JPS58103321A - Remedy for hemorrhoids - Google Patents

Abstract

PURPOSE:To provide a remedy for hemorrhoids, especially for true hemorrhoids, free from the load to the hepatic functions, by using L-carnosine or its salt as an active component. CONSTITUTION:The objective remedy for hemorrhoids contains L-carnosine or its salt (e.g. sodium salt, potassium salt, triethylamine salt, etc.) as an active component. L-Carnosine is a compound of formula, and the pH of its aqueous solution is 8.0-8.5. The compound of formula can be prepared by (1) reacting carbobenzoxy-beta-alanine with phosphorus pentachloride, (2) converting the resultant chloride to methyl ester with methanol, (3) converting the product through hydrazide to azide, (4) coupling the compound with L-histidine methyl ester, and (5) removing carbobenzoxy group by catalytic reduction. The compound of formulaIis easily soluble in water, and can be used easily as an injection by sealing the 3-5% or 10% aqueous solution in an ampule.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for hemorrhoidal disease, which is characterized by containing KL-carnosine or a salt thereof as an active ingredient.

Hemorrhoid disease is a general term for diseases that occur in or around the anus.In medical terms, it is called anal fissure (anal fissure), which is a superficial ulcer that occurs on the skin or mucous membrane of the anus. ,Ko)
Purulent inflammation in the subcutaneous or submucosal tissues, abscesses, or their manifestations or cuts! 1llIK) Hemorrhoids are varicose veins formed in the anus (commonly known as 5@anaji) and 3) Hemorrhoids are varicose veins in the anal area (commonly known as %/% u1 warts) and this is outside the anus. It can be divided into prolapse, prolapse, etc. Among these hemorrhoidal diseases, hemorrhoids and anal prolapse are extremely common lesions, and Japanese adults often suffer from go-
g.

He is said to have hemorrhoids. Originally, the vicinity of the anus is the junction point #C of the body surface vein system and abdominal visceral vein threads (portal vein system), where countless veins gather to form the rectal venous plexus and anal vein II (upper and lower hemorrhoidal veins). 11 II) to form the sho,
Abdominal pressure is often caused by habitual constipation, playing a musical instrument, asthma, diarrhea, etc.; veins are compressed due to pregnancy or sitting for long periods of time; engorgement due to drinking alcohol, etc. , causing stagnation of the flow of water and dilation of the veins, which can easily lead to varicose veins.

Hemorrhoids (mass) are classified according to their location: I (internal hemorrhoids are those that develop under the mucosa of the intestinal anal region, that is, the rectal columnar plexus, and external ones are those that develop in the anal plexus). They are called hemorrhoids. Therefore, internal hemorrhoids exist above the internal anal sphincter, which is surrounded by the mucous membrane Kll, and below the external anal sphincter, which is surrounded by the external nucleus and the anal skin KW1. When hemorrhoids occur somewhere in between and are partially covered by the skin and partially covered by mucous membranes, they are sometimes called intermediate hemorrhoids.

In addition, anal prolapse is a condition in which an internal hemorrhoid is gradually pushed out of the anus, and part or all of it prolapses outside the anus, and is essentially not different from hemorrhoids.The main symptoms are bleeding and pain during defecation. However, the degree of bleeding depends on the size of the nucleus,
It varies depending on the number and degree of erosion, and the lil that wipes the core area
! The pain ranges from those that stick to the skin, those that drip, and those that leak out, and the pain ranges from mild to severe pain, pain that only occurs during defecation, pain that lasts for a long time, and severe pain that makes it difficult to walk. They vary in size and can even make it impossible to sleep.

Anal fissures are fissure-like cracks or ulcers that occur at the border of the skin and mucous membranes of the anus.Although constitutional predispositions are also involved, they are generally more likely to occur due to the passage of hard stools, and the main symptom is severe burning pain during defecation. , with minor secondment.

In addition, hemorrhoids are caused by the opening of the private canal; external, internal, and complete hemorrhoids, @
Most of them are tuberculous, and perianal inflammation (perianal abscess) or perirectal inflammation causes acute inflammation near the anus and accumulates pus, which can be drained after it ruptures or through an incision. Many cases result in pus-filled hemorrhoids.

