JP3885135B2 - Agent for improving liver dysfunction caused by C or non-B non-C hepatitis virus - Google Patents

Description

【００３５】
これらの結果からわかるように、Ｔｈ２サイトカイン阻害剤であるＩＰＤを投与しなかった対照群は、観察期間中一過的にアスパラギン酸アミノトランスフェラーゼ（ＡＳＴ）及びアラニンアミノトランスフェラーゼ（ＡＬＴ）値の低下がみられたものの、観察終了時にはＡＳＴ116.8％、ＡＬＴ108.7％といずれの値も上昇したのに対し、ＩＰＤ投与群では観察終了時にＡＳＴ75.2％、ＡＬＴ67.5％といずれの血中濃度も有意に低下し、このことからＩＰＤに肝機能改善作用があることが判明した。
【００３６】
【発明の効果】
本発明の肝機能改善剤はトシル酸スプラタストを有効成分とすることによって、Ｃ型肝炎ウイルス又は非Ｂ非Ｃ型肝炎ウイルスの感染によって生じる肝機能異常を有意に改善することが可能である。
【図面の簡単な説明】
【図１】臨床例において行って実験結果を示す図である。具体的には、肝機能改善剤使用群（IPD投与群）および対照群について、ＩＰＤ投与開始時（投与時）のＡＳＴ及びＡＬＴの値を１００％として、投与前（８週前）及び投与後（８週後，１６週後，２４週後）のＡＳＴ及びＡＬＴの値を百分率表示で示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a preparation effective for ameliorating abnormal liver function in liver disease caused by infection with C-type or non-B non-C hepatitis virus.
[0002]
[Prior art]
It is said that there are currently 2 million hepatitis C virus carriers who are positive for hepatitis C virus antibodies in Japan. The pathogen of hepatitis C is RNA virus (HCV), and the infection route is parenterally, and it is transmitted via blood from blood transfusion, surgery, injection, etc. This viral infection develops as acute hepatitis C, and after that, there are only 10 to 20% of cases that are cured as a transient infection, and most of them are transferred to chronic hepatitis. Half of chronic hepatitis shifts to cirrhosis, and more than half develops into liver cancer. Thus, hepatitis C is a high-risk disease that shifts to liver cancer, but these treatments are still not sufficient. Currently, hepatitis C treatment includes general therapies such as rest and nutrition, antiviral agents that suppress the growth of the causative virus, or causal therapies with immune products aimed at neutralizing or eliminating viruses that have entered the body. Symptomatic treatment to improve liver enzyme elevation associated with the onset of the disease has been given.
[0003]
Treatment with interferon, the only approved treatment agent in Japan for causal therapy, is currently a commonly used treatment, but the indication is only chronic hepatitis C and may be effective. In many cases, is not effective at all, and in recent years, it has become clear that the effect is not as high as originally expected. For this reason, recently, combination therapy with interferon and other drugs has been attempted. For example, a combination therapy of interferon and antiviral Ribavirin (Ribavirin: Schering-Plough, chemical name: 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is currently in Japan (Gastroenterology, 105: 507-512, 1993).
[0004]
In addition, the results of treatment for hepatitis C by the administration of ribavirin alone have been reported overseas. According to this, treatment with ribavirin showed a transient decrease in ALT (alanine aminotransferase), but a re-elevation was observed in most cases after administration, and a decrease in HCV RNA and an improvement in liver tissue. Some findings have not been obtained, and the limitations of monotherapy with this drug have been shown (Hepatology 16: 649-654, 1992: J. Hepatol. 25: 591-598, 1996).
[0005]
On the other hand, for liver diseases such as hepatitis caused by non-B non-C hepatitis virus, there is no effective causal therapy, and treatment by symptomatic therapy using glycyrrhizin or ursodeoxycholic acid is performed. Currently.
[0006]
[Problems to be solved by the invention]
The objective of this invention is providing the pharmaceutical formulation which functions effectively with respect to the improvement of the liver function abnormality in the liver disease which arises by the infection of the hepatitis C virus or the non-B non-C hepatitis virus.
