JPWO2010018856A1 - Prevention / amelioration or treatment of cannabinoid receptor related diseases - Google Patents

Abstract

The present invention relates to a preventive / ameliorating or treating agent for CB receptor-related diseases, which contains at least one selected from the group consisting of ω3PUFAs and pharmaceutically acceptable salts and esters thereof as an active ingredient, and a method of using the same. The present invention provides a safe and highly effective preventive / ameliorating or treating agent for CB receptor-related diseases and a method for using the same.

Description

  The present invention relates to an agent for preventing / ameliorating or treating a disease involving a cannabinoid receptor, 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.

  Furthermore, the present invention relates to an agent for preventing or reducing 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 Δ ⁹ -tetrahydrocannabinol (hereinafter referred to as “Δ ⁹ -THC”), which is a major 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).

  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.

  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.

  The CB1 receptor is expressed in most nervous system tissues and is involved in the 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.

Based on 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 by CB1 receptors in the central nervous system Has been revealed. On the other hand, among the effects of Δ ⁹ -THC, regarding the effects such as a decrease in pain sensation, immunosuppression, and anti-inflammation, it is considered that the action is via a cell involved in an immune response or inflammatory reaction expressing the CB2 receptor. It has been.

  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).

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.

  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).

  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 severe mental illness are given special precautions such as not recommending treatment with Accompria® And which (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).

By the way, Δ ⁹ -THC does not exist in the animal body. Nevertheless, the presence of the CB receptor suggested the presence of an endogenous CB receptor ligand.

  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.

  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 exerts an agonistic action on CB1 and 2 receptors. In vitro studies have reported that icosatrienoic acid, icosapentoic acid (hereinafter referred to as “EPA”) or docosahexaenoic acid (hereinafter referred to as “DHA”) is located at the 2-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.

  Among PUFAs, a PUFA having the first double bond at the third position from the methyl group side is referred to as ω3 PUFAs, and α-linolenic acid, EPA, DHA and the like are exemplified.

  As an ω3 PUFAs preparation, a soft capsule containing 96.5% by mass or more of 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 capsule containing approximately 37.5% by mass of active ingredient (trade name: Lovaza (registered trademark), GlaxoSmithKline, London, UK) is a treatment for hypertriglyceridemia It is commercially available as an agent in the United States.

  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.

Pharmacological Reviews, 1986, 38, p. 151-178 Pharmacological Reviews, 1986, 38, p. 1-20 Molecular Pharmacology, 1988, 34, p. 605-613 Nature, 1990, 346, p. 561-564 Nature, 1993, 365, p. 61-65 Clinical Pharmacokinetics, 2003, Vol. 42, p. 327-360 Acomplia 20mg film-coated tablets prescription information, Sanofi-Aventis, November 28, 2007 Sanofi-Aventis, June 13, 2007, FDA Advisory Committee did not recommend approval of rimonabant (Zimulti®) for use in obese and overweight patients with associated risks factors Science, 1992, 258, p. 1946-1949 Biochemical and Biophysical Research Communication, 1995, Vol. 215, p. 89-97 Biochemical Pharmacology, 1995, Vol. 50, p. 83-90 Journal of Biological Chemistry, 1999, 274, p. 2794-2801 Journal of Biological Chemistry, 2000, 275, p. 605-612 Epadale S package insert (8th edition), Mochida Pharmaceutical, January 2007

  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.

  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.

  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.

  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) 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) 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 / 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 ω3 PUFAs 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) 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) CB1 receptor agonist is anandamide, 2-AG, dronabinol, nabiximols, 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 preventive or alleviating agent according to the above (11), 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 the above (11), 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) The above (3), 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 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 preventive or alleviating agent according to any one of (8) to (15) above, which contains EPA-E as the ω3PUFAs and pharmaceutically acceptable salts and esters thereof.

(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) 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.

  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.

  Specifically, it is expected to exhibit 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.

  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.

  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.

  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.

The present invention is described in detail below.
When EPA-E is administered orally, it exhibits CB1 receptor neutral antagonist-like action, resulting in excessive CB1 receptor such as postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorders 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).

  Inhibition of eating and body weight gain are thought to be mainly related to central CB1 receptor inhibition (Non-patent Documents 2 and 7), and neutral antagonistic action of EPA glycerides 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).

  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).

  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 hyperrepression through CB1 receptor neutral antagonist-like action, thereby inhibiting tic disorder, Tourette's 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 relates to 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.

  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. .

  In the present invention, unless otherwise specified, “ω3 PUFAs” is used to include not only ω3 PUFAs but also ω3 PUFAs derivatives such as pharmaceutically acceptable salts or esters thereof.

  Here, ω3PUFAs is used in the ordinary meaning 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 at the third position counted from the methyl group side. It refers to PUFAs that have bonds.

