与する方法が挙げられる。 Also, for example, there is a method in which both drugs are administered, and the administration of one drug is stopped when the effect starts to appear or when the effect is fully manifested. When the administration of the drug is stopped, the dose of the drug may be decreased in stages. In addition, for example, there is a method of administering the other drug during a drug withdrawal period of one drug.
　本発明のＣＢ受容体関連疾患の予防／改善または治療剤およびＣＢ受容体リガンドによる副作用の予防または軽減剤に用いられるω３ＰＵＦＡｓの投与量および投与期間は対象となる作用を現すのに十分な量および期間とされるが、その剤形、投与方法、１日当たりの投与回数、症状および副作用の程度、体重、年齢等によって適宜増減することができる。 The dose and duration of ω3PUFAs used in the preventive / ameliorating or treating agent for CB receptor-related diseases of the present invention and the preventive or alleviating side effect due to CB receptor ligand are sufficient to exhibit the intended effect and Although it is a period, it can be appropriately increased or decreased depending on its dosage form, administration method, number of administrations per day, symptoms and degree of side effects, body weight, age and the like.
　経口投与する場合は、例えば、ＥＰＡ－Ｅおよび／またはＤＨＡ－Ｅとして０．１～１０ｇ／日、好ましくは０．３～６ｇ／日、より好ましくは０．６～４ｇ／日、さらに好ましくは０．９～２．７ｇ／日を、１～３回に分けて投与するが、必要に応じて全量を１回または数回に分けて投与してもよい。 In the case of oral administration, for example, EPA-E and / or DHA-E is 0.1 to 10 g / day, preferably 0.3 to 6 g / day, more preferably 0.6 to 4 g / day, still more preferably 0.9 to 2.7 g / day is administered in 1 to 3 divided doses, but the entire dose may be administered in one or several divided doses as necessary.
　投与時間は食中または食後が好ましく、食直後（３０分以内）がより好ましい。また、乳剤などの経口用液体製剤または胆汁酸添加製剤として服薬時間の制約なく投与することもできる。 The administration time is preferably during or after meals, more preferably immediately after meals (within 30 minutes). In addition, it can be administered as an oral liquid preparation such as an emulsion or a bile acid-added preparation without any restriction on the time of medication.
　上記投与量を経口投与する場合、投与期間は症状の程度および改善度により適宜決定され、限定されるものではないが、例えば１年以上、好ましくは２年以上、より好ましくは３．５年以上、いっそう好ましくは５年以上であるが、ＣＢ受容体関連疾患の病態あるいは生化学的指標などおよびＣＢ受容体リガンドによる副作用が継続している間、ＣＢ受容体関連疾患の発症および／または再発の危険度が高い状態が続いている間、ならびにＣＢ受容体リガンドによる副作用発現および／または再発の危険度が高い状態が続いている間は投与を継続することが望ましい。また、例えば、１日おきに投与する態様または１週間に２～３日投与する態様でもよく、場合により１日～３ヵ月程度、好ましくは１週間～１ヵ月程度の休薬期間を設けることもできる。 When the above dose is administered orally, the administration period is appropriately determined depending on the degree of symptoms and the degree of improvement, and is not limited, but for example, 1 year or more, preferably 2 years or more, more preferably 3.5 years or more. More preferably, for more than 5 years, the onset and / or recurrence of the CB receptor-related disease is continued while the pathology or biochemical index of the CB receptor-related disease and the side effects due to the CB receptor ligand continue. It is desirable to continue administration while the state of high risk continues and during the state of high risk of side effects and / or recurrence due to CB receptor ligand. Further, for example, it may be administered every other day or administered for 2 to 3 days per week, and in some cases, a drug holiday of about 1 to 3 months, preferably about 1 week to 1 month may be provided. it can.
　本発明のＣＢ受容体関連疾患の予防／改善または治療剤およびＣＢ受容体リガンドによる副作用の予防または軽減剤は、有効成分を、化合物のみ（精製の際に不可避的に含まれる他の成分を含む場合もある）で投与してもよいし、一般的に用いられる適当な担体、媒体、賦形剤、結合剤、滑沢剤、着色剤、香味剤、乳化剤、懸濁化剤（例えばツイーン８０、アラビアゴム溶液）、吸収促進剤（例えばウルソデオキシコール酸などの胆汁酸）、等張化剤、ｐＨ調整剤、安定化剤、無痛化剤、嬌味剤、着香剤、保存剤、抗酸化剤、緩衝剤、着色剤、および／または滅菌水、植物油、無害性有機溶媒もしくは無害性溶解補助剤（たとえばグリセリン、プロピレングリコール）などの添加剤と適宜組み合わせて適当な医薬用製剤に調製して投与してもよい。添加剤として、例えば、乳糖、部分α化デンプン、ヒドロキシプロピルセルロース、マクロゴール、トコフェロール、硬化油、ショ糖脂肪酸エステル、ヒドロキシプロピルメチルセルロース、酸化チタン、タルク、ジメチルポリシロキサン、二酸化ケイ素、および／またはカルナウバロウなどを含有しうる。 The agent for preventing / ameliorating or treating a CB receptor-related disease of the present invention and the agent for preventing or alleviating side effects caused by a CB receptor ligand include an active ingredient, a compound alone (including other ingredients inevitably contained during purification). In some cases) or suitable commonly used carriers, media, excipients, binders, lubricants, coloring agents, flavoring agents, emulsifying agents, suspending agents (eg Tween 80). , Gum arabic solution), absorption enhancers (eg bile acids such as ursodeoxycholic acid), isotonic agents, pH adjusters, stabilizers, soothing agents, flavoring agents, flavoring agents, preservatives, antiseptics Prepare an appropriate pharmaceutical preparation by appropriately combining with oxidizing agents, buffers, coloring agents, and / or additives such as sterilized water, vegetable oil, harmless organic solvents or harmless solubilizers (eg glycerin, propylene glycol). Administer Good. Examples of additives include lactose, partially pregelatinized starch, hydroxypropylcellulose, macrogol, tocopherol, hydrogenated oil, sucrose fatty acid ester, hydroxypropylmethylcellulose, titanium oxide, talc, dimethylpolysiloxane, silicon dioxide, and / or carnauba wax. Etc. may be contained.