[0007]
[Means for Solving the Problems]
In view of the above-mentioned conventional problems, the present inventor has eagerly studied for the development of a drug that improves liver function abnormality in various liver diseases caused by infection with hepatitis C virus or non-B non-C hepatitis virus. As a result, it was found that suplatast tosylate exerts an effect of remarkably improving liver function even in cases where conventional treatment methods were ineffective. The present invention has been completed based on such findings.
[0008]
That is, the present invention is an agent for improving liver function abnormalities caused by C-type or non-B non-C hepatitis virus containing suplatast tosylate as an active ingredient.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
Suplatast tosylate (chemical name: (±)-{2- [4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl] ethyl} dimethylsulfonium p-toluenesulfonate) used in the present invention is, for example, -70698, which is a known compound, and can be easily produced according to the description of the publication. The compound comprises (1) the action of suppressing IgE antibody production by inhibiting the production of interleukin-4, which is a cytokine produced from helper T cells (Th2), and (2) of interleukin-5. In addition to the action to suppress tissue infiltration of eosinophils by suppressing production, (3) it has the action to suppress the release of chemical mediators, and as a conventional antiallergic agent, especially clinically bronchial asthma In addition, usefulness against atopic dermatitis and allergic rhinitis is recognized (trade name: IPD capsule, manufactured by Taiho Pharmaceutical Co., Ltd.).
[0010]
In the present invention, as will be apparent from clinical examples described later, suplatast tosylate having the above-described action is caused by abnormal liver function (decreased) caused by hepatitis C virus infection and non-B non-C hepatitis virus infection. It is based on the new finding that any liver function abnormality (decrease) is effective in improving and normalizing it, and this effect has never been known.
[0011]
Therefore, the present invention provides a novel medicinal use for improving liver function for suplatast tosylate.
[0012]
The liver function improving agent of the present invention containing suplatast tosylate as an active ingredient is, for example, an oral preparation such as a tablet, capsule, powder, granule, fine granule, liquid, pill, emulsion and suspension; It can be prepared as any pharmaceutical dosage form of parenterals such as suppositories, ointments, plasters and patches, each of which can be produced by conventional production methods known to those skilled in the art.
[0013]
When preparing as an oral solid preparation, excipients, binders, disintegrating agents, lubricants, coloring agents, flavoring agents, flavoring agents, etc., were added to spostotosylate, an active ingredient, as necessary. Thereafter, it can be produced into tablets, pills, capsules, powders, granules or fine granules by a conventional method. Examples of excipients include lactose, mannitol, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, glycerin, sodium alginate, or gum arabic; Alcohol, polyvinyl ether, ethyl cellulose, gum arabic, shellac, sucrose, etc .; as disintegrant, dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride or lactose, etc .; Examples of the agent include magnesium stearate or talc; examples of the corrigent include sucrose, orange peel, citric acid or tartaric acid. In addition, as the colorant and flavoring agent, known ones can be used. In addition, when using it as a tablet or a pill, you may coat by a well-known method.
[0014]
When prepared as a liquid preparation for oral use, add a corrigent, a buffer, a stabilizer or a corrigent to the active ingredient sposyl tosylate, and produce it into an oral solution, syrup, elixir, etc. by conventional methods. be able to. In this case, the above-mentioned flavoring agents can be used, sodium citrate or the like can be used as a buffering agent, and tragacanth, gum arabic or gelatin can be used as a stabilizer.
[0015]
When preparing as an injection, a pH adjuster, buffer, stabilizer, isotonic agent or local anesthetic is added to spostotosylate which is an active ingredient, and intravenous, intramuscular, It can be manufactured as an injection for subcutaneous, intradermal or intraperitoneal injection. Examples of pH adjusters or buffers include sodium citrate, sodium acetate, and sodium phosphate; examples of stabilizers include sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, and thiolactic acid. As the isotonic agent, sodium chloride, glucose and the like can be used, and as the local anesthetic, procaine hydrochloride, lidocaine hydrochloride and the like can be used.
