JP4632644B2 - Anal pressure-reducing topical preparation containing lipopolysaccharide as an active ingredient - Google Patents

Description

  The present invention relates to an anal pressure-reducing topical preparation containing lipopolysaccharide as an active ingredient, and an agent for preventing or treating anal-related diseases.

  Lipopolysaccharide (hereinafter referred to as LPS) is a cell wall component of Gram-negative bacteria, and its chemical structure is a lipopolysaccharide having a repeating structure of lipid A, which is a high molecular phospholipid, and sugar. LPS is called endotoxin. When LPS enters the body, it causes various reactions such as fever, diarrhea, intravascular disseminated blood coagulation, and excessive inflammatory reaction. It is well known to cause shock (so-called endotoxin shock). However, since many intestinal bacteria are gram-negative bacteria and there is a defense mechanism in the normal intestine, bacteria and LPS cannot pass through the intestinal mucosa and therefore do not enter the living body.

  On the other hand, as a useful action of LPS, an antitumor action, an immunostimulatory action and the like have been studied. In addition, the physiological significance of enterobacteria has been studied. However, few studies have been reported on topical LPS.

  Hirschsprung's disease is caused by a congenital absence of the Mysnel and Auerbach autonomic plexus in the intestinal wall and is usually restricted to the distal colon. No or abnormal abnormal peristalsis, resulting in persistent spasticity of the smooth muscle, partial or complete obstruction due to accumulation of intestinal contents, and normal innervation that is more proximal Expansion occurs. Obstruction is most common in the anus, but it can spread to various sites near the colon, and can extend throughout the colon and, rarely, the terminal ileum and digestive tract. Patients present with constipation and abdominal distension. As a treatment method, in infants whose ganglion cell defect is confined to the anus, there are many artificial anus constructions in the proximal part than the ganglion cell defect area. Botulinum toxin is known to be effective for Hirschsprung's disease, but this is due to the action of reducing internal anal pressure. In addition, laxative administration, dietary guidance, bowel movement adjustment and defecation guidance are performed, but if this does not improve, an internal sphincter incision is performed. (For example, refer nonpatent literature 1 and 2.).

  Crohn's disease is an inflammation characterized by right lower abdominal pain and tenderness, repeated partial obstruction caused by intestinal stricture, causing severe colic, abdominal bloating, diarrhea, vomiting, inflammation and obstruction, undernourishment and weakness Diffuse jejunitis, which usually causes illness, and usually a late event, often with fever and painful abdominal masses. There is also anal pain due to spasticity of smooth muscle. Anticholinergic drugs and diphenoxylate, loperamide, opium tincture, codeine and the like are used for symptomatic treatment for this disease. Sulfazarazine and steroids are also used. Antimetabolites such as azathioprine and 6-mercaptopurine and methotrexate have also been effective as immunosuppressants. All of these drugs have a certain effect. However, in order to improve the quality of life (QOL), it is also desirable to administer a drug that reduces pain by reducing anal pressure.

  Irritable bowel syndrome is not a single disease, but there are complaints of diarrhea or alternation of diarrhea and constipation and associated abdominal symptoms, but no organic lesions that explain those symptoms are proven in the intestinal tract and related organs It is called in this way generically. It is known that pain due to irritable bowel syndrome is due to an increase in intra-anal pressure (see, for example, Non-Patent Document 3). Although there are no specific symptoms of this disease, dull pain and colic in the lower right abdomen are common, and diarrhea and constipation are repeated. Reducing anal pressure and relieving pain in the lower abdomen is also an important treatment for increasing QOL.

  Anal fist muscle syndrome is a disease in which the depths of the anus suddenly hurt despite the absence of hemorrhoids and cuts in the anus, and the cause is unknown. Pain occurs suddenly and becomes severe pain that can be tightened. There are various causes, but most often, pain is caused by excessive contraction of the anal sphincter. Reducing anal pressure to alleviate this pain is a very effective treatment.

  In addition, it is known that in anal sphincter disorders, the anal sphincter, especially the anal fistula, is abnormally increased.

  Macrocolonia is known to develop due to muscle tension of the anal sphincter muscle due to myotonic dystrophy.In anal sphincter internal pressure measurement, both the internal anal sphincter composed of smooth muscle and the external anal sphincter composed of skeletal muscle are Tension reaction is recognized. It is also known that megacolon is caused by abuse of laxatives, pseudo obstruction of the large intestine, and persistent spasticity of the anal sphincter due to a pain disorder around the anus.