　ω３ＰＵＦＡｓは高度に不飽和であるため、抗酸化剤を有効量含有させることが望ましい。例えば、ブチレート化ヒドロキシトルエン、ブレチート化ヒドロキシアニソール、プロピルガレート、没食子酸プロピル、医薬として許容されうるキノン、アスタキサンチンおよびα－トコフェロールなどの油溶性の抗酸化剤から選ばれる少なくとも１種を抗酸化剤として有効量含有させることが望ましい。乳剤とする場合は、アスコルビン酸およびその誘導体、エリソルビン酸、亜硝酸塩、ならびにクエン酸などの水溶性の抗酸化剤と油溶性の抗酸化剤の両方を含有させることが好ましい。 Ω3PUFAs are highly unsaturated, so it is desirable to contain an effective amount of an antioxidant. For example, at least one selected from oil-soluble antioxidants such as butylated hydroxytoluene, brechated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin and α-tocopherol is used as an antioxidant. It is desirable to contain an effective amount. In the case of an emulsion, it is preferable to contain both a water-soluble antioxidant and an oil-soluble antioxidant such as ascorbic acid and derivatives thereof, erythorbic acid, nitrite, and citric acid.
　製剤の剤形は特に限定されず、経口製剤でもよいし、非経口製剤でもよい。経口製剤としては、例えば、錠剤、フィルムコーティング錠、カプセル剤、マイクロカプセル剤、顆粒剤、細粒剤、散剤、乳剤などの経口用液体製剤、シロップ剤、ゼリー剤、または吸入剤の形が好ましい。また、非経口製剤としては、例えば、軟膏、坐剤、注射剤（乳濁性、懸濁性、非水性）、用時乳濁もしくは懸濁して用いる固形注射剤、輸液製剤、または経皮吸収剤などの外用剤の形が好ましい。経口製剤は経口服用で患者に投与することができ、非経口製剤は静脈内もしくは動脈内、吸入、直腸内、膣内または外用などで患者に投与することができる。 The dosage form of the preparation is not particularly limited, and may be an oral preparation or a parenteral preparation. As the oral preparation, for example, oral liquid preparations such as tablets, film-coated tablets, capsules, microcapsules, granules, fine granules, powders, emulsions, syrups, jellies, or inhalants are preferable. . Parenteral preparations include, for example, ointments, suppositories, injections (emulsification, suspension, non-aqueous), solid injections used when emulsified or suspended, infusion preparations, or transdermal absorption. An external preparation such as an agent is preferred. Oral preparations can be administered to patients by oral administration, and parenteral preparations can be administered to patients intravenously or intraarterially, by inhalation, rectal, vaginal or external.
　経口服用できる患者に対しては、簡便な経口製剤が望ましく、とりわけカプセル、例えば、軟質カプセルやマイクロカプセルに封入して、または錠剤、フィルムコーティング錠、乳剤での経口投与が好ましい。また、腸溶製剤や徐放化製剤として経口投与してもよく、透析患者や嚥下困難な患者などにはゼリー剤として経口投与することも好ましい。 For patients who can be taken orally, simple oral preparations are desirable, and oral administration in capsules, such as soft capsules or microcapsules, or in tablets, film-coated tablets, and emulsions is particularly preferable. Moreover, it may be orally administered as an enteric preparation or sustained-release preparation, and is preferably administered orally as a jelly agent to dialysis patients or patients who have difficulty swallowing.
　また、乳剤などの経口用液体製剤として経口投与するとω３ＰＵＦＡｓおよび／またはＣＢ受容体リガンドの吸収が促進され、服薬時間の制約なく投与でき、かつ薬剤の投与量を減量できて好ましい。乳剤とする場合は、乳濁粒子の直径は小さいほうが好ましく、好ましくは平均直径５μｍ以下、より好ましくは１μｍ以下、さらに好ましくは０．５μｍ以下、いっそう好ましくは０．２μｍ以下が例示される。 Also, oral administration as an oral liquid preparation such as an emulsion is preferable because absorption of ω3PUFAs and / or CB receptor ligand is promoted, administration can be performed without any restriction on the dose, and the dose of the drug can be reduced. In the case of an emulsion, it is preferable that the emulsion particles have a smaller diameter, preferably an average diameter of 5 μm or less, more preferably 1 μm or less, still more preferably 0.5 μm or less, and still more preferably 0.2 μm or less.
　乳化剤としては、医薬製剤に使用できる乳化剤であればいずれの乳化剤も用いることができる。例えば、卵黄レシチン、大豆レシチン、卵黄リン脂質、大豆リン脂質、精製ラノリン、グリセリン、プロピレングリコール、ポリソルベートエステル、モノグリセリド、ジグリセリド、モノグリセリドの有機酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、ショ糖脂肪酸エステル、ポリグリセリン脂肪酸エステル、グリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、プロピレングリコール脂肪酸エステル、モノステアリン酸ソルビタン、トリオレイン酸ソルビタン、ラウリル硫酸ナトリウム、非イオン性界面活性剤などが例示され、好ましくは卵黄レシチン、大豆レシチン、ポリオキシエチレンポリオキシプロピレングリコール、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステルおよびプロピレングリコール脂肪酸エステルが例示的に挙げられる。乳化剤は単独で、または２種以上を併用して含有させることができる。 As the emulsifier, any emulsifier can be used as long as it can be used in pharmaceutical preparations. For example, egg yolk lecithin, soybean lecithin, egg yolk phospholipid, soybean phospholipid, purified lanolin, glycerin, propylene glycol, polysorbate ester, monoglyceride, diglyceride, monoglyceride organic acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, Examples include polyglycerin fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, sorbitan monostearate, sorbitan trioleate, sodium lauryl sulfate, and nonionic surfactant, preferably egg yolk lecithin, soybean lecithin , Polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, sorbitan fatty acid ester and propylene glycol fat Esters illustratively. The emulsifiers can be contained alone or in combination of two or more.
