JP2011219405A - Relapse inhibitor for latent infectious disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition of new type having high safety enough to withstand its long-term administration for the purpose of inhibiting the relapse of an infectious disease under a latent state, and to provide a method for using the same.SOLUTION: The pharmaceutical composition for inhibiting the relapse of a latent infectious disease is provided, being characterized by including, as active ingredient(s), at least one compound selected from the group consisting of ω3-polyunsaturated fatty acid, pharmaceutically acceptable salt thereof and ester thereof.

Description

  The present invention relates to a pharmaceutical composition for suppressing recurrence of latent infection and / or a method for suppressing recurrence of latent infection.

  Recently, human beings are suffering from infections caused by pathogens such as viruses, bacteria, fungi, and / or protozoa, and infections caused by pathogens such as prions. In the past, infectious disease treatments such as antisera, vaccines, globulin preparations, antibiotics, interferons, antivirals, and antifungals that act directly on and kill pathogens have overcome these infections. It was discovered and developed with the aim of contributing to the maintenance and promotion of human health.

  In general, infectious diseases often go through an acute phase early in the infection. In the acute phase, infection is recognized by the appearance of some symptoms such as fever and / or rash. Based on the symptom, infectious pathogens are identified and therapeutic agents are selected. Explosive growth of pathogens in the acute phase is suppressed by the administration of therapeutic agents, and many pathogens are driven out in conjunction with the host immune function. However, some pathogens may acquire drug resistance and / or bypass immune functions and lurk in the host.

  For example, post-adult HBV (hepatitis B virus) infection is clinically cured via transient acute hepatitis. However, very little HBV may pass through the immune system and remain hidden in the liver. During such latent infection, HBV does not grow, and antiviral drugs such as lamivudine that prevent HBV growth by inhibiting reverse transcriptase are ineffective. And when the HBs antibody concentration falls by rituximab administration etc., HBV may reactivate and exacerbate hepatitis and may develop severe hepatitis or fulminant hepatitis. Lamivudine has few serious side effects and a high antiviral effect, but the appearance of a resistant virus (YMDD mutant virus) associated with long-term administration is frequently observed.

  Also, for example, in HSV (herpes simplex virus) infection, acute symptoms such as skin / mucosal pain, blisters, and / or erosion appear, but these acute symptoms usually heal in a few days. However, HSV passes through the immune system in the ganglion where nerve cells supplying nerve fibers to the infected site gather, and continues to hide. And HSV may be reactivated by triggering fever, mental stress, and / or decreased immune function. In addition, chronic infection to nerves cannot be prevented even if treated with antiviral drugs at the time of the first infection.

  As described above, it is not easy to actually confirm the presence of a pathogen such as a virus hidden in a living tissue by going through the immune system. In addition, as long as no symptoms are observed, it is generally difficult to treat by conventional administration of infectious diseases such as antiviral drugs. The main reasons include the problem of side effects in long-term administration and the appearance of drug-resistant pathogens.

  Polyunsaturated fatty acids (PUFAs) are defined as fatty acids having a plurality of carbon-carbon double bonds in the molecule, and are classified into ω3, ω6, etc., depending on the position of the double bond. Examples of ω3 polyunsaturated fatty acids (ω3PUFAs) include α-linolenic acid, icosapentanoic acid (EPA), docosahexaenoic acid (DHA), and the like.

  Attempts have been made to increase infection resistance by ingesting a diet rich in ω3 polyunsaturated fatty acids (Patent Document 1). This is based on the finding that supplementation with ω3 polyunsaturated fatty acids increased the survival rate against endotoxin shock associated with infection.

  In addition, EPA, which was expected to have an antiviral effect based on the O-ring test, was administered to patients with refractory pain due to HSV infection and combined with acupuncture or electrotherapy, there was a report that pain was relieved (non-patented) Reference 1).

  In addition, when cells were infected with HSV in the presence of EPA or DHA in a test tube, there was a finding that an infection inhibitory effect was observed, but no effect was observed with EPA methyl ester (Patent Document 2).