As can be seen from the above explanation, hemorrhoids, anal fissures (hemorrhoids), and hemorrhoids are completely separate diseases, even though they are referred to as hemorrhoid diseases.Therefore, the treatment for them is based on the symptoms of hemorrhoids. Depending on the situation, Hinoki's method is adopted. Relatively mild hemorrhoids and anal fissures may be temporarily relieved by resting the area, improving irregular bowel movements and constipation caused by the cause, and stopping drinking alcohol, but generally they cannot be completely cured. Symptoms often persist or recur, therefore, drugs suitable for each treatment purpose, such as anti-inflammatory agents, vasoconstrictors,
Suppositories and ointments containing appropriate astringents, local anesthetics, analgesics, sterilizing disinfectants, etc. are used. However, when a specialist doctor diagnoses and treats a patient out of shame for the diseased area, there is a possibility that the disease has progressed and worsened due to the inappropriateness of amateur therapy using over-the-counter drugs in the early stages of disease onset. Not a few. For this reason, there are very few drugs that can reliably produce excellent effects in a short period of time as therapeutic drugs, and in particular, most drugs that are so effective as to cause the disappearance or complete cure of hemorrhoids are overlooked. Surgery is ultimately performed for all long-term illnesses. It is said that almost all cases of hemorrhoids cannot be cured with drug treatment, and that surgery can, in principle, be done at no cost.

The present inventor has focused on the unique physiological activity of L-carnosylv, which is a pedetide in vivo, and has spent many years working and researching its physiological significance and pharmacological usefulness. It was unexpectedly discovered that L-carnosine or a physiologically acceptable salt thereof has excellent efficacy as a therapeutic agent for hemorrhoid diseases, including hemorrhoids.

L-carnosinef tr h β-alanyl-L-his'f f
L-histidene and β-alanine were discovered in Liebig's meat extract by K.
=+0.00 (H,0), and is a tasteless, odorless, white crystalline powder that is easily soluble in water. The pH of its aqueous solution is 0 - g, s.

Since its discovery, many researchers have studied its physiological raison d'être, pharmacological effects, etc., but no significant pharmacological effects have been discovered on any organ, and its physiological raison d'être remains unknown until now. It is a substance. It is a substance that exists in large amounts in the liver and muscles of various types of animals, and is consumed as food (such as meat), and is biosynthesized from histidene and β-alanine. The ingested 'L-carnosine enters the bloodstream and is broken down into carnosin-k' L-histidene and β-alanine, which serve as a nutritional source, and some of it is resynthesized into carnosine (L-carnosine). β as an intermediate in lunosine biosynthesis
-alanyl-l-methyl-histidene (^n5erin)
There is e)]・ As mentioned above, carnosine is a food-like substance,
After absorption, carnosiner JeK in the blood is decomposed into nutritional amino acids, which is completely different from the fact that many pharmaceuticals are injected into the liver and place a burden on liver function. The method for synthesizing L-carnosine is known.
Biological Chanlstry, /Q
The.

7S3, /93, carbobenzoxy β-alanine was converted into chloride with phosphorus pentachloride, converted into methyl ester with methanol, converted into azide via hydroazoid, and converted into azide.
Lunosine can be obtained by coupling with histidene methyl ester and finally removing the carp-benzoxy group by contact. The present invention is L-
It also includes therapeutic agents consisting of carnosine salts, but carnosine salts include carnosine salts. salts based on phosphoric acid groups, and 7
There are many acid addition salts with pharmacologically acceptable acids based on the 2-group, and there are also acid addition salts with both the carbanoic acid and 7s-groups. Toss the calcaric acid group (salt with sodium yum,
Potassium, calcium salts include salts with metals such as (j7k i), ammonium salts and substituted ammonium salts, salts with trialkylamines and other amines such as triethylamine; Motozu (Salts include hydrochloride, sulfate, phosphate, acetate, propionate, lactate, tartrate, citrate, succinate, maleate, pensene sulfonate, toluene sulfone) These can be prepared by reacting free carnosine with a stoichiometrically calculated amount of the selected acid or base by methods known per se.

Since its discovery in 1900, lunosine has been present in large quantities in the body, and its physiological significance and pharmacological effects have been investigated. Alternatively, research has been conducted to link it to muscle function due to its presence in large amounts in muscles, but sagging is not a significant pharmacological effect, and its significant stimulatory effect on peripheral organs has not been clarified.

Next, the acute toxicity of KL-carnosine will be described.

Various doses of carnosine were administered intraperitoneally and orally to 70 acutely toxic mice, and symptoms of acute toxicity were observed at S hours after administration. LD30 is the number of deaths after 72 hours) Van der Waerde
Calculated using the n) method. L-carnosine was administered at a dosage of 0. / -0,3 m/ /, Ot K was dissolved in physiological saline.