　また、乳化補助剤、安定化剤、界面活性剤、および／または抗酸化剤などを含有させることもできる。乳化補助剤としては、ステアリン酸、オレイン酸、リノール酸、パルミチン酸、リノレン酸およびミリスチン酸などの炭素数１２～２２の脂肪酸またはそれらの塩などが例示される。安定化剤としては、フォスファチジン酸、アスコルビン酸、グリセリン、セタノール、パラオキシ安息香酸エチル、またはパラオキシ安息香酸プロピルなどが例示される。界面活性剤としては、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンアルキルエーテル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンアルキルフェニルエーテル、ポリオキシエチレンポリオキシプロピレングリコール、およびポリオキシエチレンポリオキシプロピレンアルキルエーテルなどが例示される。抗酸化剤としては、ブチレート化ヒドロキシトルエン、ブレチート化ヒドロキシアニソール、プロピルガレート、没食子酸プロピル、医薬として許容されうるキノン、アスタキサンチンおよびα－トコフェロールなどの油溶性の抗酸化剤、ならびにアスコルビン酸およびその誘導体、エリソルビン酸、亜硝酸塩およびクエン酸などの水溶性の抗酸化剤が例示される。 Further, an emulsification aid, a stabilizer, a surfactant, and / or an antioxidant can be contained. Examples of the emulsification aid include fatty acids having 12 to 22 carbon atoms such as stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid and myristic acid, or salts thereof. Examples of the stabilizer include phosphatidic acid, ascorbic acid, glycerin, cetanol, ethyl paraoxybenzoate, propyl paraoxybenzoate, and the like. Surfactants include sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, Examples include polyoxyethylene alkylphenyl ether, polyoxyethylene polyoxypropylene glycol, and polyoxyethylene polyoxypropylene alkyl ether. Antioxidants include butyrated hydroxytoluene, breached hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin and α-tocopherol, as well as ascorbic acid and its derivatives Water-soluble antioxidants such as erythorbic acid, nitrite and citric acid are exemplified.
　乳剤中のＥＰＡの含有量は好ましくは１～６０質量％、より好ましくは３～４０質量％、さらに好ましくは５～３０質量％が例示される。乳化剤の含有量は好ましくは０．１～１０質量％、より好ましくは０．２～５質量％、さらに好ましくは０．５～３質量％が例示される。 The content of EPA in the emulsion is preferably 1 to 60% by mass, more preferably 3 to 40% by mass, and further preferably 5 to 30% by mass. The content of the emulsifier is preferably 0.1 to 10% by mass, more preferably 0.2 to 5% by mass, and still more preferably 0.5 to 3% by mass.
　本発明の乳剤は、例えば、有効成分、乳化剤、グリセリン、精製水および所望により抗酸化剤などの他の添加剤を混合、加熱して溶液とし、通常のホモジナイザー、例えば、マントンゴーリン型ホモジナイザーのような加圧噴射型ホモジナイザーを用いて、例えば、圧力５０～７００ｋｇ／ｃｍ２で好ましくは１～５０回程度、より好ましくは２～２０回程度通過させて乳化を行う、あるいは、マイクロフルイダイザー、薄膜旋回型高速ミキサー、高圧ジェット流反転型乳化機、超音波型ホモジナイザーなどを用いて均質化して製造することができる。これに先立って、ホモミキサーなどを用いて予備乳化を行っても良い。 The emulsion of the present invention is mixed with, for example, an active ingredient, an emulsifier, glycerin, purified water, and other additives such as an antioxidant, if necessary, and heated to form a solution, which is a normal homogenizer, such as a Manton Gorin type homogenizer. For example, using a pressure-injection type homogenizer, emulsification is preferably performed at a pressure of 50 to 700 kg / cm 2 , preferably about 1 to 50 times, more preferably about 2 to 20 times, or a microfluidizer, a thin film It can be produced by homogenization using a swirl type high-speed mixer, a high-pressure jet flow reversal type emulsifier, an ultrasonic homogenizer, or the like. Prior to this, preliminary emulsification may be performed using a homomixer or the like.
　次に本発明を実施例により具体的に説明するが、本発明はこれら実施例に限定されるものではない。 Next, the present invention will be specifically described by way of examples, but the present invention is not limited to these examples.