Japanese Examined Patent Publication No. 7-59508 US Pat. No. 4,513,008

Omura Y, Application & electro-therapeutics research, 1990, Vol. 15, No. 1, p51-69

  In order to suppress the recurrence of an infectious disease that is in a latent state, a new type of pharmaceutical having high safety that can withstand long-term administration is required.

  The ω3 polyunsaturated fatty acid has high safety suitable for long-term administration. However, it is suggested that ω3 polyunsaturated fatty acids may have effects such as suppression of systemic inflammatory symptoms in the acute phase of infection, alleviation of pain in the overt phase of infection, and suppression of infection However, it has not been known whether it has an action of suppressing recurrence of an infectious disease in a latent state.

  The present inventor continuously administered ω3 PUFAs, particularly EPA ethyl ester, to a patient who has a history of having been treated (treated) during the actual period of infection but has a possibility of latent infection. It was found that the recurrence of infectious diseases was suppressed when administered, and the present invention was completed. In addition, the present inventors have found that ω3 PUFAs have a therapeutic effect on postherpetic neuralgia, which is a specific example of symptoms due to recurrence of latent infection.

That is, the present invention provides the following pharmaceutical compositions.
(1) To suppress recurrence of latent infections, comprising as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof Pharmaceutical composition.
(2) For suppressing post-herpetic neuralgia, comprising as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof Pharmaceutical composition.
(3) A pharmaceutical composition for treating postherpetic neuralgia, comprising as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof. .
(4) The above (1), characterized in that it contains at least one selected from the group consisting of icosapentic acid, docosahexaenoic acid, α-linolenic acid, pharmaceutically acceptable salts and esters thereof as the active ingredient. Thru | or the pharmaceutical composition in any one of (3).
(5) The pharmaceutical composition according to any one of (1) to (4) above, which contains ethyl icosapentate as the active ingredient.
(6) The pharmaceutical composition according to any one of the above (1) to (5), which is applied to a patient having a history of receiving (treating) an infectious disease treatment drug during the actual infection stage object.

The present invention also provides the following method.
(1) A method for suppressing recurrence of latent infection, comprising administering a pharmaceutical composition containing as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof .
(2) A method for suppressing the onset of neuralgia after herpes zoster, comprising administering a pharmaceutical composition containing as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof.
(3) A method for treating postherpetic neuralgia, comprising administering a pharmaceutical composition comprising as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof.
(4) The above (1), wherein a pharmaceutical composition comprising at least one selected from the group consisting of icosapentic acid, docosahexaenoic acid, α-linolenic acid, pharmaceutically acceptable salts and esters thereof as the active ingredient is administered. ) To (3).
(5) The method according to any one of (1) to (3) above, wherein a pharmaceutical composition containing icosapentic acid ethyl ester as the active ingredient is administered.
(6) The method according to any one of (1) to (5) above, which is applied to a patient having a history of receiving (treated) an infectious disease treatment drug during the actual infection stage.

  Since the pharmaceutical composition of the present invention is highly safe, it can be administered for a long period in preparation for reactivation of a latent infection. By continuously administering the pharmaceutical composition of the present invention, it is possible to maintain the therapeutic effect obtained by conventional therapeutic agents for infectious diseases over a long period of time. In addition, even when infection becomes apparent, continuous administration of the pharmaceutical composition of the present invention suppresses the progression of the disease state and reduces the number of treatments with conventional infectious disease therapeutic agents such as antiviral agents. be able to. These particularly reduce the burden and risk of patients who are restricted in the period and frequency of administration of conventional anti-infective drugs, such as elderly people. Furthermore, since the pharmaceutical composition of the present invention has a different mechanism of action from conventional therapeutic agents for infectious diseases that act directly on pathogens, long-term administration is possible without the emergence of new pathogens with resistance.

The present invention is described in detail below.
1. Omega 3 polyunsaturated fatty acids, their pharmaceutically acceptable salts and esters Polyunsaturated fatty acids (PUFAs) are defined as fatty acids having multiple carbon-carbon double bonds in the molecule. PUFAs are classified into ω3, ω6, etc., depending on the position of the double bond in the molecule. Examples of ω3 polyunsaturated fatty acids (ω3 PUFAs) include α-linolenic acid, EPA, DHA and the like.

