JPS61293927A - Preventive and remedy for hepatic disease - Google Patents

Abstract

PURPOSE:To prevent a preventive and remedy for hepatic diseases, containing one or more kinds of proteinases as active component, migrating to the liver of disordered part in large quantity, effective for the dissipation of edema and formation of blood vessel, and having remarkable effect especially for the remedy of chronic hepatitis and hepatocirrhosis. CONSTITUTION:The objective preventive and remedy for hepatic diseases can be produced by using one or more kinds of proteinases as active component. Extremely large amount of the proteinase migrates to the liver of the disordered part, exhibits the effect to dissipate the edema of the disordered tissue, to infiltrate into globoid cell, to form new blood vessel and to dissolve the fibrin. It promotes the remedy of chronic inflammation image of liver and prevents the canceration of the disordered part.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a prophylactic and therapeutic agent for liver diseases containing one or more proteolytic enzymes as an active ingredient.

[Prior Art] Liver diseases are already well known, but especially in recent years, viral hepatitis and alcoholic hepatitis have been on the rise and have become a social problem.

As stated in recent new theories, cases of transition from acute hepatitis to chronic hepatitis, from chronic hepatitis to cirrhosis, and from cirrhosis to liver cancer are increasing.

[Problems to be Solved by the Invention] Therefore, it is an urgent task at present to cure liver damage as early as possible and prevent it from becoming cancerous, and it is extremely important to save human lives.

[Means for Solving the Problems] As a result of many years of research into proteolytic enzymes, the present inventors have discovered that proteolytic enzymes are useful in preventing and treating various liver diseases. .

The present invention is based on this knowledge, and is a preventive and therapeutic agent for liver diseases containing a proteolytic enzyme as an active ingredient.

[Function and Examples] Examples of proteases that are active ingredients of the present invention include trypsin, α-chymotrypsin, promelain, papain, serratiopeptidase, seabrose, protease, streptokinase, protase, pronase, procyme, and urokinase. , vancreatin, fibrinolysin, elastase, etc., and these may be used alone or in an appropriate combination of two or more.

The prophylactic and therapeutic agent of the present invention can be administered orally in the form of tablets, capsules, powders, granules, etc., or parenterally as injections, skewers, ointments, etc., using conventional formulation techniques. Furthermore, the solution can be used in combination with other drugs, such as other liver drugs, kidney drugs, antibiotics, immunostimulants, antitumor drugs, etc. The dosage varies depending on the type of enzyme, degree of disease, administration method, dosage form, etc., but in the case of oral administration, it is 1 to 50 doses per adult per day.
The objective can be achieved with 1 g of 000 ff or, in the case of enzymes unstable in gastric fluid, with 1 to 1000 tng as an enteric preparation. In addition, when the dosage is expressed in enzyme units of each enzyme, in enteric-coated preparations, serratiopeptidase is 20,000 to 400,000 serratiopeptidase units, promelain is 40,000 to 800,000 bromelain units, and streptokinase is: 20,000 to 800,000 units, pronase 10,000 to 5
The objective can be achieved by oral administration of 00,000 tyrosine units. Depending on the type of enzyme, it is preferable to use an enteric-coated preparation.

The feature of the liver disease prevention and treatment agent of the present invention is that the absorbed proteolytic enzymes are transferred to the liver at the site of injury in extremely large amounts, and the tissues at the site of injury undergo dissipation of edema, infiltration of round cells, and new blood vessels. , dissolution of fibrin, and increase in polysaccharides, especially acidic polysaccharides, were observed, and it was recognized that a healing response was induced and promoted in chronic inflammation of the liver, such as degeneration and abnormal proliferation.

Formulation example 1 10 g of serratiopeptidase and 190 g of lactose.

After uniformly mixing 70 g of potato starch, a 3% aqueous hydroxypropyl cellulose solution was added and kneaded. The mixture is sized, and the granules are mixed with 0.3% magnesium stearate and compressed into tablets.