（実験例１）
肥満・糖尿病モデルマウスにおける摂食障害への有効性
　８週令の雄性ｏｂ／ｏｂマウス（日本チャールス・リバー）を通常食（魚粉抜きＦ－１、船橋農場）を２週間自由摂取させて１２時間明暗周期、２３±２℃で飼育した。対照群、ＥＰＡ－Ｅ群（ＥＰＡ－Ｅ投与）、リモナバン（rimonabant）群（リモナバン投与）および併用群（ＥＰＡ－Ｅ投与＋リモナバン投与）の４群（各群８匹）を群間で体重の平均値±標準誤差に統計学的有意差がないように設定した。２週間の飼育期間中、ＥＰＡ－Ｅ群にはＥＰＡ－Ｅを１０００ｍｇ／ｋｇ、リモナバン群にはリモナバンを１０ｍｇ／ｋｇおよび併用群にはＥＰＡ－Ｅ１０００ｍｇ／ｋｇおよびリモナバンを１０ｍｇ／ｋｇを５％アラビアゴム水溶液にヒスコトロン（マイクロテック・ニチオン）を用いて懸濁して１日１回経口投与した。対照群には５％アラビアゴム水溶液を１日１回経口投与した。飼育期間中毎日体重測定し、飼育最終日の摂餌量を測定した。各群の飼育最終日の摂餌量および飼育期間中の体重増加の平均値±標準誤差を算出し、Ｓｔｕｄｅｎｔ’ｓ－ｔ検定を行った。 (Experimental example 1)
Efficacy for obesity / diabetes model mice in eating disorders Eight weeks old male ob / ob mice (Nippon Charles River), regular diet (fish meal free F-1, Funabashi Farm) for 2 weeks, 12 hours The animals were reared at a light-dark cycle of 23 ± 2 ° C. The control group, EPA-E group (EPA-E administration), rimonabant group (rimonabant administration) and combination group (EPA-E administration + rimonabant administration) were divided into groups of 8 The mean value ± standard error was set so that there was no statistically significant difference. During the 2-week breeding period, EPA-E group received 1000 mg / kg EPA-E, rimonabant group 10 mg / kg rimonabant and the combination group EPA-E 1000 mg / kg and rimonabant 10 mg / kg 5% Arabic It was suspended in an aqueous rubber solution using Hiscotron (Microtech Nithion) and orally administered once a day. The control group was orally administered with a 5% gum arabic aqueous solution once a day. The body weight was measured every day during the breeding period, and the food intake on the last day of the breeding was measured. The amount of food consumed on the last day of breeding in each group and the mean value ± standard error of weight gain during the breeding period were calculated, and Student's t test was performed.
　結果を表１に示す。
Figure JPOXMLDOC01-appb-T000001
 The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
対照群に対して、＃：ｐ＜０．０５、＃＃：ｐ＜０．０１
リモナバン群に対して、＊：ｐ＜０．０５、＊＊：ｐ＜０．０１ With respect to the control group, # : p <0.05, ## : p <0.01
For rimonabant group, * : p <0.05, ** : p <0.01
　対照群とＥＰＡ－Ｅ群とでは摂餌量および体重増加は同等であったが、リモナバン群ではいずれも明らかに減少した。併用群では摂餌量は対照群と同等レベルであり、体重増加は対照群より減少したがリモナバン群に比べて有意に減少量が少なかった。 In the control group and EPA-E group, food intake and body weight gain were similar, but in the rimonabant group, both decreased clearly. In the combination group, food consumption was at the same level as in the control group, and weight gain decreased from the control group, but was significantly less than that of the rimonabant group.
　この結果は、２－ＡＧあるいは２－ＥＧや２－ＤＧなどのω３ＰＵＦＡｓを２位に結合したグリセロールがｉｎ　ｖｉｔｒｏ試験においてＣＢ受容体アゴニスト活性を有するとの従来知見から予測し得ない驚くべき作用・効果である。 This result is a surprising action that cannot be predicted from the conventional knowledge that glycerol binding ω3PUFAs such as 2-AG or 2-EG or 2-DG has the CB receptor agonist activity in the in vitro test. It is an effect.
　なぜならば、ＥＰＡ－Ｅを経口投与した場合、主として小腸もしくはリンパにおいて脱エチル化されて吸収されることが知られており、吸収されたＥＰＡの一部はグリセロールとエステル結合して２－ＥＧに代謝されると考えられる。２－ＥＧがＣＢ１受容体アゴニスト活性を有するという従来技術からは、ＥＰＡ－Ｅ単独経口投与（ＥＰＡ－Ｅ群）では、２－ＥＧによる摂食促進および体重増加促進作用が現れると考えられる。 This is because, when EPA-E is administered orally, it is known that it is deethylated and absorbed mainly in the small intestine or lymph, and a part of the absorbed EPA is esterified with glycerol to form 2-EG. It is thought to be metabolized. From the conventional technique that 2-EG has CB1 receptor agonist activity, it is considered that 2-EG provides an effect of promoting feeding and weight gain by oral administration of EPA-E alone (EPA-E group).
　しかし、ＥＰＡ－Ｅは単独経口投与では摂餌量および体重増加に影響を与えなかった。そして、それにもかかわらず、ＥＰＡ－Ｅはリモナバンと併用経口投与した場合（併用群）では、ＣＢ１受容体インバースアゴニストであるリモナバンによる主に中枢性のＣＢ１受容体過剰抑制を介した摂食抑制および体重増加抑制のいずれをも回復させた。 However, EPA-E had no effect on food intake or weight gain when administered alone orally. And nevertheless, when EPA-E is orally administered in combination with rimonabant (combination group), feeding inhibition and mainly via central CB1 receptor over-suppression by rimonabant, a CB1 receptor inverse agonist, and All the suppression of weight gain was restored.
　すなわち、ＥＰＡ－Ｅの経口投与により生じるＥＰＡのグリセリドがＣＢ１受容体に対してニュートラルアンタゴニスト様の作用を示し、このニュートラルアンタゴニスト様作用を介してＣＢ１受容体過剰抑制を抑制して摂食抑制および体重増加抑制を回復させたと考えられる。 That is, the EPA glyceride produced by oral administration of EPA-E exhibits a neutral antagonist-like action on the CB1 receptor, and through this neutral antagonist-like action, suppresses excessive inhibition of the CB1 receptor, thereby suppressing feeding and body weight. It is thought that the increase suppression was restored.