  Unless otherwise specified, the term “PUFAs” used in the present invention includes not only polyunsaturated fatty acids but also pharmaceutically acceptable salts, esters, amides, phospholipids, and glycerides thereof. Used to include fatty acid derivatives.

  The ω3 PUFAs used in the present invention may be a synthetic product, a semi-synthetic product, or a natural product. Furthermore, the form of the natural oil containing these may be sufficient. Here, the natural product means one extracted from a natural oil containing ω3 PUFAs by a known method, one obtained by crude purification, or one obtained by further highly purifying them. Semi-synthetic products include polyunsaturated fatty acids produced by microorganisms and the like, and also those obtained by subjecting the polyunsaturated fatty acids or natural polyunsaturated fatty acids 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.

  In the present invention, specific examples of ω3PUFAs include EPA, DHA, and α-linolenic acid, and pharmaceutically acceptable salts and esters thereof. Pharmaceutically acceptable salts and esters include inorganic bases such as sodium salts and potassium salts, organic bases such as benzylamine salts and diethylamine salts, salts with basic amino acids such as arginine salts and lysine salts, ethyl esters and the like. Illustrative are alkyl esters and esters such as mono-, di-, tri-glycerides. Ethyl ester is preferable, and EPA ethyl ester (EPA-E) and / or DHA ethyl ester (DHA-E) is particularly preferable.

  The purity of the ω3 PUFAs of the present invention is not particularly limited. The content of ω3PUFAs in the total fatty acid contained in the pharmaceutical composition of the present invention is preferably 25% by mass or more, more preferably 50% by mass or more, further preferably 70% by mass or more, more preferably 85% by mass or more, Preferably, the present agent 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 the composition of EPA-E / DHA-E The ratio is preferably 0.8 or more, more preferably 1.0 or more, and still more preferably 1.2 or more. EPA-E + DHA-E has a high purity, for example, the EPA-E + DHA-E content ratio in all fatty acids and derivatives thereof is preferably 40% by mass or more, more preferably 55% by mass or more, and 84% by mass The above are more preferable, and those of 96.5% by mass or more are more preferable. The content of other long-chain saturated fatty acids is preferably low, and even long-chain unsaturated fatty acids are desired to have a low ω6 type, particularly arachidonic acid content, preferably less than 2% by mass, more preferably less than 1% by mass.

  EPA-E and / or DHA-E used in the pharmaceutical composition of the present invention has less unfavorable impurities for cardiovascular events such as saturated fatty acids and arachidonic acid compared to fish oil or fish oil concentrate, and is overnutrition. It is possible to exert its effect without any problem of 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.

  This EPA-E is a high-purity EPA-E (96.5% by mass or more) -containing soft capsule (trade name Epadale: available as a therapeutic agent for obstructive arteriosclerosis (ASO) and hyperlipidemia in Japan. Mochida Pharmaceutical Co., Ltd.) can be used. Further, a mixture of EPA-E and DHA-E is, for example, about 46.5 Lovaza (Lovaza: GlaxoSmithKline: EPA-E) marketed as a therapeutic agent for hypertriglyceridemia (hyperTG) in the United States. %, Soft capsules containing about 37.5% by mass of DHA-E) can also be used.

  Refined fish oil can also be used as ω3 PUFAs.

  Moreover, monoglyceride, diglyceride or triglyceride of ω3 PUFAs or a combination thereof can be preferably used. For example, Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, York10, FA10000, EPA10G, EP10EP) Commercial products containing various ω3 PUFAs or salts or esters thereof exemplified by K85TG, K85EE and K80EE (Pronova Biopharma, Lysaker, Norway) and the like can also be obtained and used.

2. Suppression of recurrence of latent infection The pharmaceutical composition of the present invention is used for suppression of recurrence of latent infection. A latent infection is a condition in which a pathogen persists in the body without showing clinically recognized symptoms. Latent infection is defined as an infection that indicates a state of latent infection among infections. However, the latent period from the establishment of the infection to the acute infection period immediately after that does not correspond to the latent infection mentioned here. Accordingly, acute infections such as influenza virus infections and Ebola virus infections are excluded from the present invention. Examples of latent infection include herpes simplex virus infection, varicella-zoster virus infection, prion infection and the like.

