JPH09216831A - Antiviral agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antiviral agent, especially a remedy for hepatitis synergistically enhancing an effective curing rate and manifesting excellent curing effect by combinedly using an interferon with a specific metal compound. SOLUTION: This antiviral agent combinedly uses an interferon with at least one kind of selected from a group of a zinc salt and a zinc complex. The interferon is, e.g. an interferon α, an interferon β or an interferon γ, etc., of a natural type or a recombinant type, etc. As the zinc salt and the zinc complex, e.g. zinc sulfate, zinc chloride, zinc nitrate, a p-aminobenzoic acid salt or a di-(5-sulfa-8-quinolinolato) zinc (II) sodium salt, etc., is exemplified. The remedy for hepatitis is especially effective to a genotype hepatitis, a I-type or a II-type of a C-type hepatitis or a hepatitis containing a high virus amount, exceptionally to the C-type hepatitis containing respectively higher content than 10<6> copies/ml of HCV and RNA.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antiviral agent and a hepatitis therapeutic agent.

[0002]

Various treatments have been applied to hepatitis A, B and C until now, but all of them have only a transient therapeutic effect. ,
It is not a radical cure. In addition, hepatitis C is apt to become chronic and is said to have a high probability of transition to cirrhosis and liver cancer, which is a serious clinical problem.

On the other hand, interferon is known to exert a therapeutic effect on the above-mentioned hepatitis because it has effects such as antiviral action. However, the effective treatment rate is still unsatisfactory, and the effective treatment rate is low depending on the amount of virus or the genotype of the virus. For example, in case of hepatitis C, the effective treatment rate is about 35%.
That is, the effective treatment rate was only about 10 to 20% for hepatitis C in which the amount of HCV RNA was higher than 10 ⁶ copies / ml. Furthermore, five genotypes of hepatitis C (I, II, II
Among I, IV and V), the effective treatment rate is also low for type I and type II.

[0004]

In view of the above situation, the present inventor has conducted earnest studies to develop an excellent antiviral agent or therapeutic agent for hepatitis, and as a result, the group consisting of interferon, zinc salt and zinc complex was selected. It has been found that the combined use with at least one selected species synergistically increases the effective treatment rate of interferon alone, and can exhibit an excellent therapeutic effect. Furthermore, the administration of interferon alone has a low effective therapeutic rate for genotype hepatitis, especially hepatitis C types I and II, and hepatitis with high viral load, especially HCV RNA.
It has also been found to be effective against hepatitis C in amounts higher than 10 ⁶ copies / ml. The present invention has been completed based on such findings.

That is, the present invention relates to an antiviral agent, particularly a therapeutic agent for hepatitis, which comprises the combined use of interferon and at least one selected from the group consisting of zinc salts and zinc complexes.

The antiviral agent of the present invention, in particular, the therapeutic agent for hepatitis exhibits a remarkable therapeutic effect on any of hepatitis A, B and C hepatitis. In particular, the agent of the present invention can exert an excellent therapeutic effect on hepatitis C, which is a genotype of a virus for which the effective therapeutic rate is poor when administered alone with interferon, and hepatitis C, which has a high viral load, and particularly, B type and Effective against hepatitis C.

Furthermore, the drug of the present invention is also effective for zinc deficiency such as skin diseases frequently occurring in hepatitis patients, dysgeusia, hair loss, fever, eye pain, menstrual abnormality, depression and other mental symptoms. Further, the antiviral agent of the present invention can exert excellent effects against various viral infectious diseases based on its antiviral action.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The interferon used in the present invention is not particularly limited and conventionally known ones can be widely used. For example, natural type, recombinant type interferon α, interferon β, interferon γ.
And the like.