　ニュートラルアンタゴニストであればアゴニスト、アンタゴニストまたはインバースアゴニストのいずれをも拮抗的に阻害することが知られていることから、本発明の予防／改善または治療剤はＣＢ１受容体が過剰亢進あるいは過剰抑制されたことにより生じるＣＢ１受容体関連疾患の予防／改善または治療に有用である。また、本発明の副作用の予防または軽減剤はＣＢ１受容体アゴニスト、アンタゴニストまたはインバースアゴニストによる副作用の予防または軽減に有用である。さらに、本発明の予防／改善または治療剤および副作用の予防または軽減剤はＣＢ１受容体が過剰亢進あるいは過剰抑制されていない状態ではＣＢ１受容体に作用しないため、副作用を示さないという利点を有する。 Since neutral antagonists are known to antagonistically inhibit any agonist, antagonist, or inverse agonist, the preventive / improving or therapeutic agent of the present invention over- or over-suppressed the CB1 receptor. It is useful for the prevention / amelioration or treatment of CB1 receptor-related diseases caused by this. Moreover, the preventive or alleviating agent for side effects of the present invention is useful for preventing or reducing side effects caused by a CB1 receptor agonist, antagonist or inverse agonist. Furthermore, since the preventive / improving or treating agent and the side effect preventing or reducing agent of the present invention do not act on the CB1 receptor in a state where the CB1 receptor is not excessively enhanced or excessively suppressed, there is an advantage that no side effect is exhibited.
　本発明のＣＢ１受容体の過剰亢進あるいは過剰抑制に起因するＣＢ１受容体関連疾患の予防／改善または治療効果は、下記の動物モデル試験あるいは臨床モデル試験により評価することができる。 The prevention / improvement or therapeutic effect of CB1 receptor-related diseases caused by excessive enhancement or excessive suppression of the CB1 receptor of the present invention can be evaluated by the following animal model test or clinical model test.
（動物モデル試験１）
ニコチン退薬時の嫌悪モデルラットにおけるニコチン依存性への有効性
　実験装置は白・黒の２コンパートメントボックスからなる条件付け場所嗜好性試験（Conditioned Place Preference（ＣＰＰ））装置（C. Spyraki、"The Psychopharmacology of Addiction"、ed．by M．Lader、 Oxford Medical Publications、New York、１９８８年、ｐ．９７－１１４）を用い、ニコチン受容体拮抗薬であるメカミラミン（mecamylamine）により誘発されるニコチン退薬時の嫌悪モデルを用いて検討する。 (Animal model test 1)
Efficacy for nicotine dependence in aversive model rats during withdrawal of nicotine The experimental device is a Conditioned Place Preference (CPP) device (C. Spyraki, "The Psychopharmacology" consisting of two compartment boxes, black and white) of Addiction ", ed. by M. Lader, Oxford Medical Publications, New York, 1988, p. 97-114), at the time of withdrawal of nicotine induced by mecamylamine, a nicotine receptor antagonist. Consider using an aversion model.
　７週齢の雄性ＳＤ系ラットを通常食（Ｆ－１、船橋農場）を自由摂取させて１２時間明暗周期、２３℃で飼育する。対照群、ＥＰＡ－Ｅ１００群（ＥＰＡ－Ｅ１００ｍｇ／ｋｇ投与）、ＥＰＡ－Ｅ３００群（ＥＰＡ－Ｅ３００ｍｇ／ｋｇ投与）の３群（各群６匹）を設定する。飼育期間中、ＥＰＡ－Ｅ群にはＥＰＡ－Ｅを５％アラビアゴム水溶液にヒスコトロンを用いて懸濁して１日１回経口投与する。対照群には５％アラビアゴム水溶液を１日１回経口投与する。飼育３週間後よりニコチン投与および下記条件付けを行う。 7-week-old male SD rats are fed at normal temperature (F-1, Funabashi Farm) with a 12-hour light-dark cycle at 23 ° C. Three groups (6 mice in each group) are set: a control group, an EPA-E100 group (administered with EPA-E 100 mg / kg), and an EPA-E300 group (administered with EPA-E 300 mg / kg). During the breeding period, EPA-E is suspended in a 5% gum arabic aqueous solution using hiscotron and administered orally once a day during the breeding period. The control group is orally administered with a 5% gum arabic aqueous solution once a day. Administration of nicotine and the following conditions are performed from 3 weeks after the breeding.
　１２１．４ｍｇ／ｍｌのニコチン水溶液を調整し、ラットの背部皮下に植え込んだ浸透圧ポンプ（Alzet 2001型mini-osmotic pump（１μｌ／時間、７日間用））に注入して、１０mg／ｋｇ／日となるように持続投与を行う。７日目の朝にニコチン受容体拮抗薬であるメカラミン（１ｍｇ／ｍｌ）あるいは生理食塩水液を皮下投与して一方の区画に６０分間入れ、同じ日の夕方に朝とは逆の処置（朝メカラミンを投与したラットには生理食塩水を、生理食塩水を投与したラットにはメカラミンを投与）を行ってもう一方の区画に６０分間入れるという、カウンターバランス法によって条件付けを行う。 A 121.4 mg / ml nicotine aqueous solution was prepared and injected into an osmotic pump (Alzet 2001 mini-osmotic pump (1 μl / hour for 7 days)) implanted subcutaneously in the back of the rat, and 10 mg / kg / day. Administration is continued so that On the morning of the 7th day, nicotine receptor antagonist mecalamine (1 mg / ml) or physiological saline solution was administered subcutaneously and placed in one compartment for 60 minutes, and the opposite of the morning treatment (morning in the morning) Conditioning is performed by the counterbalance method, in which physiological saline is administered to rats administered with mecalamine, and mecalamine is administered to rats administered with physiological saline) and placed in the other compartment for 60 minutes.