  The recurrence of a latent infection means a state in which a latent pathogen is reactivated and the infection becomes obvious. Infection becomes manifest when it shows clinically recognized symptoms such as rash, fever, pain, and detection of pathogens in the blood. It is defined as the actual period.

  Suppression of recurrence of latent infection refers to preventing latent pathogens from being reactivated to reach a state where infection becomes manifest. I.e., extending the period until the pathogen reactivates and develops some symptoms, reducing the rate at which the pathogen reactivates and develops some symptoms, and / or reducing the severity of the onset. Means.

  The effect of suppressing the onset due to reactivation of the pathogen or the severity of symptoms when it develops by continuously administering the pharmaceutical composition of the present invention in preparation for the reactivation of the latent pathogen Can be expected. In addition, even after the onset of reactivation of a latent pathogen, the effect of suppressing and treating the progression of the disease state can be expected by continuously administering the pharmaceutical composition of the present invention.

  A suitable example of recurrence of latent infection is the development of postherpetic neuralgia. Shingles is a disease associated with recurrent infection with varicella / zoster virus and exhibits characteristic skin lesions. Usually, the eruption disappears after 5 to 10 days of antiviral drug administration, but the virus latently infects the sensory ganglia again. Post-herpetic neuralgia may develop as a recurrence symptom after herpes zoster healing. When the composition of the present invention is continuously administered to a patient who may develop postherpetic neuralgia, the development of postherpetic neuralgia can be suppressed. A preferred specific example of a patient who may develop postherpetic neuralgia is a patient who has a history of receiving antiviral drugs during the overt period of infection in which herpes zoster develops. In addition, the composition of the present invention exhibits a therapeutic effect that reduces or eliminates the severity of symptoms of postherpetic neuralgia even when administration is started after postherpetic neuralgia is observed.

  Other examples of diseases caused by reactivation of latent infection include subacute sclerosing panencephalitis (SSPE) due to measles virus, warts condyloma due to human papillomavirus (HPV), and adult T cell leukemia due to HTLV-1 virus infection And HTLV-1 myelopathy. In addition, Creutzfeldt-Jakob disease, Kourou disease, Gerstmann-Stroisler-Scheinker disease, and fatal familial insomnia caused by prion infection can be mentioned. When the composition of the present invention is continuously administered to a patient who may develop these diseases, an effect of suppressing the onset can be expected. For example, since a patient with a dural transplantation calendar may develop prion disease, such a patient can be a subject for administration of the composition of the present invention. In these diseases, since the disease state gradually progresses from the onset, by starting administration of the composition of the present invention after noticing the onset, the effect of delaying the progression of the disease state and the effect of treatment can be expected.

  In the pharmaceutical composition of the present invention, the active ingredient ω3PUFAs is taken into living tissues and cells to change the lipid composition of the cell membrane lipid raft, thereby reactivating viruses and the like hidden in the cells. It is thought to suppress. Lipid rafts are known to be involved in the invasion, genome replication, viral protein transport, assembly and budding of many viruses such as retroviruses, RNA viruses and DNA viruses (Yuyama K et al., Trends in Glycoscience). and Glycotechnology, 2003, Vol. 15, p139; Briggs JA, et al., J Gen Viol, 2003, Vol. 84, p757; Chazal N, et al., Microbiol Mol Biol Rev, 2003, Vol. , Cell Microbiol, 2002, Vol. 4, p783; Lindwasser OW et al., J Viol, 2001, Vol. 75, p7913; Suomalainen M, Traf. fic, 2002, volume 3, p705). Furthermore, lipid rafts are also known to be involved in the conversion of normal prions (PrP (C)) to abnormal prions (PrP (Sc)) (Taylor DR et al., Mol Membr Biol, 2006, No. 1). 23, p89).

