JP4245844B2 - Acupuncture treatment - Google Patents

Description

【式２】

【００１９】
浮腫率および抑制率を評価した結果を以下に示す。
【表１】

【００２０】
以上の結果より、イノシトールヘキサニコチネートは浮腫率および抑制率において抗炎症薬であるインドメタシンと同様の抗浮腫作用を示した。一方、血管拡張作用を有する硝酸イソソルビドは、抗浮腫作用を示さなかった。
【００２１】
試験例２
ペントバルビタール（25mg / kg）腹腔内麻酔下、Wistar系雄９週齢２２２〜２７３ｇのラットの直腸を摘出し、氷冷下栄養液中で歯状線より口側２ｍｍの幅の筋層を採取して幅２ｍｍ、長さ２０ｍｍの筋条片とし、セルフィンを付け、内肛門括約筋の走行に従い懸垂し、内肛門括約筋標本を作製した。
標本は混合ガス（９５％Ｏ_２−５％ＣＯ_２）送気下の栄養液を満たしたマグヌス槽に懸垂し、液温を３７℃に保ち、１ｇの負荷をかけて実験開始まで栄養液を還流し、筋緊張が一定になった後試験を開始した。
張力変化をＦＤピックアップ及び圧力アンプを介してレコーダ上に等尺に記録した。
始めに塩化バリウム溶液（３×１０^−３ｇ／ｍＬ）を添加し、後に塩化バリウム溶液（２×１０^−３ｇ／ｍＬ）を数回添加して、筋収縮が安定したときのベースラインと極大ピークの頂点までの幅をレコーダ上から読み取り、塩化バリウム収縮値（ｍｍ）とした。なお、塩化バリウム溶液を添加した後は、ウオッシュアウトを３回行うこととした。
また、下記表３の実施例及び比較例欄に記載した化合物を栄養液に分散又は溶解して試験溶液を調製し、これを添加して、さらに５分後に塩化バリウム溶液（２×１０^−３ｇ／ｍＬ）を添加して収縮値をレコーダから読み取り、被験物質収縮値（ｍｍ）とした。
被験物質の内肛門括約筋収縮抑制率は、下記の式より算出した。
【式３】

【００２２】
被験物質の調製はすべて用時調製とした。調製方法を以下に示す。
１． ニトログリセリン、硝酸イソソルビド
：無水エタノールに溶解後、[表２]の組成の栄養液で希釈した。エタノール量は試験系に影響を与えない量とした。
２． 塩酸パパベリン
：[表２]の組成の栄養液に溶解した。
３． イノシトールヘキサニコチネート
：乳鉢を用いて[表２]の組成の栄養液に懸濁した。
分散液については、光学顕微鏡により分散状態を観察した。
【００２３】
栄養液の組成を以下に示す。
【表２】