Formulation Example 2 20 g of pronase and 40 g of lactose are mixed, 10 g of hydroxypropyl methylcellulose is added, and the mixture is formed into granules, which are then evenly coated with cellulose acetate phthalate to form enteric-coated granules.

Formulation Example 3 The pronase enteric-coated granules obtained in Formulation Example 2 are filled into capsules to prepare capsules.

Clinical case 1 Male, 57 years old Diagnosis: Liver cirrhosis, mainly chronic hepatitis Complaints: Anorexia, slight pressure in the right hypochondrium, general fatigue History: The above symptoms have been present for 2 to 3 years, and on May 24th, other He was diagnosed with liver cirrhosis at the hospital.

Current symptoms: No abnormalities were found other than slight enlargement of the liver, and 1f11 blood test and ultrasound diagnosis were performed.

Ultrasound diagnosis revealed no abnormalities in both kidneys, slightly enlarged lungs, and large cystic gallbladder, but no gallstones were detected. The common bile duct was not dilated. The pancreas was slightly swollen and had a smooth surface. No significant changes were observed within the membrane.

The surface of the liver is smooth, but the tissue is slightly atrophic, the liver lumen is narrow, and there is some refraction, but there are no localized abnormalities within the liver. A liver cell biopsy revealed mild liver cirrhosis and chronic hepatitis.

Liver function test: As shown in Table 1, tests were conducted five times from May 25th to July 30th, and observations were made. At the time of the first visit, the number of yellow vapors among 13 items, cor.

Abnormalities were found in 5 items: GPT, LAP, and γ-GTP.

Treatment with pronase: Take Empinase P (manufactured by Kaken Kagaku ■, enteric coated, 1 tablet contains 9000 tyrosine units of pronase) 6 tablets a day, 2 tablets after each meal, starting from May 25th.

Inspected on June 5th. In addition to abnormal values for TTT, all items were slightly worse.

On June 18th, there was a sudden improvement, and only γ-GTP showed abnormality. On July 10th, γ-GTP also decreased. On July 30th, all values showed normal values.

Subjective symptoms also improved, and various test results returned to normal. After that, he continued taking the drug for another three months to prevent recurrence.

Clinical case 2 Female, 65 years old, Diagnosis: Chronic nephritis Complaints: General fatigue, loss of appetite Current history: Complained of general fatigue and loss of appetite for about 6 months.
I lost the energy to work.

Present symptoms: The complexion is slightly pale with a slight yellow tinge.

The abdomen was slightly enlarged, but no abnormalities such as ascites accumulation were observed.

Ultrasound diagnosis and radiograph examination: No abnormality in bilateral kidneys or lungs. The gallbladder was slightly enlarged, but no gallstones were found. There were no significant changes in the pancreas, large intestine, small intestine, stomach, or duodenum.

The two surfaces of the liver are smooth, and the liver lumen is slightly narrow, but no atrophy or localized abnormalities are observed in the liver tissue.

Liver function test: As shown in Table 2, no abnormalities were found in 6 out of 13 items in the test on November 7th.

Treatment with pronase: Take 6 tablets of Enbinase P a day, 2 tablets after each meal,
The progress was observed. On January 30th of the following year, γ-GTP returned to normal, but other conditions were slightly reduced but did not return to normal.

On March 5th, everything except TTT and ZTT became normal, and on May 1st
On the 8th, abnormalities were observed in TTT, albumin, and A/G, but albumin and A/G were low. By June 5th, everything was normal. This was the 213th day since the start of treatment.

Clinical Examples 1 to 5: Treatment of liver disease with pronase. Oral administration of 6 tablets of Empinase P per day on each side.

[Margins below] As shown in Table 3, Envinase P was administered orally to one case of liver cirrhosis and four cases of chronic hepatitis, and it showed extremely effective results in these cases, which are considered difficult to cure.

Clinical Case 6 Male, 55 years old Diagnosis: Chronic hepatitis Treatment with Serratiopeptidase: Dazen (manufactured by Takeda Pharmaceutical Company Ltd., 1 tablet contains 10,000 Serratiopeptidase units (5mg))
The patient took 6 tablets of the drug per day, 2 tablets after each meal, and observed the progress. The results are shown in Table 4.