In the present invention, the zinc salt and the zinc complex are not particularly limited, and widely known ones can be widely used.
For example, zinc sulfate, zinc chloride, zinc nitrate, zinc phosphate, zinc aluminate, zinc fluoride, zinc iodide, zinc hydroxide, zinc carbonate, zinc chromate, zinc benzoate, zinc acetate, zinc p-aminobenzoate. , Zinc p-dimethylaminobenzoate,
Zinc p-phenolsulfonate, zinc p-methoxycinnamate, zinc lactate, zinc gluconate, zinc citrate, zinc salicylate, zinc stearate, zinc laurate, zinc myristate, zinc oleate, 2,5-pyridinedicarboxylic acid Zinc acid, zinc 2,6-pyridinedicarboxylate, 4-
Zinc pyridinedicarboxylate, 2,4-dicarboxypyridine zinc, 3-hydroxy-2-carboxypyridine zinc, 3-n-propoxy-2-carboxypyridine zinc, 3-n-hexyloxy-2-carboxypyridine zinc, 5 -N-propoxy-2-carboxypyridine zinc, 5-n-butoxy-2-carboxypyridine zinc,
5- (2-ethyl-hexyloxy) -2-carboxypyridine zinc, 6-n-butoxy-2-carboxypyridine zinc, 3-methoxy-2-carboxypyridine zinc, 5-methoxy-2-carboxypyridine zinc, 6 −
Methoxy-2-carboxypyridine zinc, 6-n-hexyloxy-2-carboxypyridine zinc, 3-methyl-2-carboxypyridine zinc, 4-methyl-2-carboxypyridine zinc, 4-tert-butyl-2-carboxy Pyridine zinc, 5-methyl-2-carboxypyridine zinc, 5-n-hexyl-2-carboxypyridine zinc, 3-n-undecyl-2-carboxypyridine zinc, 4-n-undecyl-2-carboxypyridine zinc, 5 -N-butyl-2-carboxypyridine zinc, 6
-N-undecyl-2-carboxypyridine zinc, 4-
Nitro-2-carboxypyridine zinc, 4-chloro-2
-Carboxypyridine zinc, 5-hydroxy-2-carboxypyridine zinc, 4-bromo-2-carboxypyridine zinc, 4-fluoro-2-carboxypyridine zinc, 6-chloro-2-carboxypyridine zinc, 2-carboxypyridine N -Zinc oxide, polaprezinc,
Zinc picolinate, zinc nicotinate, zinc nicotinamide, zinc 3,4-dihydroxybenzoate, zinc bis-histidine, zinc hinokitiol, di (5-sulfa-8)
-Quinolinolite) zinc (II) sodium salt, protoporphyrin zinc, porphyrin zinc, picolinic acid zinc zinc and the like. In the present invention, these zinc salts and / or
Alternatively, the zinc complex may be used alone or in combination of two or more.

The antiviral agent (hepatitis therapeutic agent) of the present invention is
It is usually used in the form of a general pharmaceutical preparation. Formulations are commonly used fillers, fillers, binders, moisturizers, disintegrants,
It is adjusted by using a diluent such as a surface active agent and a lubricant or an excipient. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills,
Examples include powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), ointments, inhalants, sprays and the like. When molding into tablet form,
As a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, excipients such as crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, Binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate,
Agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, disintegration of sucrose, stearin, cocoa butter, hydrogenated oil, etc. Inhibitors, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, Lubricants such as boric acid powder and polyethylene glycol can be used. Further, the tablet is a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet,
Gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets can be used. When molded into the form of pills, as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, binders such as ethanol, laminaran , Disintegrating agents such as agar and the like can be used. For molding into a suppository, carriers such as polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides can be used. The capsules are prepared by a conventional method, usually by mixing the above-exemplified various carriers with the active ingredient compound of the present invention and filling them into hard gelatin capsules or hard capsules. When prepared as an injection, the solutions, emulsions and suspensions are preferably sterile and isotonic with blood. When molding into these forms, water, lactic acid aqueous solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used as a diluent. In this case, a sufficient amount of salt to prepare an isotonic solution,
Glucose or glycerin may be contained in the pharmaceutical preparation, and ordinary solubilizers, desiccants, soothing agents and the like may be added. Further, if necessary, coloring agents, preservatives, flavors, flavors, sweeteners, and other pharmaceuticals may be contained in the pharmaceutical preparation. In formulating pastes, creams and gels, for example white petrolatum as a diluent,
Paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. can be used.

In the present invention, the interferon and at least one selected from the group consisting of a zinc salt and a zinc complex may be simultaneously contained in the pharmaceutical preparation, or the interferon and the zinc salt may be contained in separate pharmaceutical preparations. And at least one selected from the group consisting of zinc complexes may be separately contained, and these pharmaceutical preparations may be used in combination for the treatment of hepatitis and the like. For example, an interferon lyophilization agent and a desiccant of a zinc salt and / or a zinc complex can be combined and dissolved in distilled water for injection to be used.

The amount of at least one selected from the group consisting of interferon and zinc salts and zinc complexes to be contained in the pharmaceutical preparation of the present invention is not particularly limited as long as it is an effective amount, and is appropriately selected from a wide range.

The method of administration of the pharmaceutical preparation of the present invention is not particularly limited and may be variously determined according to the age, sex and other conditions of the patient, the state of the disease, various preparation forms, etc., but it is usually systemic or local. Orally or parenterally. For example, it is orally administered in the form of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, and is intravenously, intramuscularly, or intradermally in the form of injections, optionally mixed with a normal replacement fluid. , Subcutaneously or intraperitoneally, or rectally as a suppository, orally or intranasally as a spray or inhalant,
Alternatively, it is applied as an ointment.

The human dose of the pharmaceutical preparation of the present invention is appropriately selected according to age, body weight, symptoms, therapeutic effect, administration method, treatment time and the like, but interferon is usually about 1 to 30 million IU / body per day. , Preferably about 2 to 20 million IU / body, particularly preferably about 5 to 10 million IU / body, and at least one selected from the group consisting of a zinc salt and a zinc complex is usually administered per day. The dosage may be in the range of 5-800 mg / body, preferably about 200-600 mg / body, and the formulation may be administered once to several times a day. Of course, as described above, since the dosage varies under various conditions, a dosage smaller than the above-mentioned dosage range may be sufficient, or may be required beyond the range.