  None of the drugs aimed at improving QOL by reducing anal pressure with preventive or therapeutic agents for these diseases.

  On the other hand, an increase in anal pressure has been observed in hemorrhoid diseases such as anal fissures and hemorrhoids. The anal sphincter contracts, and as a result, the tissues and nerves in the anus are compressed, causing intense pain. Surgery is being performed for the treatment of these diseases, but pharmacological prophylaxis or treatment is desired because patients and their families often resist surgery and often suffer from fecal incontinence. It is rare.

On the other hand, application of nitroglycerin ointment and injection of botulinum toxin have been studied for the purpose of reducing anal pressure. However, nitroglycerin ointment has a problem that side effects such as headache and burning of the anus occur frequently, and injection of botulinum toxin has a problem that it requires hospital visit.
Langer JC, Birnbaum EE, Schmidt RE, “Histology and Function of the internal anal sphincter after injection of botulinum toxin "Journal of Surgical Research, (USA), Academic Press, 1997, 73, 2, p.113-116. Edited by Joji Utsunomiya, “Knowledge of Anal Diseases Useful for Practitioners”, Nagai Shoten, 1995, p.203 Krag E, "Irritable bowl syndrome: current concepts and future trends", Scandinavian Journal of Gastroenterology Suppl, Scandinavia, 1985, 109, p.107-115

  An object of the present invention is to provide an anal pressure-reducing topical preparation, a method for lowering anal pressure, and a prophylactic or therapeutic agent for anal-related diseases, which comprise lipopolysaccharide as an active ingredient.

  As a result of intensive studies in view of the above-mentioned problems of the prior art, the present inventors have found that a preparation containing lipopolysaccharide reduces anal pressure and completed the present invention.

  That is, the present invention provides the following external preparations for lowering anal pressure, methods for lowering anal pressure, and agents for preventing or treating anal-related diseases.

  Item 1. An anal pressure-reducing topical preparation containing lipopolysaccharide as an active ingredient.

  Item 2. Item 2. An external preparation for anal pressure reduction according to Item 1, which is applied to the anorectal region and the perianal region.

  Item 3. Item 3. A method for reducing anal pressure, wherein the anal pressure-reducing external preparation according to item 1 or 2 is applied to the anus.

  Item 4. Item 4. The method for reducing anal pressure according to Item 3, wherein the application part is an anal mucosa or a trauma site.

Item 5. Item 5. Prophylactic or therapeutic agent for anal fissure or hemorrhoid comprising lipopolysaccharide as an active ingredient. A prophylactic or therapeutic agent for constipation comprising lipopolysaccharide as an active ingredient.

  Item 7. A prophylactic or therapeutic agent for Hirschsprung's disease comprising lipopolysaccharide as an active ingredient.

  Item 8. A preventive or therapeutic agent for Crohn's disease comprising lipopolysaccharide as an active ingredient.

  Item 9. A prophylactic or therapeutic agent for irritable bowel syndrome comprising lipopolysaccharide as an active ingredient.

  Item 10. An agent for preventing or treating anal sphincter disorders comprising lipopolysaccharide as an active ingredient.

  Item 11. A preventive or therapeutic agent for megacolon comprising lipopolysaccharide as an active ingredient.

  Item 12. A prophylactic or therapeutic agent for anal fistula syndrome comprising lipopolysaccharide as an active ingredient.

  Item 13. A prophylactic or therapeutic agent for hemorrhoid diseases comprising lipopolysaccharide as an active ingredient.

  The anal pressure-reducing external preparation, anal pressure-reducing method, and anal-related disease preventive or therapeutic agent of the present invention are characterized by comprising lipopolysaccharide (hereinafter sometimes referred to as LPS) as an active ingredient.

  Anal-related diseases include hemorrhoids (eg anal fissure, hemorrhoids), constipation, Hirschsprung disease, Crohn's disease, irritable bowel syndrome, anal sphincter disorder, anal fistula syndrome (sudden anal pain), megacolon, etc. Is exemplified. The anal pressure-reducing external preparation of the present invention is useful for the prevention or treatment of these diseases because the lipopolysaccharide contained therein has an anal pressure-reducing action.

  In any of the aforementioned diseases, an increase in anal pressure is observed, and the disease is improved by a decrease in anal pressure. Therefore, the anal pressure lowering agent of the present invention having an anal pressure lowering action is useful for these diseases.