[0016]
In the case of preparing as a suppository, it can be produced by a conventional method after adding a base usually used in a suppository and, if necessary, a surfactant or the like, to the sposyl tosylate which is an active ingredient. As the base, for example, an oily base such as macrogol, lanolin, cacao oil, fatty acid triglyceride, witepsol (manufactured by Dynamite Nobels) can be used.
[0017]
When preparing as an ointment, the active ingredient suplatast tosylate is blended with bases usually used in ointments and, if necessary, stabilizers, wetting agents, preservatives, etc. Can be manufactured. As the base, liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like; as the preservative, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like can be used.
[0018]
When preparing as a patch, the above-mentioned ointment or cream, gel or paste containing splatto tosylate as an active ingredient may be applied to the support by a conventional method. As the support, woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane, or a foam sheet made of cotton, suf, or chemical fiber can be used.
[0019]
The amount of suplatast tosylate as an active ingredient to be blended in each of the above pharmaceutical dosage forms (formulations) is not constant depending on the symptom of the patient to which this is applied, the dosage form, etc., but about 5 for oral dosage forms per dosage unit form. It is desirable that the dosage is ˜500 mg, 0.1 to 50 mg for injections and transdermal administration, and about 5 to 1000 mg for suppositories. Further, the dose of the liver function improving agent of the present invention having the above dosage forms is appropriately selected according to the patient's symptoms, body weight, age, sex, other conditions, etc., and cannot be defined unconditionally, but is an active ingredient In terms of the amount of suplatast tosylate, it is usually once a day for each adult in the range of 10 to 1000 mg for oral preparations, 0.1 to 100 mg for injections and transdermal preparations, and 5 to 1000 mg for suppositories. It is preferable to administer several times.
[0020]
In addition, the liver function improving agent of the present invention is usually administered as a single agent, but can also be administered in combination with other agents when the effect is insufficient. What can be combined includes other preventive and therapeutic agents for hepatitis C, or liver function improving agents that improve aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT). More specifically, natural alpha, beta interferon, interferon (IFN) such as recombinant alpha-2a or alpha-2b interferon and antiviral agents such as ribavirin; liver hydrolyzate (trade name: prohepanol), Examples of the liver function improving agent include thiopronin (trade name: thiola), glycyrrhizin (trade name: strong minophagen C, glycyrone), ursodeoxycholic acid (trade name: urso), and Sho-saiko-to.
[0021]
【Example】
Next, the present invention will be described with reference to formulation examples and clinical examples as examples, but the present invention is not limited to these examples.
<Formulation example>
Formulation Example 1 Suplatast tosylate tablet 100mg
Lactose 47mg
Corn starch 50mg
Crystalline cellulose 50mg
Hydroxypropylcellulose 15mg
Talc 2mg
Magnesium stearate 2mg
Ethylcellulose 30mg
Fatty acid glycerin ester 2mg
titanium dioxide 2 mg
300mg per tablet
Tablets were prepared according to a conventional method at the above blending ratio.
[0022]
Formulation Example 2 Capsules Suplatast Tosilate 100mg
Lactose 50mg
Corn starch 47mg
Crystalline cellulose 50mg
Talc 2mg
Magnesium stearate 1 mg
250mg per capsule
Capsules were prepared at the above blending ratio according to a conventional method.
[0023]
Formulation Example 3 Granules Suplatast Tosilate 200mg
Mannitol 540mg
Corn starch 100mg
Crystalline cellulose 100mg
Hydroxypropylcellulose 50mg
talc 10 mg
1000mg per package
Granules were prepared at the above blending ratio according to a conventional method.
[0024]
Formulation Example 4 Fine Granules Suplatast Tosilate 200mg
Mannitol 520mg
Corn starch 100mg
Crystalline cellulose 100mg
Hydroxypropylcellulose 70mg
talc 10 mg
1000mg / pack
A fine granule was prepared according to a conventional method at the above blending ratio.
[0025]
Formulation Example 5 Syrup Splatast Tosilate 50mg
Refined white sugar 1000mg
1 mg ethyl parahydroxybenzoate
Perfume appropriate amount Colorant appropriate amount
purified water Appropriate amount
Total volume 2ml
A syrup preparation was prepared according to a conventional method at the above blending ratio.