　条件付けの翌日（８日目）に薬物、ニコチンおよびメカラミン投与を行わずに、白・黒のコンパートメントに滞在する時間を１５分間測定する。メカラミンの皮下投与によって条件付けされたコンパートメントから退避した時間が長くなるほどニコチン退薬時の嫌悪効果が強く現れていることを示している。 Measure the time to stay in the white / black compartment for 15 minutes without administering drugs, nicotine and mecalamine on the day after conditioning (day 8). It shows that the aversion effect at the time of withdrawal of nicotine appears more strongly as the time withdrawn from the compartment conditioned by subcutaneous administration of mecalamine increases.
　ＥＰＡ－Ｅ投与により、メカラミンの皮下投与によって条件付けされたコンパートメントから退避した時間は用量依存的に短くなり、メカラミン誘発嫌悪効果が抑制されることが予測される。 EPA-E administration is expected to reduce the time withdrawn from the compartment conditioned by subcutaneous administration of mecalamine in a dose-dependent manner and suppress the mecalamine-induced aversive effect.
（臨床モデル試験１）
術後認知障害（幻肢および幻肢痛）への有効性
　交通外傷等で四肢切断術を施行し術後幻肢痛を訴えている患者２０名を、切断部位および幻肢痛分類（大塚哲也：切断に伴う幻肢、幻肢痛、整形外科ＭＯＯＫ４０、 金原出版、１９８５年、ｐ．１５２－１５９）に差異がない様に、対照群およびＥＰＡ－Ｅ群の２群（各群１０人）に分ける。ＥＰＡ－Ｅ群にはエパデールカプセル３００（ＥＰＡ－Ｅ３００ｍｇ含有）を、対照群にはオリーブオイル３００ｍｇ含有ソフトカプセルを毎食直後に２カプセルずつ経口投与する。投与開始３ヶ月後に幻肢および幻肢痛の有無・発生頻度を評価する。 (Clinical model test 1)
Efficacy for postoperative cognitive impairment (phantom limbs and phantom limb pain) Twenty patients with limb amputation due to traffic injury etc. and complaining of postoperative phantom limb pain : Phantom limbs associated with amputation, phantom limb pain, orthopedic surgery MOOK40, Kanehara Publishing, 1985, p.152-159), two groups (10 in each group) of control group and EPA-E group Divide into The EPA-E group is orally administered with Epadale capsule 300 (containing 300 mg of EPA-E), and the control group is administered with 2 capsules of olive oil 300 mg immediately after each meal. Evaluate the presence and frequency of phantom limbs and phantom limb pain 3 months after administration.
　ＥＰＡ－Ｅ群では対照群に比べて幻肢および幻肢痛の消失率は高く、また発生頻度は低いことが予測される。 The EPA-E group is expected to have a higher rate of disappearance of phantom limbs and phantom limb pain and a lower incidence than the control group.
（臨床モデル試験２）
チック障害への有効性
　チック障害と診断された６歳から１２歳の児童１０名にエパデールＳ６００（ＥＰＡ－Ｅ　６００ｍｇ含有）を毎食直後に１包ずつ経口投与する。投与前および３ヵ月後にチックの数、重篤度および頻度をイエール全般チック重傷度尺度(Ｙａｌｅ　Ｇｌｏｂａｌ　Ｔｉｃ　Ｓｅｖｅｒｉｔｙ　Ｓｃａｌｅ（以下、「ＹＧＴＳＳ」という。）　Ｌｅｃｋｍａｎ　ＪＦ．、ジャーナル　オブ　アメリカン　アカデミー　オブ　チャイルド　アンド　アドレセント　サイキアトリー（Ｊｏｕｒｎａｌ　ｏｆ　Ａｍｅｒｉｃａｎ　Ａｃａｄｅｍｙ　ｏｆ　Ｃｈｉｌｄ　ａｎｄ　Ａｄｌｅｓｃｅｎｔ　Ｐｓｙｃｈｉａｔｒｙ）１９８９年、第２８巻、ｐ．５６６－６７３)を用いて評価する。 (Clinical model test 2)
Efficacy for Tic Disorders Epadale S600 (containing 600 mg of EPA-E) is orally administered to 10 children aged 6 to 12 years old diagnosed with tic disorders immediately after each meal. Yale Global Tic Severity Scale (YGTSS) Lekman JF., Journal of American Academy of Child and Address Psychology, before and 3 months after administration, measured in terms of Yale Global Tic Severity Scale (YGTSS) Evaluation is performed using Journal of American Academy of Children and Address Psychiatry (1989, Vol. 28, pp. 566-673).
　ＥＰＡ－Ｅ投与によりＹＧＴＳＳスコアは明らかに低下することが予測される。 It is predicted that the YGTSS score will be clearly reduced by administration of EPA-E.
