JPH04368369A - Therapeutic agent for hepatopathy - Google Patents

Abstract

PURPOSE:To obtain a therapeutic agent for hepatopathy, containing zinc dipicolinate as an active ingredient, excellent in improving action on zinc deficiency and useful for treating the hepatopathy, especially cirrhosis. CONSTITUTION:A therapeutic agent for hepatopathy containing zinc dipicolinate expressed by the formula as an active ingredient. The zinc dipicolinate can directly or, together with normally used pharmaceutical carriers, be administered. The aforementioned therapeutic agent can be prepared into the form of an oral agent such as tablet, capsule, granule or various solutions for oral use or a parenteral agent such as injection or suppository according to a conventional method. The dose of the zinc dipicolinate is 0.1-200mg/day for an adult (50kg body weight) administered in one to several divided portions. The above-mentioned therapeutic agent for the hepatopathy is well absorbed and has high migration to tissues.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to pharmaceuticals, and more particularly to a therapeutic agent for liver diseases.

0002

[Prior Art] Liver diseases, especially chronic active hepatitis,
Low serum zinc concentrations are often observed in patients with liver cirrhosis, chronic alcoholic liver disease, etc., and it has been reported that serum zinc concentrations generally decrease as the disease progresses from chronic hepatitis to liver cirrhosis. [Yasuyuki Arakawa et al., Modern Medicine, 45(4), 668-677 (1990)]. This is thought to be caused by decreased absorption of zinc in the intestinal tract and increased excretion into the urine.

[0003] Zinc also stimulates ornithine transcarbamylase (ornithine transcarbamylase), which plays a part in ammonia metabolism.
thin transcarbamylase) and glutamine synthetase (glutamine syn
It is present in metalloenzymes such as thetase and is an important component in exhibiting its enzymatic activity. For this reason, there are reports that hyperammonemia is likely to occur when zinc is deficient [Rabbani, P. et al. , Am.
J. Physiol. , 235, 203 (19
78)]. Zinc is also used in other alcohol dehydrogenases (alcohol dehydrogenases).
e), is a component of many metalloenzymes such as DNA polymerase and RNA polymerase, and its deficiency is thought to be involved in various biological dysfunctions [Ruiz, A. D. et al. , Gastr
oenterol Clin. Biol. , 12,
584 (1988)]. Furthermore, it has been pointed out that liver cirrhosis often exhibits hepatic encephalopathy due to ammonia metabolic disorder during the decompensation phase, and hyperammonemia is more likely to occur in zinc-deficient states.

[0004] Therefore, it is important to improve hypozincemia in liver diseases such as chronic active hepatitis, liver cirrhosis, and chronic alcoholic liver damage. For this purpose, oral administration of zinc sulfate is also used to treat hypozincemia in these diseases, but the results are not always satisfactory, especially in the decompensated phase of liver cirrhosis, when there is no significant increase in serum zinc concentration. Not obtained.

[0005]

[Problems to be Solved by the Invention] Therefore, the object of the present invention is to provide a therapeutic agent for liver diseases that can improve zinc deficiency in liver diseases, especially liver cirrhosis, by oral administration and can replace conventional zinc sulfate. do.

[0006]

[Means for Solving the Problems] Under these circumstances, the present inventors have conducted intensive research to solve the above problems, and as a result, the following formula (1) has been developed.

[0007]

[Case 2]

It was discovered that zinc dipicolinate represented by the following formula satisfies these requirements, and the present invention was completed.

That is, the present invention provides a therapeutic agent for liver diseases containing zinc dipicolinate as an active ingredient.

Zinc dipicolinate can be easily prepared, for example, by the method described in US Pat. No. 4,315,927. This compound is associated with anemia, skin lesions, especially acrodermatitis (Acrodermatitis).
Zinc is known to be useful as an ameliorating agent for Z. tis enteropathica) and growth disorders, but it is completely unknown that it can significantly ameliorate zinc deficiency in liver diseases.

