JPH0156050B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a liver disease prevention and treatment agent containing pronase 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 disorders as early as possible and to prevent canceration, 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 pronase is useful for the prevention and treatment of various liver diseases. The present invention is based on this knowledge, and is a preventive and therapeutic agent for liver diseases containing pronase as an active ingredient. [Effects and Examples] The prophylactic and therapeutic agent of the present invention can be prepared using conventional formulation techniques.
For example, it can be administered orally as a tablet, capsule, powder, granule, etc., or parenterally as an injection, suppository, ointment, etc. Furthermore, this drug 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 1 per day per adult.
The purpose can be achieved with 50,000 mg or, in the case of enzymes unstable in gastric juice, with 1 to 1,000 mg as an enteric preparation. Furthermore, when the dosage is expressed in enzyme units of each enzyme, the purpose can be achieved by oral administration of 10,000 to 500,000 tyrosine units of pronase in an enteric preparation. 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 pronase is transferred to the liver at the site of injury in an extremely large amount, and the tissue at the site of injury shows disappearance of edema, infiltration of round cells, neovascularization, and fibrosis. The dissolution of substances and the 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. Reference Formulation Example 1 After uniformly mixing 10 g of serratiopeptidase, 190 g of lactose, and 70 g of potato starch, 3% hydroxypropylcellulose aqueous solution is added and kneaded. The mixture is sized, and the granules are mixed with 0.3% magnesium stearate and compressed into tablets. Formulation Example 1 20 g of pronase and 40 g of lactose are mixed, 10 g of hydroxypropyl methyl cellulose is added, the mixture is formed into granules, and the mixture is evenly coated with cellulose acetate phthalate to form enteric-coated granules. Formulation Example 2 The pronase enteric-coated granules obtained in Formulation Example 1 are filled into capsules to prepare capsules. Clinical case 1 Male, 57 years old Diagnosis: Liver cirrhosis, chronic hepatitis Chief complaint: Anorexia, slight pressure in the right hypochondrium, general malaise History of present illness: The above symptoms have been present for 2 to 3 years, and since May
On the 24th, he was diagnosed with liver cirrhosis at another hospital. Current symptoms: No abnormalities were found other than slight enlargement of the liver, and serum tests and ultrasound diagnosis were performed. Ultrasound diagnosis: There were no abnormalities in both kidneys, the spleen was slightly enlarged, and the gallbladder was large and cystic, but no gallstones were found. The common bile duct was not dilated. The pancreas was slightly swollen and had a smooth surface. No significant changes were observed within the pancreas. Liver: The surface is almost 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 first examination, the jaundice index, GOT, GPT,
Abnormalities were found in 5 items: LAP and γ-GTP. Treatment with Pronase: Empinase P (manufactured by Kaken Chemical Co., Ltd., enteric coated, 1 tablet contains Pronase 9000)
6 tablets (containing tyrosine units) per day, 2 tablets after each meal
I have been taking tablets orally since 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 improved, and various test results returned to normal. After that, to prevent recurrence, 3 more
I continued taking oral medication for several months.

[Table] Clinical case 2 Female, 65 years old, Diagnosis: Chronic hepatitis Chief complaint: General fatigue, loss of appetite History of present illness: About 6 months ago, the patient complained of general fatigue and loss of appetite, and had lost the will to work. Current 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 X-ray examination: No abnormality in bilateral kidneys or spleen. The gallbladder was slightly enlarged, but no gallstones were found. pancreas,
There were no significant changes in the large intestine, small intestine, stomach, or duodenum. Liver: The surface is 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 of the 13 items tested on November 7th.

[Table] Treatment with pronase: 6 tablets of Empinase P per day, 2 tablets after each meal,
The patient was taken orally and the progress was observed. On January 30th of the following year, γ-
GTP became normal, but other symptoms were slightly reduced but did not return to normal. On March 5th, everything except TTT and ZTT became normal, and on May 18th, abnormalities were found in TTT, albumin, and A/G;
G was low. By June 5th, everything was normal. This was the 213th day after the start of treatment. Clinical cases 1 to 5: Treatment of liver disease with pronase In each case, 6 tablets of Empinase P were taken orally per day.