  By administering ω3 PUFAs, the present inventor changes the fat environment that constitutes the raft, and can suppress reactivation of pathogens that are latent in the host body through reactions on the host side other than the immune system I found. In addition, the composition of lipid rafts is changed by continuously administering the pharmaceutical composition of the present invention even after onset of reactivation of a pathogen that is in a latent state, thereby suppressing the growth and activity of pathogens such as viruses. It was found that the effect of suppressing and treating the progression of the disease state can be exerted.

  Accordingly, one aspect of the present invention is a therapeutic agent for infectious diseases associated with lipid rafts, characterized by containing ω3PUFAs as an active ingredient. However, in order to change the composition of lipid rafts by administration of ω3 PUFAs, it is necessary to administer at least one week or more, so that it is difficult to apply to acute infections.

  In addition, since ω3 PUFAs has safety suitable for long-term administration, it is suitable for treatment of latent infections to which conventional infectious disease therapeutic agents such as antiviral agents cannot be applied. Therefore, a preferred embodiment of the present invention is a therapeutic agent for latent infection characterized by containing ω3PUFAs as an active ingredient. A preferred embodiment of the present invention is also the treatment of latent infections and related pathologies, particularly in the elderly.

3. Pharmaceutical composition and administration method The dosage and administration period of ω3PUFAs used in the pharmaceutical composition of the present invention are sufficient to produce the intended effect, but the dosage form, administration method, per day The dosage may be adjusted according to the number of administrations, degree of symptoms, weight, age, etc.

  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 total amount may be divided into 1 or several doses as necessary. In addition, the administration time is preferably during or after meals, more preferably immediately after meals (within 30 minutes). When the above dose is administered orally, the administration period is at least 2 weeks or more, preferably 3 months or more, more preferably 1 year or more, and further preferably 3 years or more. Moreover, for example, it can be administered every other day for 2 to 3 days per week.

  When EPA-E is continuously orally administered to healthy adult males, the EPA plasma concentration reaches a steady state in one week. EPA / AA (arachidonic acid) ratio is often used as one index from the pharmacological and clinical viewpoints, but plasma EPA / AA exceeds 1.0 in one week of administration and doubles that before administration It will be about. As an indicator of continuous administration, the dosage and administration interval were adjusted so that the blood concentration of ω3PUFAs in the first week after administration could be maintained and / or the plasma EPA / AA ratio would be 1.0 or higher. do it.

  In the pharmaceutical composition of the present invention, the active ingredient ω3PUFAs is incorporated as a fatty acid component of the tissue in the living body, and the virus is hidden in the cell by a specific action mechanism that changes the lipid composition of the cell membrane lipid raft. It is considered that it exerts the action of suppressing the reactivation of the. Therefore, the mechanism of action is different from conventional anti-infective drugs that act directly on pathogens. Therefore, the pharmaceutical composition of the present invention does not cause emergence of a new resistant pathogen, which is a problem with conventional therapeutic agents for infectious diseases.

  In the pharmaceutical composition of the present invention, ω3PUFAs, which are active ingredients, are taken into living tissues and cells, change the lipid composition of rafts present on the cell membrane, and exhibit the effect of suppressing the recurrence of latent infections In addition, the amount taken into the tissue in the living body may be set, and it may be set lower than the usual ω3 PUFAs dose generally used as a pharmaceutical. For example, in the case of EPA-E and / or DHA-E, the daily dose is preferably 0.1 g or more and less than 2 g, more preferably 0.2 g or more and 1.8 g or less, and further preferably 0.3 g or more. 0.9 g or less, and preferably 0.1 g or more and 0.3 g or less in the case of a low dose.

  The pharmaceutical composition of the present invention can be administered with the active ingredient as it is, or an appropriate carrier, medium, excipient, binder, lubricant, coloring agent, flavoring agent, or as required. Sterile water and vegetable oil, further harmless organic solvents, harmless solubilizers (eg glycerin, propylene glycol), emulsifiers, suspending agents (eg Tween 80, gum arabic solution), isotonic agents, pH adjusters, stable An appropriate pharmaceutical preparation can be prepared and administered by appropriately combining with additives such as a soothing agent, soothing agent, flavoring agent, flavoring agent, preservative, antioxidant, buffering agent, or coloring agent. it can. Additives include, for example, lactose, partially pregelatinized starch, hydroxypropylcellulose, macrogol, tocopherol, hydrogenated oil, sucrose fatty acid ester, hydroxypropylmethylcellulose, titanium oxide, talc, dimethylpolysiloxane, silicon dioxide, carnauba wax, etc. Yes.