【００２４】
内肛門括約筋収縮抑制率測定結果を評価した結果を以下に示す。
【表３】

【００２５】
以上の結果より、イノシトールヘキサニコチネートは筋弛緩薬である塩酸パパベリンと同様の内肛門括約筋収縮抑制効果を示した。
また、平滑筋を弛緩させる作用のあるニトログリセリンよりも優れた内肛門括約筋収縮抑制効果を示した。
【００２６】
【発明の効果】
本発明の痔疾治療剤は、イノシトールヘキサニコチネート、シクランデラート、酒石酸ニコチニックアルコール、ヘプロニカート、塩酸イソクスプリン、クエン酸ニカメタート、硫酸バメタンまたは塩酸トラゾリンを有効成分として含有することにより、弛緩作用、抗浮腫作用、血液循環改善効果を奏することができ、有効性の高い痔疾治療剤を提供することができる。
また、局所に投与することにより、全身作用が軽減され、副作用の軽減が図られることとなり、安全性の高い痔疾治療剤を提供することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel therapeutic agent for hemorrhoids that treats hemorrhoids such as anal fissures, anal ulcers, anal sphincter renunculation, internal hemorrhoids, and external hemorrhoids.
[0002]
[Prior art]
A hemorrhoid is a disease that occurs in the anus or rectum, and is roughly classified into hemorrhoids, anal fissures, and hemorrhoids, and the symptoms are characterized by symptoms such as bleeding, pain, swelling, and itching.
Hemorrhoids refers to changes in the anal venous plexus like varicose veins. Hemorrhoids are gradually formed by repeated congestion in the anal venous plexus due to constipation, pregnancy, asthma, prolonged sitting, eating and drinking. There are inner hemorrhoids and outer hemorrhoids depending on the site of hemorrhoids.
Anal fissure refers to a rupture of the anal epithelium that is rapidly caused by excessive progress. It is also called anal fissure, rupture, tear and tear, and the main symptoms are anal pain and bleeding during defecation.
A fistula is a fistula that exists in and around the anal canal. In general, it is caused by non-specific bacterial infection.
[0003]
In many of the therapeutic agents for hemorrhoids, anti-inflammatory agents, local anesthetics, vasoconstrictors, astringents, etc. are used alone or as a combination agent. In some cases, an attempt has been made to treat anal fissure by temporarily bringing the internal anal sphincter into relaxation or paralysis for the purpose of treating anal fissure. For this purpose, nitroglycerin ointment, nifedipine ointment and the like are used. In nitroglycerin ointment, nitroglycerin is metabolized in the body and becomes a non-choline adrenergic inhibitory nerve transmitter, NO (nitrogen monoxide), and exerts an action of relaxing smooth muscle. Nifedipine, which is a calcium antagonist, relaxes vascular smooth muscle by suppressing the inflow of Ca, which is a substance related to muscle excitation and contraction, into smooth muscle.
[0004]
[Problems to be solved by the invention]
Components such as anti-inflammatory drugs, local anesthetics, vasoconstrictors, and astringents are intended to improve symptoms of epilepsy, are symptomatic, and are not strictly intended for treatment. In addition, nitroglycerin ointment and nifedipine ointment, which is a calcium antagonist, are generally considered to have systemic effects regardless of the route of administration. In such a case, a person having a cardiovascular disease may have already been used, and there is a problem that it is difficult to separate or control the pharmacological action. In addition, nitroglycerin has a high frequency of side effects such as headaches, and there is a caution from this viewpoint in use.
Under such circumstances, it is difficult to say that a conventional anti-manic agent has sufficient effects. Therefore, an object of the present invention is to provide a drug for treating hemorrhoids that is highly safe and effective.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to achieve the above object, the present inventor has found that inositol hexanicotinate, cyclandelate, nicotinic alcohol tartrate, hepronicart, isoxpurine hydrochloride, nicamethate citrate, bamethane sulfate, or torazoline hydrochloride are conventional anti-wrinkle agents. It has been found that it has a safe and highly effective treatment for hemorrhoids having a combination of a relaxing action, an anti-edema action, and an effect of improving blood circulation, and further studies have been made to complete the present invention. That is, an object of the present invention is to provide a therapeutic agent for hemorrhoids containing inositol hexanicotinate, cyclandelate, nicotinic alcohol tartrate, hepronicart, isoxpurine hydrochloride, nicamethate citrate, bamethane sulfate or trazoline hydrochloride as active ingredients.
[0006]
That is, the present invention
