JPH10330265A - Therapeutic agent for liver disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a therapeutic agent for liver diseases having promoting action of bilirubin excretion and bile acid excretion and capable of relieving jaundice symptom by including folic acid or its salt as an active ingredient. SOLUTION: This medicine has folic acid whose chemical name is N-[4-[[(2- amino-4-hydroxy-6-ptelidyl)methyl]amino]benzoyl]-L-glutamic acid or its salt. The medicine can be prepared in dosage form suitable for oral, parenteral or topical administration by formulating the above compound with a conventional additive, etc. The daily dose of the medicine is 1-1,000 mg, preferably 5-800 mg. The medicine is effective against jaundice including obstructive jaundice and has not only treating effect, also but preventing effect. The medicine has high safety and remarkable medical usability.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a therapeutic agent for liver disease, and more particularly to a therapeutic agent for liver disease containing folic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Obstructive jaundice symptoms may occur postoperatively or with the metastasis of liver / lymph node to a malignant tumor, or with liver disease or biliary tract disease. When such jaundice symptoms are observed, if left unchecked, liver failure or renal failure may be caused and death may occur.

Conventionally, as a means for alleviating the above-mentioned symptoms of obstructive jaundice, percutaneous transhepatic biliary drainage (PTBD) has been performed as a first-line treatment. However, since such PTBD is a surgical procedure, the procedure itself is painful for the patient. In addition, the physician also has a large burden such as requiring skill in the procedure and requiring preoperative and postoperative management. Furthermore, obstructive jaundice, in which the symptoms of jaundice do not improve with PTBD, is often seen, so PTBD is not always a complete treatment method.

[0004] On the other hand, as agents for alleviating the symptoms of jaundice, bile-forming agents such as ursodesoxycholic acid and dehydrocholic acid, and cholesterol agents are known. It is known that even if the disease is successful, it has little effect on obstructive jaundice.

[0005]

Therefore, for obstructive jaundice symptoms, instead of PTBD, which is a burden on both the patient and the physician, a less burdensome, effective yellowing treatment, for example, occlusion as a medical treatment method There has been a strong demand for the development of a therapeutic method by oral or injection administration of an effective drug for icterus. Recently, leucovorin, an anti-folate antimetabolite, was newly found to have a significant yellowing effect by lowering the serum total bilirubin level in patients with obstructive jaundice, and it was newly discovered that leucovorin was an active ingredient. An agent for treating jaundice has been proposed (JP-A-7-291864).
issue). According to this therapeutic agent, it is possible to improve the jaundice symptoms of patients with obstructive jaundice without performing a surgical operation, and further, a remarkable improvement effect is recognized even in a case where improvement of jaundice was not observed by PTBD. Than was done
It is a very useful drug clinically and provides a great deal of light for patients with obstructive jaundice.

However, considering that leucovorin itself is a very expensive drug, the economic burden on the patient is considerable. Therefore, development of an inexpensive drug that has the same therapeutic effect as leucovorin and that can be administered orally has been awaited.

[0007] As a result of studying to solve the above-mentioned problems under the current situation, the present inventors have found that folic acid, which is clinically used as a folate deficiency improving agent, has an effect of promoting bilirubin excretion. The present invention has been newly found, and the present invention has been completed based on such findings.

[0008]

That is, the present invention provides a therapeutic agent for liver disease containing folic acid or a pharmacologically acceptable salt thereof as an active ingredient. According to the therapeutic agent of the present invention, it was confirmed that folic acid as an active ingredient promotes bilirubin excretion and bile acid excretion, thereby reducing jaundice symptoms.

Accordingly, the present invention also provides a therapeutic agent for jaundice containing folic acid or a pharmacologically acceptable salt thereof as an active ingredient as a specific embodiment, and in another embodiment, folic acid or a drug thereof. Provided is a bilirubin excretion enhancer containing a physiologically acceptable salt as an active ingredient. The therapeutic agent provided by the present invention is characterized by being able to improve the jaundice symptoms of jaundice patients including obstructive jaundice, and is therefore a clinically useful agent.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Folic acid used as an active ingredient in the present invention has a chemical name of N- [4-[[(2-amino-4-
Hydroxy-6-pteridyl) methyl] amino] benzoyl] -L-glutamic acid. The active ingredient folic acid can also be used as a therapeutic agent of the present invention in the form of a pharmacologically acceptable salt. Such salts are conventional non-toxic salts and include salts with bases, ie, salts with inorganic bases, such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, , Calcium salts, magnesium salts, etc.). These pharmacologically acceptable salts include both anhydrous salts which are anhydrous and hydrates which are hydrates. Further, the compound is a tautomer of folic acid, N- [4-[[(2-amino-1,4-dihydroxy-4-oxo-6-pteridyl) methyl] amino] benzoyl] -L-glutamic acid Is also included.

The dose of folic acid as a therapeutic agent of the present invention is as follows:
It is not particularly limited and varies depending on the administration method, but 1 mg to 1,000 mg /
Day, preferably within the range of 5 mg to 800 mg / day.