  Preferred ω3 PUFAs are exemplified by EPA, DHA and α-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.

  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

  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.

  The 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 these. 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.

  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.

  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 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.

  That is, the purity of ω3PUFAs in all fatty acids is preferably high, the EPA + DHA purity which is ω3PUFAs 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.

  EPA-E and / or DHA-E used in the preventive / ameliorating or therapeutic agent or the 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.

  For this EPA-E, for example, Epadale (Mochida Pharmaceutical) available in Japan can be used.

  Moreover, the mixture of EPA-E and DHA-E can obtain and use Lovaza (trademark) (GlaxoSmithKline) marketed in the United States, for example.

  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.

  For example, Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International plc, Yorkshire, UK), as well as EPAX6000FA, EPAX5000TG, EPAX4570T, EAX2050T , K85EE and K80EE (Pronova BioPharma ASA, Lysaker, Norway) and other products containing various ω3 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 It is a receptor capable of recognizing a penetrating type, a G protein-coupled type, etc., and is used to mean a receptor to which Δ ⁹ -THC or an analog thereof binds.

That is, the CB receptor referred to in the present invention is similar to the CB1 receptor or CB2 receptor, includes a receptor to which Δ ⁹ -THC or a similar compound binds, and is a CB1 receptor or CB2 which is a known CB receptor. 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.

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, analogs of Δ ⁹ -THC referred to in the present invention include natural cannabinoids exemplified by cannabinol, cannabidiol, cannabigerol and cannabicycrol, and anandamide , 2-AG, 2-arachidonyl glyceryl ether, virodhamine, palmitoyl ethanolamide, N-archydonyl-dopamin, etc. Cannabinoids (also referred to as “endogenous cannabinoids”), as well as 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 52122-2, 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 receptor-related disease” is used to include biological responses mediated by CB receptors and related syndromes, disorders and diseases.

  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 .

  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.

  Syndromes, disorders and diseases associated with diabetes include glucose dysregulation, insulin resistance, glucose intolerance, 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.

  Syndromes, disorders and diseases associated with glaucoma include increased intraocular pressure, impaired ocular circulation, impaired optic nerve, rainbow vision, decreased visual acuity, ocular 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.), cocaine, 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, disorders and diseases associated with muscle spasms include multiple sclerosis, cerebral palsy, tremors, and infantile thermal spasms.

  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.

  Syndromes, disorders and diseases related to immunity and inflammation include allergies, arthritis, rheumatoid arthritis, dermatitis, autoimmune diseases, immunodeficiencies, 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.

  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. .

  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.

  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 response. The ligands are classified into agonists and antagonists or inverse agonists depending on the reaction expression pattern, and these are included.

  As both CB1 and CB2 receptor agonists, endocannabinoids such as anandamide and 2-AG, 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 (Astra Zeneca), KN-38-7271 (Bayer AG), Org-28611, Org-26828, and SCH-900111. (Organon Bioscience Organon BioScience NV, Oss, The Netherlands) and SAB-378 (Novartis Pharma AG, Basel, Switzerland). Examples of agonists specific for the CB2 receptor include GW-842166X (GlaxoSmithKline) and S-777469 (Yoshio Shionogi).

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).

  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.

  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.

  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.

  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. Of these, the most frequently reported adverse reactions 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.

  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. 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.

  The method for preventing or reducing the side effects caused by the CB receptor ligand is not particularly limited, and a step of administering ω3PUFAs may be included. 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.

  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.

  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.

  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” refers to the action / effect of either one of the drugs 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. .

  In the case of administration with these time differences, for example, there is 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.

  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.

  Further, for example, there is a method in which both drugs are administered and dosing of one drug is stopped at the time 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.

  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.

  In the case of oral administration, for example, 0.1 to 10 g / day, preferably 0.3 to 6 g / day, more preferably 0.6 to 4 g / day, more preferably EPA-E and / or DHA-E. 0.9 to 2.7 g / day is administered in 1 to 3 divided doses, but the total amount may be divided into 1 or several doses as needed.

  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.

  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. In addition, for example, an embodiment in which it is administered every other day or an embodiment in which it is administered for 2 to 3 days a week is possible, and in some cases, a drug holiday of about 1 day 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), 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). Even if administered There. 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.

  Since ω3 PUFAs is highly unsaturated, it is desirable to contain an effective amount of an antioxidant. For example, at least one selected from oil-soluble antioxidants such as butyrated 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.

  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.

  For patients who can be taken orally, simple oral preparations are desirable, and oral administration in capsules, such as soft capsules and 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.

  Further, oral administration as an oral liquid preparation such as an emulsion is preferable because absorption of ω3 PUFAs and / or CB receptor ligands is promoted, administration can be performed without any restriction on the dose time, 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.