  LPS is a structural component characteristic of the cell wall of Gram-negative bacteria and exists in the outer membrane (H. Mayer, RNTharanthan, J, weckesser, "Methods in Microbiology", ed. By G. Gottschalk, Vol 18, p.157. , Academic Press, Florida (1985)). LPS was prepared by Westphal's hot phenol water extraction method (O. Westphal, K. Jann, “Methods in Carbohydrate Chemistry”, ed. By R. Whistler, Vol. 5, p. 83, Academic Press, New York ( 1965), but the yield of the Galanos phenol-chloroform-petroleum ether extraction (PCP) method (C. Galanos, O. Luderitz, O. Westphal, Eur. J. Biochem., 9, 245 (1969)) LPS can be obtained by these methods, and LPS is generally available from bacteria, especially Gram-negative bacteria, but also from plant sources. Can do.

  Moreover, the formulation form of the external preparation for anal pressure reduction and the preventive or therapeutic agent for anus-related diseases of the present invention is not particularly limited as long as it is a form applicable to the anus. For example, ointments, suppositories, creams, gels, liniments, lotions, emulsions, powders, suspensions, aerosols, etc., and plasters, poultices, tapes with a base supported on a support Agents, plaster agents and the like. Of these dosage forms, ointments, suppositories, creams, gels, lotions, and emulsions are preferable, and ointments are more preferable.

  In addition, the amount of lipopolysaccharide as an active ingredient in the anal pressure-reducing topical preparation of the present invention, an agent for preventing or treating anal-related diseases, is not particularly limited as long as an anal pressure-reducing action is observed, and the dosage form, It can be appropriately selected according to the patient's symptoms. For example, in the case of an ointment, an appropriate amount of ointment containing an effective amount of LPS is usually applied to the affected area one to several times a day.

  Any base may be used as long as it is pharmaceutically acceptable, and conventionally known ones can be used as appropriate. For example, sodium alginate, gelatin, corn starch, tragacanth gum, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, carrageenan, mannan, agarose, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer , Polymers such as polyvinyl ether, polyvinyl pyrrolidone, carboxyvinyl polymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose; beeswax, olive oil, cacao oil, sesame oil, soybean oil, camellia oil, peanut oil, cow oil, pig oil, chicken oil, Oils and fats such as lanolin; white petrolatum, yellow petrolatum, paraffin, liquid paraffin, ceresin wax, scuba Hydrocarbons such as orchid, light liquid paraffin and microcrystalline wax; gelled hydrocarbon (for example, trade name Plastibase, manufactured by Bristol-Myers Squibb); higher fatty acids such as stearic acid; cetanol, octyldodecanol, stearyl alcohol, etc. Higher alcohols; polyethylene glycol (eg, macrogol 400, macrogol 4000, etc.); polyhydric alcohols such as propylene glycol and glycerin; monooleate, stearic acid glyceride, octyldodecyl myristate, isopropyl myristate, hard fat, etc. Fatty acid esters: water, physiological saline, phosphate buffer and the like.

  For example, in the case of an ointment, hydrocarbons, fatty acid esters, gelled hydrocarbons, beeswax, polyethylene glycol and the like are used. In the case of creams, hydrocarbons, surfactants, water, glycerin, cetanol, stearyl alcohol and the like are used. In the case of a lotion agent, hydrocarbons, water, carboxyvinyl polymer, glycerin, cetanol, propylene glycol and the like are used. Furthermore, water, surfactant, carboxyvinyl polymer, lower alcohols, etc. are used for the gel agent.

  Examples of the surfactant include polysorbate 80, lecithin derivative, propylene glycol fatty acid ester such as self-emulsifying propylene glycol monostearate, glycerin fatty acid ester such as glyceryl monostearate, polyoxyethylene glycerin fatty acid ester, polyglycerin fatty acid ester Sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene alkylphenyl formaldehyde condensate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sterol / hydrogenated sterol, Polyoxyethylene alkyl esters such as polyethylene glycol fatty acid esters and polyoxyethylene cetyl ether , Polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene lanolin, lanolin alcohol, beeswax derivative, polyoxyethylene alkylamine, fatty acid amide, polyoxyethylene alkyl ether phosphate, phosphate, Examples include sodium carboxymethyl starch, hydrophobic soft silicic acid anhydride, and polymer emulsifier. Although not limited to these, glycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, regardless of the dosage form Etc. are often used.