（動物モデル試験２）
鼻咽頭部機械刺激しゃっくり様反射モデルネコにおける有効性
　体重３～５．５ｋｇのネコを体重に偏りがない様に対照群およびＥＰＡ－Ｅ群の２群（各群３匹）を設定する。飼育期間中、ＥＰＡ－Ｅ群にはＥＰＡ－Ｅ１０００ｍｇ／ｋｇを５％アラビアゴム水溶液にヒスコトロンを用いて懸濁して１日１回経口投与する。対照群には５％アラビアゴム水溶液を１日１回経口投与する。４週間飼育後、ペントバルビタール麻酔して直径５ｍｍの気管チューブを喉頭下に挿入する。このチューブを介して綿棒で口蓋垂後ろの鼻咽頭部を機械的に刺激することでしゃっくり様反応を誘発する。しゃっくり様反応は喉頭の後部輪状軟骨および横隔膜に設置した電極による電気的筋収縮図で確認する。しゃっくり様反応時の肋膜内圧を、食道の２／３の位置に設置したラテックスバルーンを介して圧トランスデューサーで測定する。１０回の刺激によるしゃっくり様反射時の肋膜内圧を合計してしゃっくり様反射の強度とする（Ｏｓｈｉｍａ　Ｔ．、アネセシア　アンド　アナルゲシア（Ａｎｅｓｔｈｅｓｉａ　ａｎｄ 　Ａｎａｌｇｅｓｉａ）、２００４年、第９８巻、３４６－３５２）。 (Animal model test 2)
Efficacy in nasopharyngeal mechanical stimulation hiccup-like reflex model cats Two groups (three in each group) of the control group and the EPA-E group are set so that cats with a body weight of 3 to 5.5 kg are not biased. During the breeding period, EPA-E 1000 mg / kg is suspended in a 5% gum arabic aqueous solution using hiscotron and administered orally once a day. The control group is orally administered with a 5% gum arabic aqueous solution once a day. After breeding for 4 weeks, anesthesia with pentobarbital is performed and a tracheal tube having a diameter of 5 mm is inserted under the larynx. A hiccup-like reaction is induced by mechanically stimulating the nasopharyngeal head behind the uvula with a cotton swab through this tube. Hiccup-like reaction is confirmed by electrical muscle contraction with electrodes placed on the posterior cricoid cartilage and diaphragm of the larynx. The intracapsular pressure during the hiccup-like reaction is measured with a pressure transducer via a latex balloon placed at 2/3 of the esophagus. The intracapsular pressure at the time of hiccup-like reflexes by 10 stimuli is summed to give the intensity of hiccup-like reflexes (Oshima T., Anthesia and Analgesia, 2004, Vol. 98, 346-352).
　ＥＰＡ－Ｅ投与群は対照群に比べ、しゃっくり様反射強度が低下することが予測される。 It is predicted that the hiccup-like reflex intensity will be lower in the EPA-E administration group than in the control group.
　常法に従い、ＥＰＡ－ＥおよびＣＢ受容体リガンドとの配合剤を製造する。 According to a conventional method, a compounding agent with EPA-E and a CB receptor ligand is produced.
（製剤実施例１）
ＥＰＡ－Ｅとリモナバンとの配合乳剤
　ＥＰＡ－Ｅ１８ｇ、リモナバン０．２ｇにリン脂質３．６ｇ、オレイン酸ナトリウム０．１５ｇおよびホスファチジン酸０．１５ｇを加えて４０～７５℃で加熱溶解させる。これに精製水２００ｍｌを加え、次いでグリセリン７．５ｇを加え、２０～４０℃の精製水で全量を３００ｍｌとし、ホモミキサーを用いて予備乳化する。これをマントンゴーリン型ホモジナイザーを用いて、１段目１２０ｋｇ／ｃｍ２、合計圧５００ｋｇ／ｃｍ２の加圧下で１０回通過させて乳化する。これにより、平均粒子径０．２μｍ以下の乳化液を得る。この乳化液を３０ｍｌずつアンプルに分注し、１アンプルあたりＥＰＡ－Ｅとして１．８ｇ、リモナバンとして２０ｍｇを含有する乳剤を得る。 (Formulation Example 1)
Blended emulsion of EPA-E and rimonabant Add phospholipid 3.6g, sodium oleate 0.15g and phosphatidic acid 0.15g to EPA-E 18g and rimonabant 0.2g and heat dissolve at 40-75 ° C. To this is added 200 ml of purified water, 7.5 g of glycerin is added, and the total volume is made up to 300 ml with purified water at 20 to 40 ° C., and pre-emulsified using a homomixer. This is emulsified by passing 10 times under a pressure of 120 kg / cm 2 in the first stage and a total pressure of 500 kg / cm 2 using a Manton Gorin type homogenizer. Thereby, an emulsion having an average particle size of 0.2 μm or less is obtained. 30 ml of this emulsion is dispensed into ampoules to obtain an emulsion containing 1.8 g of EPA-E and 20 mg of rimonabant per ampoule.
（製剤実施例２）
ω３脂肪酸とドロナビノールとの配合乳剤
　ω３脂肪酸（Ｌｏｖａｚａ（登録商標）（Ｋ８５ＥＥ）：ω３脂肪酸約９０％、ＥＰＡ－Ｅ＋ＤＨＡ－Ｅ約８４％含有、ＥＰＡ－Ｅ：ＤＨＡ－Ｅ＝約１．２：１）１００ｇ、ドロナビノール１００ｍｇ、濃グリセリン２５ｇ、卵黄リン脂質１２ｇを秤量し、注射用蒸留水を加えて１Ｌとし、ホモミキサーで分散させる。これをマントンゴーリン型ホモジナイザーを用いて、１段目１００ｋｇ／ｃｍ２、２段目５０ｋｇ／ｃｍ２の加圧下で通過させて乳化する。これにより、平均粒子径１μｍ以下の乳化液を得る。この乳化液を４０ｍｌずつガラスボトルに分注し、１ボトルあたりＥＰＡ－Ｅ＋ＤＨＡ－Ｅとして約３．３６ｇ、ドロナビノールとして４ｍｇを含有する乳剤を得る。 (Formulation Example 2)
Emulsion of ω3 fatty acid and dronabinol ω3 fatty acid (Lovaza® (K85EE): about 90% ω3 fatty acid, about 84% EPA-E + DHA-E, EPA-E: DHA-E = about 1.2: 1 ) Weigh 100 g, dronabinol 100 mg, concentrated glycerin 25 g, and egg yolk phospholipid 12 g, add 1 L of distilled water for injection, and disperse with a homomixer. Which using a Manton Gaulin homogenizer, emulsification is passed under pressure of the first stage 100 kg / cm 2, 2-stage 50 kg / cm 2. Thereby, an emulsion having an average particle diameter of 1 μm or less is obtained. 40 ml of this emulsion is dispensed into glass bottles to obtain an emulsion containing about 3.36 g as EPA-E + DHA-E and 4 mg as dronabinol per bottle.