(1) A therapeutic agent for hemorrhoids comprising inositol hexanicotinate, cyclandelate, nicotinic alcohol tartrate, hepronicart, isoxpurine hydrochloride, nicamethate citrate, bamethane sulfate or trazoline hydrochloride as an active ingredient for treatment of hemorrhoids,
(2) A hemorrhoid treatment agent comprising inositol hexanicotinate, cyclandelate, nicotinic alcohol tartrate or hepronicart as an active ingredient for hemorrhoid treatment,
(3) In addition, one or more selected from corticosteroids, local anesthetics, antipyretic analgesic / anti-inflammatory agents, anti-inflammatory / anti-pruritic / wound healing agents, vitamins, sulfa drugs, antiseptics, antihistamines, antipruritic / enteric agents The hemorrhoid treatment agent according to (1) or (2),
(4) The agent for treating hemorrhoids according to any one of (1) to (3), wherein the agent is for anal or rectal administration,
(5) Any one of the above (1) to (4), wherein the dosage form is selected from suppositories, ointments, aerosols, solutions, suspensions, emulsifiers, patches, poultices, liniments and lotions. Remedy for hemorrhoids,
(6) The hemorrhoid treatment agent according to any one of (1) to (5), wherein the dosage form is a suppository or an ointment,
(7) Use of inositol hexanicotinate, cyclandelate, nicotinic alcohol tartrate, hepronicart, isoxpurine hydrochloride, nicamethate citrate, bamethane sulfate or trazoline hydrochloride active ingredient for treatment of hemorrhoids,
About.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The active ingredient for the treatment of hemorrhoids of the present invention is inositol hexanicotinate, cyclandelate, nicotinic alcohol tartrate, hepronicart, isoxsuprine hydrochloride, nicamethate citrate, bamethane sulfate or trazoline hydrochloride. The active ingredient for treatment of hemorrhoids according to the present invention is preferably inositol hexanicotinate, cyclandelate, nicotinic alcohol tartrate or hepronicart. More preferred is inositol hexanicotinate. The effective dose when used as a hemorrhoid treatment agent is usually in the range of 50 mg / day to 2000 mg / day.
[0008]
The pharmaceutically acceptable carrier may be either an oleaginous base or a water-soluble base. Examples of the oleaginous base include normal fats such as cacao butter, lauric fat, beef tallow or semi-synthetic hard fat. Base that is solid, or liquid or semi-solid at room temperature, for example, palm oil, palm kernel oil, camellia oil, olive oil, soybean oil, sesame oil, corn oil, other medium chain fatty acid triglycerides, liquid paraffin, white Vaseline, purified lanolin or isopropyl myristate, such as glyceryl monostearate, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, dextrin fatty acid ester, sucrose fatty acid ester, etc. Surfactants and Stearyl alcohol, including but one or more combinations of higher alcohols such as cetanol, as long as it is pharmaceutically acceptable is not limited thereto.
Examples of the water-soluble base include, but are not limited to, glycerin, polyethylene glycol, sorbitol, 1,3-butylene glycol, propylene glycol, ethanol, purified water, and the like.
As a carrier used for a suppository, a hard fat is preferable. Moreover, as a carrier used for ointment, white petrolatum, medium chain fatty acid triglyceride, and liquid paraffin are preferable.
[0009]
If necessary, the agent for treating hemorrhoids according to the present invention may further contain one or more agents that are usually used as agents for treating hemorrhoids. Such agents include, for example, corticosteroids such as prednisolone acetate, hydrocortisone or betamazone, local anesthetics such as lidocaine or dibucaine, e.g. antipyretic analgesic and anti-inflammatory agents such as indomethacin, aspirin, sodium salicylate, etc. Anti-inflammatory agents such as lysozyme chloride or glycyrrhetinic acid, for example, antipruritic agents such as crotamiton, wound healing agents such as allantoin, for example vitamin agents such as liver oil, ergocalciferol, riboflavin, pyridoxine hydrochloride, tocopherol or tocopherol acetate, for example , Sulfisomidine, sodium sulfisomidine, sulfa drugs such as homosulfamine or sulfadiazine, chlorhexidine hydrochloride, cetrimide, decalinium chloride or benzalkonium chloride Fungicides, such as diphenhydramine, diphenhydramine hydrochloride, antihistamines such as chlorpheniramine maleate, although such Tomekata-intestinal disorders include, without being limited thereto.
[0010]