Symptoms of addiction to Shi-Runosine are: is, oo.

Approximately 30 minutes after intraperitoneal injection 4 (LD,...), the patient's spontaneous movements began to decline, and he took a prone position, and his respiratory rate decreased and became irregular, but the righting reflex or withdrawal reflex disappeared. Half of the patients showed occasional fist-to-tail reactions and developed clonic convulsions. As the symptoms progressed further, the patient repeatedly rolled over, and the reflex light path in response to contact stimulation caused the patient to develop convulsions, progressing to tonic convulsions 11, which led to death.

Half of the cases died after 1 hour and 30 minutes, after 1 hour KgO@, and after S hour, all cases died.

/! Although there was almost no effect after oral administration of 0.000 μ/kg, 10 cases died after 12 hours.

Chapter/Table Riichi carnosine LD.

The acute toxicity (wolfberry time value) to DD male mice is as shown in the table, and it can be said that L-carnosine is a compound with extremely low toxicity.

The therapeutic agent of the present invention may be in any dosage form as long as carnosine can be conveniently applied to the disease, such as ointments, powders, injections, troches, suppositories, etc.
Medicinal forms of hinoki such as enema preparations can be prepared, and these may be used alone or in combination depending on the symptoms.

To prepare the ointment, according to techniques well known in the pharmaceutical industry, a fine powder of carnosine is added to an ointment base such as beeswax, sesame seeds, etc. in an amount to give an ointment of the desired concentration.

Animal and vegetable oils such as peanut oil, olive oil, lard, and beef tallow;
dehydrated lanolin, yellow and white petrolatum, glycerin,
o6, resin, higher alcohol, glycol, hydrocarmenglu ointment, surfactant, preservative, or a mixture thereof, and thoroughly stir and knead until homogeneous.

To make a powder formulation, synthesize 1 carnosine to 200
Pour into a glass container as a mesh-sized acid powder, approx.
Dry heat evaporate at a temperature of 0° C. for several hours.

Half-open is made in the same way as ointment, for example, a preservative and carnosine are mixed uniformly in a dissolved half-open base, and then cast! 1. Pour IVC, solidify and increase.

[-Since carnosine is easily hydrated and soluble, KL-carnosine can be easily converted to 711% SO or 1O under aseptic operation.
An aqueous solution of I11 can be made. This 1 is sealed in an ampoule under an inert gas flow and injected using ordinary injection IrF. In addition, carnosine powder was lyophilized into ampoules or vials by an uncontrolled operation, and immediately before injection, it was dissolved in distilled water.
It may be used immediately for injection as an aqueous solution for vomiting, vomiting, or vomiting.

Next, we will discuss formulation examples of the stay-at-home agent of the present invention.

Formulation example/(half-open) Phosco E-7 using synthesized Shichiriki Runosinwo! I (Marumen Pharmaceutical Co., Ltd.) as a base, the following treatment (half-opened portion) - Carnosine O, Cof / IF ethyl benzoate 0.000g! ;f
Hosco E-7. A half-open product was produced in an appropriate amount.

L-1) Lunosine and ethyl paraoxybenzoate 200
Phosco E-9j passed through a mesh sieve and dissolved at 50℃
K IIllll was prepared by adding K little by little to make it uniform. Pressure was applied to the mold at 3 g°C, and the mixture was allowed to cool to solidify at room temperature, and then cooled in a refrigerator. This was removed from the mold and wrapped in fine paper.

Formulation example, 2 (ointment) Synthesized Shichiriki Lunosine 1kF @I, No1 Hydrocar/
The following treatment using N'l'lu soft blue base as a base [-Carnosine lOt Hydropower-- N'l'ul Ointment A 90t100? A lθ 1 plaster was prepared.

Formulation Example 3 (Powder) Synthesized carnosine was made into a fine powder using an electric mortar and sieved through a 200-mesh sieve.

This acid powder was placed in a glass container and sterilized by dry heat at 721° C. for 3 hours to obtain a powder.

Formulation Example 1I (injection) Under non-toxic operation, an equivalent mixture of powders of KL-carnosine and L-carnosine hydrochloride was mixed with 3, 54 or 10
4 (all 4 L) was filled into an ampoule as an aqueous solution.

Next, clinical examples using the therapeutic agent of the present invention will be shown.

Claims (1)

[Claims] A therapeutic agent for hemorrhoidal diseases containing lunosine or its salt as an active ingredient.