[0026]
Formulation Example 6 Injection Suplatast Tosilate 10mg
Distilled water for injection Appropriate amount
2ml in one tube
An injection was prepared according to a conventional method at the above blending ratio.
[0027]
Formulation Example 7 Suppository Suplatast Tosilate 100mg
Witepsol W-35 1400mg
(Registered trademark, made by Dynamite Nobel)
1500mg per piece
A suppository was prepared according to a conventional method at the above blending ratio.
[0028]
<Clinical cases>
(1) Among patients who visited the hospital where the subject inventor works for two years from August 1998 to August 2000, hepatitis C or non-B non-C hepatitis was diagnosed. 39 patients with chronic liver disease whose hepatitis symptoms (sustained high AST / ALT) were not improved by the above-mentioned treatment method, and whose patient's consent was obtained, were used as subjects. These 39 cases were divided into two groups, the liver function improving agent use group of the present invention (21 cases) and the control group (18 cases). In the liver function improver use group (21 cases), 18 were hepatitis C patients (9 chronic hepatitis, 9 cirrhosis), 3 non-B non-C hepatitis patients (2 chronic hepatitis, 1 cirrhosis 1) The control group was 18 patients with hepatitis C (10 cases of chronic hepatitis, 8 cases of cirrhosis).
[0029]
As the liver function improving agent, the capsule prepared in the above Production Example 2 containing suplatast tosylate (hereinafter abbreviated as “IPD”) as an active ingredient was used.
[0030]
(2) Treatment content The liver function improving agent use group (21 cases) has been taking ursodeoxycholic acid orally 100 to 200 mg once a day three times a day from 3 months before treatment of all cases IPD. Two of them were switched to IPD administration only, and the remaining 19 were switched to the combined use of IPD and ursodeoxycholic acid. IPD was orally administered at a dose of 100 mg three times a day. During the observation period, no additional combination of other liver function improving agents was performed.
[0031]
In the control group (21 cases), all cases of ursodesixic acid are taken orally at 100 to 200 mg once a day three times a day. During the observation period, no additional combination of other liver function improving agents was performed.
[0032]
The observation period is 8 weeks before IPD use and 24 weeks of IPD use period, 32 weeks in total. At least once every 2 months, we will have an outpatient visit and have an interview, examination, blood test (in blood, aspartate aminotransferase ( AST) value and alanine aminotransferase (ALT) value).
[0033]
For the liver function improving agent use group (IPD administration group) and the control group, the AST and ALT values at the start of IPD administration (during administration) were set to 100%, before administration (before 8 weeks) and after administration (after 8 weeks). , 16 weeks, and 24 weeks later), the effect was determined by the percentage display of the AST and ALT values. The results are shown in Table 1 and FIG. The values listed in the table are the average values of the IPD administration group (21 cases) and the control group (18 cases).
[0034]
[Table 1]

[0035]
As can be seen from these results, the control group that did not receive IPD, a Th2 cytokine inhibitor, showed a temporary decrease in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels during the observation period. Although AST was 116.8% and ALT was 108.7% at the end of observation, both values increased in the IPD administration group, while AST 75.2% and ALT 67.5% at the end of observation It was found that IPD has an effect of improving liver function.
[0036]
【The invention's effect】
The liver function improving agent of the present invention can significantly improve liver function abnormality caused by infection with hepatitis C virus or non-B non-C hepatitis virus by using suplatast tosylate as an active ingredient.
[Brief description of the drawings]
FIG. 1 is a diagram showing the results of experiments conducted in clinical cases. Specifically, for the liver function improving agent use group (IPD administration group) and the control group, the AST and ALT values at the start of IPD administration (during administration) were set to 100% before administration (8 weeks before) and after administration. AST and ALT values (8 weeks, 16 weeks, 24 weeks later) are shown as percentages.

Claims (2)

Hepatitis C or non-B According to the non-C hepatitis liver dysfunction improvement agents and tosylate spline data strike the active ingredient. It is liver dysfunction ameliorating agent by the hepatitis C virus, improving agent according to claim 1.

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