  In particular, since ω3 PUFAs are highly unsaturated, at least one selected from antioxidants such as butyrated hydroxytoluene, brechated hydroxyanisole, propyl gallate, gallic acid, pharmaceutically acceptable quinones and α-tocopherol. It is desirable to contain an effective amount of as an antioxidant.

  The dosage form of the preparation varies depending on the combined form of the active ingredients of the pharmaceutical composition of the present invention, and is not particularly limited, but is preferably an oral preparation or a parenteral preparation, and more preferably an oral preparation. Preferred examples of the oral preparation include tablets, film-coated tablets, capsules, microcapsules, granules, fine granules, powders, oral liquid preparations, syrups, jellies, or inhalants. In addition, examples of parenteral preparations include ointments, suppositories, injections (emulsification, suspension, non-aqueous), solid injections used when emulsified or suspended, infusion preparations, and transdermal absorption agents. The external preparation is preferably exemplified. Oral preparations are administered orally or by inhalation, parenteral preparations are administered intravenously, intraarterially, rectally or vaginally or externally, and are administered to the patient by the preferred route according to the respective dosage form. For patients that can be taken orally, a simple oral formulation is desirable, especially oral administration in capsules, such as soft capsules or microcapsules, or in tablets or film-coated tablets. In addition, the oral preparation is preferably administered orally 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.

  The pharmaceutical composition of the present invention can contain a second drug in addition to ω3 PUFAs. The second drug is not particularly limited, but preferably does not diminish the effects of the present invention. Examples include liver protectants, hypoglycemic agents, antihyperlipidemic agents, antihypertensive agents, antioxidants, and anti-inflammatory agents. Illustrated.

  The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable excipient in addition to the active ingredient. As appropriate, known antioxidants, coating agents, gelling agents, flavoring agents, flavoring agents, preservatives, antioxidants, emulsifiers, pH adjusting agents, buffering agents, coloring agents and the like may be contained.

  The pharmaceutical composition of the present invention can be formulated according to a conventional method. The powder of ω3 PUFAs is, for example, water containing (A) EPA-E, (B) dietary fiber, (C) starch hydrolyzate and / or low saccharified reduced starch hydrolyzate, and (D) a water-soluble antioxidant. The oil emulsion is obtained by a known method such as drying under high vacuum and pulverization (Japanese Patent Laid-Open No. 10-99046). Using the obtained EPA-E powder, granules, fine granules, powders, tablets, film-coated tablets, chewable tablets, sustained release tablets, orally disintegrating tablets (OD tablets), etc. are obtained according to conventional methods. be able to. In the case of chewable tablets, for example, EPA-E is emulsified in a water-soluble polymer solution such as hydroxypropylmethylcellulose, and the obtained emulsion is sprayed onto an additive such as lactose to obtain a powder (JP-A-HEI 8-157362), and can be obtained by a known method such as tableting. If it is an orally disintegrating tablet, it can be produced according to known methods, for example, JP-A-8-333243, and if it is an oral film preparation, for example, JP-A-2005-21124.

  The pharmaceutical composition of the present invention is desirably released and / or absorbed so that the pharmacological action of the active ingredient can be expressed. The compounding agent of the present invention excels in the release of active ingredients, absorbs active ingredients, disperses active ingredients, exhibits excellent storage stability of the compound, or provides patient convenience or compliance It is desirable to have at least one of the effects.

  The pharmaceutical composition of the present invention is effective for suppressing recurrence of latent infection in animals, particularly mammals. Mammals are not particularly limited, but are preferably humans, domestic animals or domestic animals, and particularly preferably humans. The livestock animal is not particularly limited as long as it can be recognized by those skilled in the art, but is preferably a cow, a horse or a pig. The domestic animal is not particularly limited as long as it can be recognized by those skilled in the art, but is preferably a dog, a cat or a rabbit.