  Further, if necessary, solubilizing agents such as polyvinylpyrrolidone; inorganic fillers such as kaolin, bentonite, zinc oxide, titanium oxide; anti-aging agents; pH regulators such as triethanolamine; humectants such as glycerin and propylene glycol ; Preservatives such as methyl paraoxybenzoate, propyl paraoxybenzoate, benzalkonium chloride, benzethonium chloride, citric acid, sodium citrate, paraoxybenzoic acids, boric acid, borax, camphor; xanthan gum, sodium chondroitin sulfate, liquid paraffin , Glycerin, polyethylene glycol, polyvinylpyrrolidone, and the like may be added.

  As the base of the tape agent, any pharmaceutically acceptable one can be used, and conventionally known ones can be used. For example, acrylic adhesive, rubber adhesive, silicon adhesive, urethane An acrylic adhesive and a rubber-based adhesive are preferably used. Moreover, as a property of the pressure-sensitive adhesive at the time of spreading on the support, any of solvent-based, emulsion-based, hot-melt-based and the like can be used.

  Examples of the acrylic pressure-sensitive adhesive include a pressure-sensitive adhesive mainly composed of polyalkyl (meth) acrylate obtained by copolymerizing alkyl (meth) acrylate, and a polyfunctional monomer copolymerizable with alkyl (meth) acrylate. Or a copolymer with other vinyl monomers.

  Examples of the alkyl (meth) acrylate include 2-ethylhexyl (meth) acrylate and dodecyl (meth) acrylate. Examples of the polyfunctional monomer include 1,6-hexane glycol dimethacrylate and tetraethylene glycol diacrylate. Examples of the other vinyl monomer include N-vinyl-2-pyrrolidone and vinyl acetate. Is mentioned.

  Examples of the rubber-based pressure-sensitive adhesive include pressure-sensitive adhesives mainly composed of natural rubber, styrene-isoprene-styrene block copolymer, styrene-olefin-styrene block copolymer, etc., and in general, rosin, hydrogenated rosin, rosin A tackifier such as ester, terpene resin, terpene phenol resin, petroleum resin, coumarone resin, coumarone-indene resin is added.

  The support is appropriately selected according to the dosage form (for example, a poultice, a tape, etc.), but preferably has a drug impermeable or hardly permeable and flexible, such as cellulose acetate, ethyl cellulose, Polyethylene, polypropylene, polyvinyl chloride, vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-butyl acrylate-carbon monoxide copolymer, poly Examples thereof include resin films such as vinylidene chloride, polyurethane, nylon, polyethylene terephthalate, and polybutylene terephthalate; aluminum sheets, woven fabrics, nonwoven fabrics, and laminated sheets thereof.

  The dosage of the anal pressure-reducing topical preparation and the prophylactic or therapeutic agent for anal-related diseases of the present invention varies depending on the type of disease, the degree of symptoms, etc., but the daily dose to the patient is usually 0.3 to 0.3 in terms of LPS. The amount is 3000 ng / kg, preferably 3 to 3000 ng / kg, and more preferably 3 to 300 ng / kg, and this is applied to the affected area once or divided into appropriate times.

  The anal pressure-reducing external preparation and the prophylactic or therapeutic agent for anal-related diseases of the present invention are produced by a conventionally known method according to the dosage form. For example, when producing an oily ointment, the raw material base is heated and melted, mixed, and half cooled, and then LPS is added to the base and kneaded. When producing creams and emulsions, the solid base was dissolved in a water bath and kept at about 75 ° C., and the water-soluble base was dissolved in water and heated to the same temperature or slightly higher temperature. A thing is added and LPS is added and kneaded and manufactured. Moreover, when manufacturing a gel, for example, a polymer is added to water and heated to swell. To this, a water-soluble base and bacteria dissolved in a solvent are added, mixed and dissolved, and then cooled to produce. Furthermore, when producing a lotion agent, for example, a polymer is added to water and heated to swell. To this, a water-soluble base dissolved in a solvent is added, and LPS is further added to this, mixed and dispersed, and then cooled to produce. Examples of the mixing / dissolving method include a method using a mortar and pestle, a method using a kneader, and a method using an emulsifier, and the method is appropriately selected depending on the properties of the base and the amount of preparation.

  According to the present invention, it is possible to reduce anal pressure by the action of LPS. In addition, since LPS as an active ingredient has an anal pressure lowering action, anal-related diseases (eg, anal diseases such as anal fissure, hemorrhoids), constipation, Hirschsprung's disease, Crohn's disease, irritable bowel syndrome, anal It is useful for the prevention or treatment of sphincter disorders, anal fistula syndrome, megacolon, anal sphincter disorders, hemorrhoids and the like.