　本発明の、ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つを有効成分として含有するＣＢ受容体関連疾患の予防／改善または治療剤は、安全性が高く、有効性に優れ、かつ、使いやすく、ＣＢ受容体、特にＣＢ１受容体の過剰亢進および過剰抑制により生じる症候群、障害または疾患に対する予防／改善または治療効果を示すことが期待される。特に、術後認知低下、ニコチン依存症、難治性のしゃっくり、チック障害または嗜好（味覚）の異常を呈する患者で予防／改善または治療効果を示すことが期待される。 The prophylactic / ameliorating or treating agent for CB receptor-related diseases of the present invention containing at least one selected from the group consisting of ω3PUFAs and pharmaceutically acceptable salts and esters thereof as an active ingredient is highly safe, It is expected to show a preventive / improving or therapeutic effect on a syndrome, disorder or disease caused by excessive enhancement and excessive suppression of the CB receptor, particularly the CB1 receptor. In particular, it is expected that patients who exhibit postoperative cognitive decline, nicotine addiction, refractory hiccups, tic disorders or abnormal taste (taste) will have a preventive / improving or therapeutic effect.
　本発明の、ω３ＰＵＦＡｓならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つを有効成分として含有するＣＢ受容体リガンドによる副作用の予防または軽減剤は、安全性が高く、有効性に優れ、かつ、使いやすく、ＣＢ受容体リガンド、特にＣＢ１受容体アンタゴニストまたはインバースアゴニスト投与により生じる副作用の予防または軽減効果を示すことが期待される。特に、悪心、抑うつ症状に伴う気分変動、不安、不動性めまい、自殺企図、摂食障害、記憶障害または薬物依存性に対して予防または軽減効果を示すことが期待される。 The preventive or alleviating side effect of a CB receptor ligand containing at least one selected from the group consisting of ω3PUFAs and pharmaceutically acceptable salts and esters thereof as an active ingredient of the present invention is highly safe and effective. It is expected to exhibit an effect of preventing or reducing side effects caused by administration of a CB receptor ligand, particularly a CB1 receptor antagonist or inverse agonist. In particular, it is expected to show a preventive or alleviating effect on nausea, mood swings associated with depressive symptoms, anxiety, immobility dizziness, suicide attempts, eating disorders, memory disorders or drug dependence.
　また、本発明によりＣＢ受容体リガンドの副作用を軽減することができ、これらの副作用のためにＣＢ受容体リガンド投与を行えなかった患者や中断せざるを得なかった患者において治療を継続することができる。 In addition, the side effects of CB receptor ligands can be reduced by the present invention, and treatment can be continued in patients who have failed to administer CB receptor ligands due to these side effects or who have had to be interrupted. it can.
　また、ω３ＰＵＦＡｓとＣＢ受容体リガンドとの配合剤やキット剤とすることで患者の服薬の負担を軽減し、服薬コンプライアンスを高めることで更に予防／改善または治療効果を高めることができる。 In addition, it is possible to reduce the burden of patient medication by using a combination drug or kit of ω3 PUFAs and a CB receptor ligand, and to further increase the prevention / improvement or treatment effect by increasing medication compliance.

Claims (6)

  1. 　ω３多価不飽和脂肪酸ならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つを有効成分として含有するカンナビノイド１受容体関連疾患の予防／改善または治療剤。 A preventive / ameliorating or treating agent for cannabinoid 1 receptor-related diseases comprising as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids and pharmaceutically acceptable salts and esters thereof.
  2. 　カンナビノイド１受容体関連疾患が術後認知低下、ニコチン依存症、難治性のしゃっくり、チック障害および嗜好（味覚）の異常からなる群から選ばれる少なくとも１つである請求項１記載の予防／改善または治療剤。 The prevention / amelioration according to claim 1, wherein the cannabinoid 1 receptor-related disease is at least one selected from the group consisting of postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorders, and abnormal taste (taste). Therapeutic agent.
  3. 　ω３多価不飽和脂肪酸ならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つを有効成分として含有するカンナビノイド１受容体リガンドによる副作用の予防または軽減剤。 An agent for preventing or reducing side effects caused by a cannabinoid 1 receptor ligand containing as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids and pharmaceutically acceptable salts and esters thereof.
  4. 　カンナビノイド１受容体リガンドがドリナバン、リモナバン、スリナバン、オテナバン、イビピナバン、タラナバン、およびＡＺＤ－２２０７からなる群から選ばれる少なくとも１つである請求項３記載の予防または軽減剤。 The prophylactic or alleviating agent according to claim 3, wherein the cannabinoid 1 receptor ligand is at least one selected from the group consisting of drinaban, rimonabant, sulinaban, otenaban, ibipinabane, taranaban, and AZD-2207.
  5. 　カンナビノイド１受容体リガンドによる副作用が悪心、抑うつ症状に伴う気分変動、不安、不動性めまい、自殺企図、摂食障害および薬物依存性からなる群から選ばれる少なくとも１つである請求項３または４記載の予防または軽減剤。 5. The side effect of the cannabinoid 1 receptor ligand is at least one selected from the group consisting of nausea, mood swings associated with depressive symptoms, anxiety, immobility dizziness, suicide attempts, eating disorders, and drug dependence. Preventive or alleviating agent.
  6. 　ω３多価不飽和脂肪酸ならびにその製薬学上許容しうる塩およびエステルからなる群から選ばれる少なくとも１つを投与する、カンナビノイド１受容体関連疾患を予防／改善または治療する方法。
          A method for preventing / ameliorating or treating a cannabinoid 1 receptor-related disease, comprising administering at least one selected from the group consisting of ω3 polyunsaturated fatty acids and pharmaceutically acceptable salts and esters thereof.
PCT/JP2009/064292 2008-08-13 2009-08-13 Prophylactic/ameliorating or therapeutic agent for cannabinoid receptor-related disease WO2010018856A1 (en)

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