  The pharmaceutical composition of the present invention is expected to show a recurrence-inhibiting effect of latent infection, particularly in patients who have a history of being treated (treated) with an infectious disease treatment drug during the actual infection stage. Examples of infectious disease treatment agents include those that act directly on pathogens, such as viral nucleic acid synthesis inhibitors and reverse transcriptase inhibitors, and those that activate host immune functions to eliminate pathogens and infected cells. There are things to guide. These conventional therapeutic agents for infectious diseases are different from the compositions of the present invention in terms of the mechanism of action. Typical examples of conventional therapeutic agents for infectious diseases include antiviral agents such as acyclovir and immunostimulants such as interferon.

  The timing for starting administration of the pharmaceutical composition of the present invention is not particularly limited. Administration of the pharmaceutical composition of the present invention can be started from the time when it is confirmed that the patient is affected by an infectious disease that may cause latent infection, or when it is recognized that the patient may be affected. That is, the pharmaceutical composition of the present invention may be administered during the actual infection period, or may not be performed in parallel with the administration of the conventional therapeutic agent for infectious diseases during the actual infection period. Moreover, you may start administration of the pharmaceutical composition of this invention after completion | finish of administration of the conventional infectious disease therapeutic agent in an infection overt period.

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

(Example 1) Inhibitory effect of ω3PUFAs on post-herpetic neuralgia onset (1-1) Preparation of post-herpetic neuralgia onset model animal A method for preparing post-herpetic neuralgia onset model animal is described in JP-A-2002-330666. Follow the method. Mice (BALB / c female, 6 weeks old, Japan SLC) are anesthetized (pentobarbital, 5 mg / kg), and the right hind limb and abdomen are depilated. The epidermis 5 × 5 mm in the lower knee joint of the hind limb after depilation is wounded with an injection needle or the like, and 1 × 10 ⁶ PFU / 10 μl of HSV-1 (7401H strain) is dropped and applied for infection. VZV virus that causes shingles in humans is highly species-specific and does not infect mice, so HSV-1 that can induce symptoms similar to shingles in mice may be used.

  5 days after infection, acyclovir is orally administered at a dose of 10 mg once a day, 5 times a day every 3 hours for 7 days. Antiviral treatment eliminates rashes and cures shingles in most animals. Among animals after disappearance of the eruption, an animal that exhibits postherpetic neuralgia is selected. On the 10th to 40th day after the disappearance of the rash, a test method using von Frey Hair, a test method using a brush, a test method using radiant heat, a test method using pressure stimulation or needle stimulation, and a vaporizable liquid such as acetone was used. Using a test method using cooling stimulation, etc., the pain response is examined, an animal expressing postherpetic neuralgia is selected, and the incidence of postherpetic neuralgia is calculated.

(1-2) Suppression of postherpetic neuralgia onset by administration of EPA-E Using the model animal prepared in (1-1), an EPA administration group and a subject group are set. In the EPA administration group, 1000 mg / kg of EPA-E is suspended in a 5% aqueous gum arabic solution and orally administered once a day. The control group is orally administered with a 5% gum arabic aqueous solution once a day. The administration start time is either the start of antiviral drug administration or the disappearance of the rash. Pain responses are examined on the 25th and 40th days after the disappearance of the eruption, an animal expressing postherpetic neuralgia is selected, and the incidence of postherpetic neuralgia is calculated. In the EPA administration group, the incidence of postherpetic neuralgia is lower and / or the severity rate in the onset case is lower than in the control group.

(Example 2) Confirmation of antiviral effect of ω3 PUFAs via lipid raft Simian virus 40 (SV40) enters cells by lipid raft-mediated endocytosis on the cell membrane (Pelkmans, Science, 2002, No. 1). 296, p535-539). On the other hand, vesicular stomatitis virus (VSV) enters cells by clathrin-mediated endocytosis without lipid rafts. By examining the infection inhibitory effect of the test substance on SV40 and VSV, it can be determined whether or not the test substance acts on lipid rafts and exhibits an antiviral effect.