Although the administration method is not particularly limited, anal or rectal administration is preferable in the present invention. Specifically, ointments are applied directly to the anus or suppositories are administered into the rectum. By directly applying the hemorrhoid treatment agent to the affected area, bleeding, pain, swelling, itching, etc. of the affected area can be effectively treated.
[0011]
Examples of the dosage form used in the present invention include, but are not limited to, suppositories, ointments, aerosols, solutions, suspensions, emulsions, patches, poultices, liniments, lotions and the like. . Preferably, a dosage form such as a suppository or ointment that can be administered accurately to the administration site of the affected area is preferable. As the suppository, for example, a base suppository, a gelatin capsule suppository, a tablet suppository and the like can be used. Ointments, liquids and the like are usually applied around the anus, but can be injected into the anus and rectum by storing them in an injection container as desired.
[0012]
【Example】
Examples of the present invention will be described below. However, the following disclosure is only preferred examples of the present invention, and does not limit the technical scope of the present invention.
[0013]
Example 1
[Formulation example]
Inositol hexanicotinate 200mg
Hard fat 1500mg
Inositol hexanicotinate was added and dispersed in a hard fat previously heated to 50 ° C. and melted, and this liquid was filled into a suppository mold and solidified at room temperature to obtain a hemorrhoid treatment agent.
[0014]
Example 2
[Formulation example]
Cyclandelato 10g
Medium chain fatty acid triglyceride 15g
2.5g glyceryl monostearate
Vaseline 72.5g
Treatment of hemorrhoids with medium-chain fatty acid triglycerides heated to 60 ° C by adding cyclandelate, and adding this solution to petrolatum and glyceryl monostearate previously melted at 70 ° C and cooling them together An agent was obtained.
[0015]
Example 3
[Formulation example]
Inositol hexanicotinate 10g
Lidocaine 3g
Medium chain fatty acid triglyceride 15g
2.5g glyceryl monostearate
Petrolatum 69.5g
Dissolve lidocaine in medium-chain fatty acid triglyceride heated to 60 ° C, add inositol hexanicotinate to this, disperse it, and add this solution to petrolatum previously melted at 70 ° C and glyceryl monostearate and mix evenly. Upon cooling, a hemorrhoid treatment agent in the form of an ointment was obtained.
[0016]
Example 4
[Formulation example]
Hebronicat 100mg
Lidocaine 60mg
Tocopherol acetate 60mg
Allantoin 20mg
Hard fat 1460mg
Lidocaine and tocopherol acetate are added and dissolved in a hard fat previously heated to 50 ° C. and dissolved, and hebronicato and allantoin are added and dispersed therein. This solution is filled in a suppository mold and solidified at room temperature. A therapeutic agent was obtained.
[0017]
Example 5
[Formulation example]
7.5g tartrate nicotinic alcohol
Lidocaine 3g
Liquid paraffin 25g
Medium chain fatty acid triglyceride 15g
Dextrin palmitate 6g
Petrolatum 43.5g
Lidocaine is dissolved in a mixture of medium-chain fatty acid triglyceride and liquid paraffin heated to 60 ° C., cooled to 40 ° C., nicotinic alcohol tartrate and dextrin palmitate are added, and dispersed uniformly. Vaseline melted at 0 ° C. was added and immediately heated to 90 ° C. This liquid was cooled to near room temperature with cold water to obtain a hemorrhoid treatment agent in the form of a semisolid ointment.
[0018]
Test Example 1 Effect test on dextran footpad edema A group of 10 5-week-old male Wistar rats was marked with magic on the rat right hind limb and the footpad volume was measured using a plethysmometer (UNICOM, TK-10). Measured and used as a pre-dose value.
Examples and Comparative Examples shown in Table 1 below were dissolved or dispersed in physiological saline to prepare an administration solution, and 0.05 mL of this solution and 0.05 mL of 1% dextran physiological saline were administered subcutaneously to the right hind leg footpad.
The footpad volume was measured again 1, 2, 3 and 5 hours after administration. The edema rate and the inhibition rate were calculated from the difference between the footpad volume after induction with respect to the footpad volume before edema induction with dextran-saline administration. A physiological saline solution was used for the control group.
[Formula 1]