Zinc dipicolinate exhibits an excellent ameliorating effect on zinc deficiency in liver cirrhosis, as shown in the Examples below. Furthermore, this compound is 144 mg for adults.
/day was orally administered for 4 weeks without causing any abnormalities [A
gentsand Actions, 21, 1/2
, 223-228 (1987)] and is highly safe.

Zinc dipicolinate (1) can be administered neat or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be appropriately selected and used as required. Such dosage forms include oral preparations such as tablets, capsules, granules, and various oral liquid preparations; injections;
Examples include parenteral agents such as suppositories. In addition, if necessary, it can be used as an edible zinc deficiency treatment by combining with various vitamins, carbohydrates as an energy source such as sucrose, protein sources such as casein, amino acids such as methionine, and electrolytes such as salt. .

[0013] The amount of zinc dipicolinate to be administered is not particularly limited and may be appropriately selected from a wide range;
It is preferable to administer the drug in one to several doses at a dose of 0.1 to 200 mg/day.

[0014] Among the therapeutic agents for liver diseases of the present invention, oral preparations include:
Manufactured according to conventional methods. That is, tablets are prepared by mixing zinc dipicolinate with pharmaceutical excipients such as gelatin, starch, milk powder magnesium stearate, talc, gum arabic, etc., and capsules are prepared by mixing zinc dipicolinate with non-formed zinc dipicolinate. Oral liquid syrups and elixirs are prepared by mixing with active pharmaceutical fillers or diluents and filling hard gelatin capsules, soft capsules, etc. Zinc dipicolinate is mixed with sweeteners such as sucrose, methyl paraben, etc. It is manufactured by mixing with preservatives such as propylparabens, colorants, and flavoring agents.

Parenteral preparations are also prepared according to conventional methods, for example, by dissolving zinc dipicolinate in a sterilized liquid carrier. The carrier in this case is preferably water or saline. Solutions with the desired clarity, stability and suitability for parenteral use are prepared, for example, by dissolving zinc dipicolinate in water and an organic solvent and then in polyethylene glycol having a molecular weight of 200-5000. Preferably, such a liquid agent contains a lubricant such as sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, or polyvinyl alcohol. Furthermore, the above liquid preparation may contain bactericides and fungicides such as benzyl alcohol, phenol, and thimerosal, and if necessary, sucrose, local anesthetics, stabilizers, buffers, and the like. In addition, from the viewpoint of stability, drugs for parenteral administration may be filled into capsules, etc., frozen, water removed using normal freeze-drying techniques, and liquid preparations prepared from the freeze-dried powder immediately before use. can.

[0016]

EXAMPLES In order to explain the present invention in more detail, examples will be given below.