  HeLa cells are cultured in medium with or without ω3 PUFAs and then infected with SV40 or VSV. After incubation for several hours to several days, the number of virus-infected cells is measured. The number of infected cells when ω3 PUFAs is added and the number of infected cells when ω3 PUFAs are not added are compared to determine the antiviral effect of ω3 PUFAs. Since ω3 PUFAs shows an antiviral effect against SV40 and does not show an antiviral effect against VSV, it can be confirmed that ω3 PUFAs exerts an antiviral effect by acting on lipid rafts.

(Example 3) Inhibitory effect of postherpetic neuralgia onset in patients suffering from herpes zoster by administration of ω3 PUFAs For patients suffering from herpes zoster and who were treated with antiviral drugs acyclovir, vidarabine, valacyclovir or famciclovir -E administration group and EPA-E non-administration group are set. In the EPA-E administration group, Epadale S (registered trademark) 900 (containing EPA-E 900 mg) is administered twice a day after the administration of the antiviral agent is completed. In the EPA-E non-administration group, EPA or a pharmaceutically acceptable salt or ester thereof is not administered during the test period. Follow up the incidence of postherpetic neuralgia in both groups over time. In the EPA-E administration group, it can be confirmed that the incidence of postherpetic neuralgia is low, the onset time is delayed, and / or the severity of the onset case is reduced compared to the EPA-E non-administration group .

(Example 4) Inhibitory effect of postherpetic neuralgia in patients suffering from herpes zoster by administration of ω3PUFAs EPA-E is orally administered to 900 to 2700 mg per day for patients suffering from herpes zoster and developing postherpetic neuralgia (PHN) As a result, the severity of postherpetic neuralgia was reduced or completely disappeared in all cases (Table 1). In addition, no side effects due to EPA-E administration were observed. This result was a remarkable effect compared with the conventional PHN therapeutic agent. Table 2 shows a comparison between the effective rate of conventional PHN therapeutic agents (the proportion of the number of patients in whom the pain relief effect was observed among the administered patients) and the incidence of side effects. The effective rate and the incidence of side effects of existing PHN therapeutics were calculated from NNT (numbers needed to treat) and NNH (numbers needed to harm) described in the literature (Kazushige Murakami et al., History of Medicine, 2007, No. 1) 223, No. 9, p747-752). As shown in Table 2, the effective rate of existing PHN therapeutics is around 30% and the incidence of side effects is around 20%, whereas when EPA-E is administered, the efficacy rate is 100% and side effects The expression rate showed a remarkable effect of 0%. In addition, EPA-E administration started immediately after the onset of PHN was observed, and the symptom-improving effect tended to be higher. It has been suggested that if administration of ω3 PUFAs is started to a patient who is expected to develop herpes zoster, a higher therapeutic effect and / or a suppression effect of PHN is expected. Furthermore, even in old cases (cases 3, 4, 8 to 11) in which pain has continued for more than several months since the onset of PHN, an improvement effect was observed in the shortest one week after starting EPA-E administration . Treatment of old cases of PHN is considered to be extremely difficult, but it was a surprising effect that improvement was observed by administration of EPA-E. Even if EPA-E is administered over a long period of time, no side effects are observed, and it is expected that PHN symptoms can be eliminated by continuing EPA-E administration for improved cases (cases 3, 6, 8 to 11). it can.

Claims (6)

  A pharmaceutical composition for suppressing recurrence of latent infection, comprising as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof object.   A pharmaceutical composition for inhibiting post-herpetic neuralgia, comprising as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof .   A pharmaceutical composition for treating postherpetic neuralgia, comprising as an active ingredient at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof.   4. The composition according to claim 1, wherein the active ingredient contains at least one selected from the group consisting of icosapentic acid, docosahexaenoic acid, α-linolenic acid, pharmaceutically acceptable salts and esters thereof. A pharmaceutical composition according to claim 1.   The pharmaceutical composition according to any one of claims 1 to 4, comprising icosapentic acid ethyl ester as the active ingredient.   The pharmaceutical composition according to any one of claims 1 to 5, which is applied to a patient who has a history of being administered a therapeutic agent for an infectious disease during the overt period of infection.