[Table] As shown in Table 3, 1 case of liver cirrhosis and 4 cases of chronic hepatitis
For example, Empinase P was administered orally, and it showed extremely effective results for these cases, which are considered difficult to cure. Reference clinical case 1 Male, 55 years old Diagnosis: Chronic hepatitis Treatment with serratiopeptidase: Dazen (manufactured by Takeda Pharmaceutical Co., Ltd., 1 tablet contains 10,000 serratiopeptidase units (5mg)) per day The patient took 6 tablets after each meal and 2 tablets after each meal, and the progress was observed. The results are shown in Table 4.

[Table] As shown in Table 4, serratiopeptidase showed an effective therapeutic effect. Reference clinical case 2 Male, 59 years old Diagnosis: Chronic hepatitis Treatment with Seaprose S: Take 6 tablets of Onoprose (manufactured by Ono Pharmaceutical Co., Ltd., 1 tablet contains 5 mg of Seaprose S) per day, 2 tablets after each meal. The progress was observed. The results are shown in Table 5.

【table】

[Table] As shown in Table 5, Seaprose S showed effective therapeutic results. Reference clinical case 3 Male, 48 years old Diagnosis: Chronic hepatitis Treatment with protase: Protase P (manufactured by Meiji Seika Co., Ltd., 1 tablet contains 10 mg of protase and 50 mg of pancreatin)
The patient took 3 tablets a day, 1 tablet after each meal, and observed the progress. The results are shown in Table 6.

[Table] As shown in Table 6, protase showed effective therapeutic results. Reference clinical case 4 Male, 62 years old Diagnosis: Chronic hepatitis Treatment with elastase ES: 6 tablets of Elasteam (manufactured by Eisai Co., Ltd., 1 tablet contains 1800 elastase units of elastase ES) per day, 2 tablets after each meal I took it orally and observed the progress. The results are shown in Table 7.

[Table] As shown in Table 7, elastase ES showed effective therapeutic results. Reference clinical case 5 Male, 45 years old Diagnosis: Chronic hepatitis Treatment with bromelain and trypsin: Kymotab (manufactured by Mochida Pharmaceutical Co., Ltd., containing 20,000 units of bromelain (50 mg) and 2,500 units of trypsin (1 mg) in one tablet) per day. The patient took 4 tablets, one at a time, and observed the progress. The results are shown in Table 8.

【table】

[Table] As shown in Table 8, bromelain and trypsin showed effective therapeutic results. Reference clinical case 6 Male, 60 years old Diagnosis: Chronic hepatitis Treatment with streptokinase: 8 tablets of Validase (manufactured by Takeda Pharmaceutical Co., Ltd., containing 10,000 units of streptokinase and 2,500 units of streptodornase per tablet) per day, 1 time 2
The patient was given tablets orally and the progress was observed. The results are shown in Table 9.

[Table] As shown in Table 9, streptokinase showed effective therapeutic results. Regarding the results of the clinical case described above and some other cases, Empinas P., Dazen,
onoprose, proctase P, elastime,
Table 10 summarizes the liver test results from the treatment with Kymotab or Validase. However, each test drug example was administered orally for 4 months in the same amount as in Clinical Examples 1 to 5 and Reference Clinical Examples 1 to 6. Furthermore, the meanings of the determination results in the table are as follows. Significantly effective: When all abnormal values disappear at the end of the clinical trial Effective: Abnormal values at the end of the clinical trial are 1/2 of the pre-administration level
Moderately effective: The abnormal value at the end of the clinical trial is 1/1/2 of the pre-administration level.
2. Invalid: If the abnormal value at the end of the clinical trial remains unchanged from before administration.

[Table] Animal test example [Liver disease] The effect of proteolytic enzymes on liver disease was tested. Carbon tetrachloride (0.5 ml/kg) was administered intraperitoneally to rats with an average body weight of 250 g to induce hepatitis. Blood was collected 24 hours later and GOT and GPT, which are indicators of liver damage, were measured. The enzyme was orally administered at the respective doses 6, 5, 2, 1 day before and on the day of carbon tetrachloride administration. The results are shown in Table 11.

【table】

[Table] [Effects of the Invention] The preventive and therapeutic agent of the present invention containing pronase as an active ingredient is highly effective in treating liver diseases, particularly chronic hepatitis and cirrhosis, and can prevent transition to cancer.

Claims (1)

[Claims] 1. A liver disease prevention and treatment agent containing pronase as an active ingredient.