[Formula 2]

[0019]
The results of evaluating the edema rate and the inhibition rate are shown below.
[Table 1]

[0020]
From the above results, inositol hexanicotinate showed an anti-edema action similar to that of indomethacin, an anti-inflammatory drug, in terms of edema rate and inhibition rate. On the other hand, isosorbide nitrate having a vasodilatory action did not show an anti-edema action.
[0021]
Test example 2
Under intraperitoneal anesthesia with pentobarbital (25 mg / kg), the Wistar male 9-week-old 222-273 g rat's rectum was removed, and the muscle layer 2 mm wide from the dentate line was collected in nutrient solution under ice-cooling. Then, a strip of 2 mm in width and 20 mm in length was formed, a self fin was attached, and it was suspended according to the running of the internal anal sphincter to prepare an internal anal sphincter specimen.
The sample is suspended in a Magnus tank filled with nutrient solution under mixed gas (95% O ₂ -5% CO ₂ ), kept at a liquid temperature of 37 ° C., and loaded with 1 g of nutrient solution until the start of the experiment. The test was started after reflux and muscle tone became constant.
The tension change was recorded isometrically on a recorder via an FD pickup and a pressure amplifier.
First, add the barium chloride solution (3 × 10 ⁻³ g / mL), and then add the barium chloride solution (2 × 10 ⁻³ g / mL) several times. The width to the peak of the maximum peak was read from the recorder and used as the barium chloride shrinkage value (mm). In addition, after adding a barium chloride solution, it was decided to wash out 3 times.
In addition, a test solution was prepared by dispersing or dissolving the compounds described in Examples and Comparative Examples in Table 3 below in a nutrient solution, and this was added, and after another 5 minutes, a barium chloride solution (2 × 10 ⁻³ g / mL) was added, and the contraction value was read from the recorder to obtain the test substance contraction value (mm).
The inhibition rate of the internal anal sphincter contraction of the test substance was calculated from the following formula.
[Formula 3]

[0022]
All test substances were prepared at the time of use. The preparation method is shown below.
1. Nitroglycerin, isosorbide nitrate: After dissolving in absolute ethanol, it was diluted with a nutrient solution having the composition shown in [Table 2]. The amount of ethanol was determined so as not to affect the test system.
2. Papaverine hydrochloride: dissolved in a nutrient solution having the composition of [Table 2].
3. Inositol hexanicotinate: suspended in a nutrient solution having the composition of [Table 2] using a mortar.
About the dispersion liquid, the dispersion state was observed with the optical microscope.
[0023]
The composition of the nutrient solution is shown below.
[Table 2]

[0024]
The results of evaluating the measurement results of the internal anal sphincter contraction inhibition rate are shown below.
[Table 3]

[0025]
From the above results, inositol hexanicotinate showed an internal anal sphincter contraction inhibitory effect similar to that of papaverine hydrochloride, which is a muscle relaxant.
In addition, it showed a superior inner anal sphincter contraction inhibitory effect than nitroglycerin, which has the action of relaxing smooth muscle.
[0026]
【The invention's effect】
The therapeutic agent for hemorrhoids of the present invention contains inositol hexanicotinate, cyclandelate, nicotinic alcohol tartrate, hepronicart, isoxpurine hydrochloride, nicamethate citrate, bamethane sulfate or trazoline hydrochloride as an active ingredient, thereby relaxing, antiedema action, It is possible to provide a hemorrhoid treatment agent that has an effect of improving blood circulation and is highly effective.
Further, when administered locally, systemic effects are reduced and side effects are reduced, and a highly safe hemorrhoid treatment agent can be provided.

Claims (6)

A hemorrhoid treatment agent comprising inositol hexanicotinate as an active ingredient for hemorrhoid treatment. Furthermore, adrenocortical hormones, local anesthetic, antipyretic analgesics, anti-inflammatory agents, anti-inflammatory, antipruritic, wound healing agents, vitamins, sulfa drugs, disinfectants, antihistamines, comprising one or two or more selected from Tome瀉-antiflatulent claims Item 6. The hemorrhoid treatment agent according to Item 1 . The agent for treating hemorrhoids according to claim 1 or 2 , which is used for anal or rectal administration. The therapeutic agent for hemorrhoids according to any one of claims 1 to 3 , wherein the dosage form is selected from suppositories, ointments, aerosols, solutions, suspensions, emulsifiers, patches, poultices, liniments and lotions. The agent for treating hemorrhoids according to any one of claims 1 to 4 , wherein the dosage form is a suppository or an ointment. Use of inositol hexanicotinate for the manufacture of a hemorrhoid treatment.