  It is considered that the anal pressure lowering action according to the present invention is exerted by LPS being administered to the anorectal region and the perianal region to relax the anal sphincter and reduce the anal pressure.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples. In this embodiment, the anal pressure is used as an index of anal pressure, and in the drawings and the description thereof, the anal pressure may be simply referred to as anal pressure.

Example 1: Effect of topical application of commercially available LPS on rat internal pressure and blood pressure
Using 6 Slc: SD male rats (9 to 10 weeks old, Japan SLC Co., Ltd.), the effect on the intra-anal pressure and blood pressure of LPS topical application was examined. A stock solution (10 mg / mL) obtained by freezing commercially available LPS (Escherichia coli O111: B4, manufactured by Sigma, product number L2630, lot 110K4060) at −80 ° C. is used for measuring endotoxin (distilled water, manufactured by Seikagaku Corporation) (Endotoxin free)) was diluted 10-fold, and these diluted solutions were applied into the anus of the rat at a dose of 0.3 mL / kg. The anal pressure and blood pressure were measured twice before application and at 2 and 4 hours after application. The anal pressure was evaluated by the area under the anal pressure curve for 7 minutes (anal pressure area) and the number of contractions of 20 mmH ₂ O or more (the number of anal pressure contractions) from 1 to 8 minutes after the start of measurement of each anal pressure measurement record. The evaluation results, the results of the intraanal pressure and blood pressure after application, are shown in FIGS. 1 to 5 in terms of the change rate (%) with respect to the average value of the values measured twice before application as 100%.

  1, 2, 4 and 5, both the number of anal pressure contractions and the anal pressure area decreased in a dose-dependent manner from 2 to 4 hours after application, and it was confirmed that LPS was effective in reducing anal pressure. In addition, as shown in FIG. 3, no extreme decrease in blood pressure was observed. Furthermore, as far as the rats were observed, LPS endotoxin shock was not observed.

Details of this test are described below.
Test method
1) Calibration by differential pressure transducer, carrier amplifier, recorder and water negative pressure Carrier amplifier (11-G4113-01, Gould) and recorder (Unicoder, U-228, JEOL) and difference A pressure transducer (DP45, validin) was connected. After calibration with negative water pressure, a balloon-mounted catheter for measuring the pressure inside the anus was connected to the differential pressure transducer, and the pressure inside the anus was started.

2) Measurement method of intra-anal pressure (1) Measurement procedure The intra-anal pressure was determined by placing two Slc: SD male rats in an abdominal position on an experimental table without anesthesia and holding them lightly while using two balloons from Vinograd et al. ( Vinograd I et al .: Animal model for the study of internal anal sphincter activity. Eur Surg Res 17: 259-263, 1985). In other words, one balloon (MB-5, outer diameter 3 mm, length 15 mm, made by Star Medical) attached to the distal end of a catheter (French size: 5 Fr, outer diameter 1.7 mm) with a surgical thread (No. 3) Two catheters were connected to each other, and a catheter for measuring the internal pressure of the anus with two balloons (two balloons having a total length of about 2.5 cm) was prepared. Connect a pressure transducer (DP45, validin) to the anal balloon catheter, insert the tip balloon into the rectum and the posterior balloon into the anus, and keep it at a fixed position for about 10 minutes. Anal pressure was measured. The anal pressure catheter and balloon were filled with water (about 0.15-0.2 mL of water was injected into the balloon and lightly inflated). About 1 minute before the end of the anal pressure measurement, the rectal balloon was temporarily inflated with a total amount of about 0.7 to 0.8 mL of water to confirm the presence of a rectal anal reflex.
(2) Selection of animal for measuring anal pressure An individual who has shown a contraction waveform that is repeated several times as an internal pressure, and then measured the internal pressure of the anus several times approximately every hour, and was able to measure a similar internal pressure waveform Was selected as an animal for measuring anal pressure.
(3) Evaluation of anal pressure The anal pressure is the area under the anal pressure curve (anal pressure area) for 7 minutes from the start of measurement of each anal pressure measurement record (anal pressure area) and the number of contractions (anal pressure) of 20 mmH ₂ O or more. (Shrinkage number). The anal pressure area is traced by the path of the layer function in the “Adobe Photoshop ver.3.0” software for Macintosh, and the area under the anal pressure curve is inverted black, and the inverted black area is the NIH Image for Macintosh. Calculated at 1.62. The number of anal pressure contractions was 20 mmH ₂ O or more. Further, for each evaluation, the rate of change (%) of the value of each measurement time with respect to the previous value (0 hour) was calculated.