Example 1 Effect of zinc dipicolinate on improving zinc deficiency in liver cirrhosis: 11 patients with liver cirrhosis (age 39-60)
An oral zinc tolerance test was conducted using zinc dipicolinate and zinc sulfate on subjects (aged 15 to 30 years old). Upon waking up, after blood and urine were collected in a fasting state, 120 mg of zinc dipicolinate was administered.
/ 50 kg of body weight or 106 mg of zinc sulfate / 50 kg of body weight
Administer orally with 300 ml of water, 60 minutes after administration, 12
Blood and urine were collected at 0 and 180 minutes. Using these samples, zinc concentrations in serum, red blood cells, and urine were measured. The measurement was carried out using a 180-80 polarized Zeeman atomic absorption spectrophotometer (manufactured by Hitachi, Ltd.) using the standard addition method according to the Freseemann method of atomic absorption spectrometry. Tests were conducted once each on zinc dipicolinate and zinc sulfate in the same cirrhotic patient, separated by one week. The results are shown in Figures 1-3. The horizontal axis of each figure is the time after loading both zinc agents (
Figure 1 shows the serum zinc concentration (μg/dl), and the vertical axis shows the serum zinc concentration (μg/dl
), Figure 2 shows the zinc concentration in red blood cells (μg/dl), and Figure 3 shows the zinc concentration in red blood cells (μg/dl).
indicates the urinary zinc concentration (μg/dl), respectively. From Figure 1, serum zinc concentration was higher in the zinc dipicolinate administration group than in the zinc sulfate administration group at 120 minutes and 18 minutes after administration.
Significantly higher at 0 minutes. Moreover, in the zinc sulfate-administered group, the zinc concentration reached its peak 120 minutes after oral administration;
However, in the zinc dipicolinate administration group, a tendency to further increase was observed even 180 minutes after oral administration. From Figure 2, there was no significant difference in the zinc concentration in red blood cells between the two groups, but in the zinc sulfate administration group,
While no increasing trend in zinc concentration was observed after loading,
In the group treated with zinc dipicolinate, there was a tendency for the zinc concentration after loading to increase. From Figure 3, the urinary zinc concentration is
Compared to the zinc sulfate administered group, the zinc dipicolinate administered group had significantly higher levels at 120 and 180 minutes after loading, indicating that more was excreted in the urine. Furthermore, when zinc dipicolinate was administered for a long period of time to a patient with liver cirrhosis who had taste disturbance, tongue atrophy, swelling, and formation of deep fissures, these findings improved. Furthermore, long-term administration of zinc dipicolinate to cirrhotic patients with chronic recurrent hepatic encephalopathy improved the symptoms. Based on these results, zinc dipicolinate is clearly better absorbed than zinc sulfate and has a higher rate of tissue transfer, so it is useful as a treatment for liver diseases, especially for improving zinc deficiency in patients with liver cirrhosis. I understand that.

Example 2 Zinc dipicolinate was continuously administered to a cirrhotic patient exhibiting chronic recurrent hepatic encephalopathy. 30mg
/ day, the reduction in blood ammonia levels was insufficient;
Since increasing the dose to 60 mg/day, the value has completely decreased to normal.
My consciousness also became clear. The course of this case is shown in Figure 4.

Example 3 Preparation of tablets: (Formulation)
Amount (g)
zinc dipicolinate
10 Lactose (Japanese Pharmacopoeia product)
40 Cornstarch (Japanese Pharmacopoeia product) 20 Crystalline cellulose (Japanese Pharmacopoeia product)
20 Hydroxypropyl cellulose (
5 Magnesium stearate (Japanese Pharmacopoeia product) 2 (Production method) Zinc dipicolinate, lactose, cornstarch and crystalline cellulose were thoroughly mixed, granulated with a 5% aqueous solution of hydroxypropylcellulose, and passed through a 200 mesh sieve. This was carefully dried and compressed into 100 tablets using a conventional method.
0 tablets were prepared.

[0020]

[Effects of the Invention] As described above, the liver disease treatment agent containing zinc dipicolinate as an active ingredient of the present invention has better absorption and higher tissue transfer than conventional zinc sulfate, and has an effect on improving zinc deficiency. Therefore, it is useful as a therapeutic agent for liver diseases, especially liver cirrhosis.

[Brief explanation of the drawing]

FIG. 1 is a diagram showing the change in serum zinc concentration in a group administered with zinc dipicolinate and a group administered with zinc sulfate in patients with liver cirrhosis.

FIG. 2 is a diagram showing the change in zinc concentration in red blood cells in a zinc dipicolinate administration group and a zinc sulfate administration group in patients with liver cirrhosis.

FIG. 3 is a diagram showing the changes in urinary zinc concentration in a group administered with zinc dipicolinate and a group administered with zinc sulfate in patients with liver cirrhosis.

FIG. 4 is a diagram showing the course of symptoms caused by administration of zinc dipicolinate in a liver cirrhosis patient exhibiting chronic recurrent hepatic encephalopathy.

Claims (2)

[Claims] Claims: 1. A therapeutic agent for liver diseases, which contains zinc dipicolinate represented by formula (1) as an active ingredient. 2. The liver disease therapeutic agent according to claim 1, which is a liver cirrhosis therapeutic agent.