[0015]

[Examples] The results of pharmacological tests and formulation examples are shown below.

Pharmacological test 1 Interferon α10 million IU was intramuscularly administered continuously for 2 weeks to a patient with hepatitis C having a viral load (HCV RNA level) of 10 ⁶ copies / ml or more, and then administered every other day from the 3rd week for 3 days every other day. went. Patient A (hepatitis C type III, HCV RNA amount was 2 × 10 ⁶ orally from the start of interferon α administration)
copies / ml) and patient B (hepatitis C type III, HCV RN)
A quantity is 1 × 10 ⁶ copies / ml) and zinc sulfate is 300 m
g for patient C (hepatitis C type II, HCV RNA amount 1 ×
300 mg of Polaprezinc for 10 ⁷ copies / ml)
Was used together once a day, and the virus amount was measured by competitive quantification and qualitative test of amplicon.

As a result, patient A was determined to have HCV after 2 weeks.
RNA amount was less than 1 × 10 ² copies / ml, and patient B had HCV RNA amount less than 1 × 10 ² copies / ml after 3 weeks.
Patient C had HCV RNA level of 1 × 10 ² cop 4 weeks later.
It was found that each of them fell below ies / ml.

Pharmacological test 2 Hepatitis C patient a (hepatitis C type II, HCV RNA amount 1 × 10 ⁷ copies / ml), hepatitis C patient b (hepatitis C II
Type, HCV RNA amount 1 × 10 ⁷ copies / ml, and hepatitis C patient c (hepatitis C type II, HCV RNA amount 3 ×)
Interferon α100 for 10 ⁵ copies / ml)
After continuous intramuscular injection of 0,000 IU for 2 weeks, administration was carried out every other day from the 3rd week, three times a week. From the start of interferon α administration, 300 mg of zinc sulfate was orally used once a day, and the virus amount was measured by competitive quantification and qualitative test of amplicon.

As a result, the patient a was determined to have HCV R after 8 days.
NA amount was 1 × 10 ² copies / ml or less, patient b had HCV RNA amount less than 1 × 10 ² copies / ml after 29 days, and patient c had HCV RNA amount 4 × 10 ² copies after 8 days. /
It was found that the values decreased to below ml.

Pharmacological test 3 Hepatitis C patient A (hepatitis C type II, HCV RNA amount 1 × 10 ⁷ copies / ml), hepatitis C patient b (hepatitis C II
Type, HCV RNA amount is 5 × 10 ³ copies / ml, and patients with hepatitis C (hepatitis C type II, HCV RNA amount is 5 ×)
10 ⁶ copies / ml), similar to the pharmacological tests 1 and 2, 10 million IU of interferon α was continuously administered intramuscularly for 2 weeks, and then administered every other day from the 3rd week, three times a week. Oral zinc sulfate 300m from the start of interferon α administration
g was used once a day in combination, and the viral load was measured by competitive quantification and qualitative test of amplicon.

The results of pharmacological test 1, pharmacological test 2 and pharmacological test 3 are summarized in Table 1. Table 1 also shows the viral load 6 months after the final administration of interferon α and zinc sulfate, as well as the results measured by competitive quantification and qualitative test of Amplicor. In Table 1, the viral load (HCV RNA
When the amount was 1 × 10 ² copies / ml or less, it was indicated as (−), and when it was more than that, it was indicated as (+). Moreover, the blank portion in Table 1 is not measured. In addition, in the patient c, a remarkable decrease in the viral load was not observed.

[0022]

[Table 1]

Formulation Example 1 The following components were admixed in a conventional method and punched out to obtain 100 tablets each containing 5 million IU mg of interferon α and 150 mg of zinc salt.

Interferon α 5,000,000 IU Polaprezinc 15 g Sodium lauryl sulfate 0.2 g Magnesium stearate 0.2 g Crystalline cellulose 4.6 g Formulation example 2 Interferon α 5 million IU Zinc sulfate 0.2 g Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene-sorbitan monooleate 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g Distilled water for injection 10.0 ml The above parabens, sodium metabisulfite and Sodium chloride is dissolved with stirring at 80 ° C. in about half of the above distilled water. The resulting solution is cooled to 40 ° C., and the active ingredient compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, are dissolved in the above solution. Next, distilled water for injection is added to the solution to prepare a final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.

Claims (2)

[Claims] 1. An antiviral agent comprising a combination of interferon and at least one selected from the group consisting of zinc salts and zinc complexes. 2. A hepatitis therapeutic agent comprising a combination of interferon and at least one selected from the group consisting of zinc salts and zinc complexes.