3) Measurement of blood pressure Immediately after each intra-anal pressure measurement, blood pressure was measured noninvasively using a rat mouse sphygmomanometer (Muromachi Kikai Co., Ltd., MK-2000).

4) Examination by application of LPS diluent (1) Application and intraanal pressure measurement procedure The intraanal pressure was measured twice before application, and the average value was taken as the previous value (0 hour). After measuring the previous value, the LPS dilution was applied to the anus in amounts of 0.3 ng / kg, 3 ng / kg, 30 ng / kg, 300 ng / kg, and 3000 ng / kg per kg of body weight. Similarly, 0.3 mL / kg was applied to the blank. The anal pressure and blood pressure were measured 2 and 4 hours after application.

Example 2: Effect of nitric oxide synthase inhibitor in ointment containing E. coli dead bacteria suspension
Slc: SD male male rats (9-10 weeks old, Nippon SLC Co., Ltd.), intraocular pressure by topical application of E. coli dead liquid suspension containing LPS (commercially available from Maruho Co., Ltd.) The effect on was examined. The ointment was applied into the anus of the rat in an amount of 160 mg / kg. Three hours after application, distilled water for injection containing L-NAME (Ng-nitro-L-arginine methyl ester) or aminoguanidine, which is a nitric oxide synthase inhibitor, was dropped into the anus (inhibitor dose was 1). 10 mg per anus).

  Moreover, it measured similarly about the rat (4 animals) and placebo (4 animals) which apply | coated the ointment, without adding a nitric oxide synthesis inhibitor.

  The anal pressure was measured twice before application and every hour after application until 6 hours later. The measurement method and the evaluation method are the same as in Example 1. The results are shown in FIGS. Suppression of anal pressure-reducing effect (decrease in anal pressure area and number of anal pressure contraction) by ointment 1 and 2 hours after administration of nitric oxide synthase inhibitor (4 and 5 hours after application of ointment) It was confirmed that the action of LPS was inhibited by the inhibitor. From this result, it was confirmed that the decrease in anal pressure was due to nitric oxide and the action was due to LPS in the ointment.

It is a graph which shows the change rate of the anal pressure contraction number 2 hours after LPS dilution liquid application and 4 hours. It is a graph which shows the change rate of the anal pressure area 2 hours after LPS dilution liquid application and 4 hours after. It is a graph which shows the change rate of the blood pressure 2 hours after LPS dilution liquid application and 4 hours after. It is a graph which shows the relationship between the LPS application amount and the anal pressure contraction number change rate. It is a graph which shows the relationship between LPS application amount and anus pressure area change rate. It is a graph which shows the influence of L-NAME (A) which is a nitric oxide inhibitor, or aminoguanidine (B) with respect to the anal pressure contraction number reduction | decrease effect | action of the ointment containing E. coli dead bacteria suspension. The arrow indicates the time when the inhibitor was administered. It is a graph which shows the influence of the nitric oxide inhibitor (A) or aminoguanidine (B) with respect to the anal pressure area reduction effect | action of the ointment containing E. coli dead bacteria suspension. The arrow indicates the time when the inhibitor was administered.

Claims (5)

An anal pressure-reducing topical preparation for application to the anorectal region and the perianal region, comprising lipopolysaccharide as an active ingredient. Constipation及 beauty of at least one disease selected from the group consisting of hemorrhoidal disease with increasing anal pressure for preventing or treating, the lipopolysaccharide of the active ingredient, for application around anorectal region and anal Anal pressure reduction external preparation. The anal pressure-reducing topical preparation according to claim 2, wherein the hemorrhoid disease associated with increased anal pressure is anal fissure or hemorrhoid associated with increased anal pressure. For improving the quality of at least one life of patients suffering from a disease selected from the group consisting of hemorrhoidal diseases associated with constipation及 beauty anal pressure rise, and lipopolysaccharide as an active ingredient, anorectal region and anal around An anal pressure-reducing topical preparation for application. The anal pressure-reducing topical preparation according to claim 4, wherein the hemorrhoid disease associated with increased anal pressure is anal fissure or hemorrhoid associated with increased anal pressure.