  As an emulsifier, any emulsifier can be used as long as it can be used in a pharmaceutical preparation. For example, egg yolk lecithin, soybean lecithin, egg yolk phospholipid, soybean phospholipid, purified lanolin, glycerin, propylene glycol, polysorbate ester, monoglyceride, diglyceride, organic acid ester of monoglyceride, 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.

  Moreover, an emulsification adjuvant, a stabilizer, surfactant, and / or an antioxidant can also 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, brechated 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.

  The content of EPA in the emulsion is preferably 1 to 60% by mass, more preferably 3 to 40% by mass, and still more 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. For example, a pressure injection type homogenizer is preferably used for emulsification by passing it 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.

  EXAMPLES Next, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.

(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, the EPA-E group (EPA-E administration), the rimonabant group (rimonabant administration) and the 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 rearing period, EPA-E group was 1000 mg / kg EPA-E, rimonabant group was 10 mg / kg rimonabant and the combination group was 1000 mg / kg EPA-E and 10 mg / kg rimonabant 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 intake 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.

The results are shown in Table 1.

With respect to the control group, ^# : p <0.05, ^## : p <0.01
For rimonabant group, ^* : p <0.05, ^** : p <0.01

  The control group and EPA-E group had similar food intake and weight gain, but the rimonabant group had a clear decrease. 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.

  This result is a surprising effect that cannot be predicted from the conventional knowledge that glycerol binding ω3PUFAs such as 2-AG, 2-EG, 2-DG, etc., at the 2-position has CB receptor agonist activity in an in vitro test. It is an effect.

  This is because, when EPA-E is administered orally, it is known that it is mainly deethylated and absorbed 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).

  However, EPA-E did not affect 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.

  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.

  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.

  The prevention / improvement or therapeutic effect of a CB1 receptor-related disease 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.

(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.

  Seven-week-old male SD rats are fed at normal temperature (F-1, Funabashi Farm) at 23 ° C. with a 12-hour light-dark cycle. 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, the EPA-E group is orally administered once a day after suspending EPA-E in 5% gum arabic aqueous solution using hiscotron. 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 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.

  On the day following conditioning (day 8), the time spent in the white / black compartment is measured for 15 minutes without administration of drugs, nicotine and mecalamine. 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.

  With EPA-E administration, the time withdrawn from the compartment conditioned by the subcutaneous administration of mecalamine is predicted to be dose-dependently shortened and the mecalamine-induced aversive effect is expected to be suppressed.

(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 Epadale capsule 300 (containing 300 mg of EPA-E) is orally administered to the EPA-E group, and 2 capsules of olive oil 300 mg containing soft capsules are orally administered to the control group immediately after each meal. Evaluate the presence and frequency of phantom limbs and phantom limb pain 3 months after administration.

  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.

(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”) Leckman JF., Journal of American Academy of Child and Addressed Sci. Evaluation is carried out using Journal of American Academy of Children and Address Psychiatry (1989, Vol. 28, p. 656-673).

  It is expected that the YGTSS score is clearly reduced by EPA-E administration.

(Animal model test 2)
Efficacy in nasopharyngeal mechanical stimulation hiccup-like reflex model cats 2 groups (3 animals each) of the control group and the EPA-E group are set so that cats weighing 3 to 5.5 kg are not biased. During the breeding period, 1000 mg / kg of EPA-E is suspended in a 5% aqueous gum arabic 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 strength of hiccup-like reflexes (Oshima T., Anthesia and Analgesia, 2004, Vol. 98, 346-352).

  The EPA-E-administered group is expected to have a lower hiccup-like reflection intensity than the control group.

  According to a conventional method, a combination drug with EPA-E and CB receptor ligand is produced.

(Formulation Example 1)
Emulsion emulsion of EPA-E and rimonabant To 18 g of EPA-E and 0.2 g of rimonabant, 3.6 g of phospholipid, 0.15 g of sodium oleate and 0.15 g of phosphatidic acid are added and dissolved by heating at 40 to 75 ° C. To this is added 200 ml of purified water, 7.5 g of glycerin is added, and the total amount is made up to 300 ml with purified water of 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 emulsified liquid is dispensed into ampoules to obtain an emulsion containing 1.8 g of EPA-E and 20 mg of rimonabant per ampoule.

(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 emulsified liquid 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 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.

  The agent for preventing or reducing side effects caused by a CB receptor ligand containing at least one selected from the group consisting of ω3 PUFAs and pharmaceutically acceptable salts and esters thereof as an active ingredient 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 have 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.

  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.

  In addition, the combination of ω3PUFAs and a CB receptor ligand or a kit can reduce the burden of patient medication, and the compliance / enhancement can further enhance the prevention / improvement or treatment effect.

Claims (6)

  A prophylactic / ameliorating or therapeutic 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.   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.   An agent for preventing or alleviating side effects caused by a cannabinoid 1 receptor ligand 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.   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. 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. 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.