[0012] The therapeutic agent of the present invention may be an inorganic or organic solid or liquid pharmaceutical carrier or diluent commonly used in the preparation of pharmaceuticals, such as starch, lactose, sucrose, crystalline cellulose, calcium hydrogen phosphate and the like. Excipients; binders such as acacia, hydroxypropylcellulose, alginic acid, gelatin, polyvinylpyrrolidone; stearic acid, magnesium stearate, and calcium stearate. Lubricants such as hydrogenated vegetable oils; disintegrators such as modified starch, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose; dissolution aids such as nonionic surfactants and anionic surfactants;
It can be formulated into a dosage form suitable for oral, parenteral or topical administration.

[0013] Dosage forms suitable for oral administration include solid preparations such as tablets, coatings, capsules, troches, powders, fine granules, granules and dry syrups, and liquid preparations such as syrups. Dosage forms suitable for parenteral administration include, for example, injections, drops, suppositories and the like. Ointments, tinctures,
Creams, gels and the like. These preparations can be prepared using a method known per se in the field of pharmacology. However, it must be noted that intravenous administration is contraindicated for folic acid itself. Therefore, from this point of view, it is particularly preferable that the therapeutic agent of the present invention is used in a dosage form for oral administration.

The therapeutic agent of the present invention can be used in combination with other drugs, for example, an anticancer drug and a choleretic drug, based on the pathogenesis of the onset of jaundice.

[0015]

EXAMPLES The usefulness of the therapeutic agent of the present invention will be described below by describing the results of pharmacological tests, safety and specific formulation examples.

[Pharmacological test] Bilirubin secretion promoting effect in rats Test method Normal rats were divided into two groups (n = 4 to 5 in each group),
5 mg / kg and each of the control solutions were intravenously administered to each group for one week. After the final administration, the bile duct was cannulated, and the bile excretion of each rat and the concentrations of bile acids and bilirubin in the bile were measured over time,
Bile flow and excretion rates of bile acids and bilirubin were determined.

2. Results Changes in bile flow and excretion rates of bile acids and bilirubin in normal rats after drug administration are shown in Table 1.

[0018]

[Table 1]

As is clear from the results in the table, it was confirmed that folate significantly increased the excretion rate of bilirubin. On the other hand, no effect was observed on the bile flow rate of folate and the excretion rate of bile acid. From this, the above-mentioned bilirubin excretion promoting action is independent of the bile flow rate and the excretion rate of bile acid. It was also shown to be effective against obstructive jaundice with reduced sickness.

II. Bilirubin in diseased rats
Bile acid excretion promoting effect Test Method Pathological rats with intrahepatic bile umbilical cord (model rats with ANIT hepatopathy) were prepared by orally administering 100 mg / kg of ANIT to rats. Six groups of rats (n of each group)
= 15), 5% or 25 mg / kg of folic acid, 50 mg / kg of dl-leucovorin as a positive control, 5 or 25 mg / kg of 1-leucovorin and each of the control solutions for each group, 3 days before ANIT treatment. It was administered intravenously for one week from the day. In addition, the rats without ANIT treatment were treated as a non-treatment group (n = 5). On the third day after the treatment, the concentrations of bilirubin and bile acid in the serum of each rat were measured. The evaluation was shown by the ratio of each concentration to the solvent administration group.

2. Results Changes in bile flow and excretion rates of bile acids and bilirubin in normal rats after drug administration are shown in Table 2.

[0022]

[Table 2]

As is clear from the results in the table, it was confirmed that folate significantly reduced the concentration of bilirubin and bile acid in serum of rats. This suggests that folic acid, which is an active ingredient of the present invention, can be a therapeutic agent having a preventive effect on intrahepatic bile umbilical cord. Summarizing the suggestions obtained from the results of Tables 1 and 2 above, not only the therapeutic effect of folate on liver disease but also the preventive effect could be confirmed.

[Safety] It is already known that folic acid is a sufficiently safe drug when used as a medicine. Specifically, the LD ₅₀ value by intravenous administration is 600 mg / kg for mice and 500 mg / kg for rats. The sodium salt, which is a pharmacologically acceptable salt of folic acid, also had a value having the same safety.

[Preparation Example] Composition: folic acid 5 g lactose 120 g microcrystalline cellulose 25 g corn starch 25 g 5% hydroxypropylmethylcellulose aqueous solution 100 ml magnesium stearate 5 g Tablets A tablet containing 5 mg of folic acid in a weight of 180 mg was prepared.

[0026]

As described in detail above, folic acid, which is an active ingredient of the present invention, has a remarkable bilirubin excretion promoting effect, is effective against jaundice including obstructive jaundice, and has only therapeutic effects. It also has a preventive effect. Therefore, the therapeutic agent of the present invention is extremely useful clinically as a therapeutic agent for liver diseases, particularly as a therapeutic agent for jaundice, has high safety, and has remarkable medical utility.

Claims (3)

[Claims] 1. A therapeutic agent for liver disease, comprising folic acid or a pharmaceutically acceptable salt thereof as an active ingredient. 2. A therapeutic agent for jaundice comprising folic acid or a pharmacologically acceptable salt thereof as an active ingredient. 3. A bilirubin excretion enhancer containing folic acid or a pharmaceutically acceptable salt thereof as an active ingredient.