[Margin below] As shown in Table 4, serratiopeptidase showed an effective therapeutic effect.

Clinical case 7 Male, 59 years old Diagnosis: Chronic hepatitis Treatment with Seabrose S Nionobrose (manufactured by Ono Pharmaceutical Co., Ltd., 1 tablet contains 35 mg of Seabrose) was taken orally 6 tablets a day, 2 tablets after each meal, and the progress was observed. did. The results are shown in Table 5.

[Margin below] As shown in Table 5, Seaprose S showed effective therapeutic results.

Clinical case 8 Male, 48 years old Diagnosis: Chronic hepatitis Treatment with protase: Protase P (manufactured by Meiji Seika, 1 tablet contains 1 protase)
The patient took 3 tablets a day (containing 0 mg and vancreatin 50 mg), one tablet after each meal, and observed the progress. 6th result
Shown in the table.

[As shown in Table 6 in the margin below, protase showed effective therapeutic results.

Clinical case 9 Male, 62 years old Diagnosis: Chronic hepatitis Treatment with elastase ES: Elastime (manufactured by Eisai, 1 tablet contains elastase ES)
(containing 1800 units of lastase) was administered orally, 6 tablets a day, 2 tablets after each meal, and the progress was observed.

The results are shown in Table 7.

[Margin below] As shown in Table 7, elastase BS showed effective therapeutic results.

Clinical case 10 Male, 45 years old Diagnosis: Chronic hepatitis Treatment with promeline and trypsin: Kymotab (
Manufactured by Kaori Pharmaceutical ■, 20,000 units of bromelain in 1 tablet (5
0mg) and 2500 units of trypsin (1mg))
The patient took 4 tablets a day, 1 tablet at a time, and observed the progress. The results are shown in Table 8.

[As shown in Table 8 in the margin below, promelain and trypsin showed effective therapeutic results.

Clinical case 11 Male, 60 years old Diagnosis: Chronic hepatitis Treatment with streptokinase: Validase (manufactured by Takeda Pharmaceutical Co., Ltd., 1 tablet contains 10,000 units of streptokinase and 2,500 units of streptodornase)
The patient was taking 8 tablets a day, 2 tablets at a time, and observing the progress.

The results are shown in Table 9.

[Margin below] As shown in Table 9, streptokinase showed effective therapeutic results.

Regarding the results of the clinical case described above and some other cases, the Empicas P1 Dazen, Onoprose,
Table 10 summarizes the results of various liver test values based on the results of treatment using proctase P1 elastime, chymotab, or pallidase. However, each test drug was administered orally for 4 months in the same amount as in Clinical Examples 1 to 1.

Furthermore, the meanings of the determination results in the table are as follows.

Significantly effective: Effective when all abnormal values on the end of the clinical trial disappear.Slightly effective: When the abnormal value on the end of the clinical trial is less than 1/2 of the pre-administration level: Abnormal values on the end of the clinical trial are 172 Invalid if the abnormal value at the end of the clinical trial does not change from before administration Animal test example [Liver disease] The effect of proteolytic enzymes on liver disease was tested. Rats with an average weight of 250 g were given 0.5 carbon tetrachloride intraperitoneally.
ml/kg was administered to induce hepatitis, blood was collected 24 hours later, and GOT and GPT, which are indicators of liver damage, were measured. The enzymes were orally administered at the respective doses on 6.5.2.1 day before and on the day of carbon tetrachloride administration.

The results are shown in Table 11.

[Margins below] [Effects of the invention] The preventive and therapeutic agent containing the proteolytic enzyme of the present invention as an active ingredient,
It is highly effective in treating liver diseases, especially chronic hepatitis and cirrhosis, and can prevent the transition to cancer.

Claims (1)

[Claims] 1. A liver disease preventive and therapeutic agent containing one or more proteolytic enzymes as an active ingredient.