HK1136834A - Agent for prevention or treatment of iron overload - Google Patents

Description

Prophylactic or therapeutic agent for iron overload

Technical Field

The present invention relates to a prophylactic or therapeutic agent for Iron Overload (Iron Overload) comprising 22 beta-methoxyolean-12-en-3 beta, 24(4 beta) -diol or a pharmacologically acceptable salt thereof.

Background

Chronic iron overload is characterized by: iron deposition increases locally or in systemic tissues. In the tissue examination, it is generally called hemosiderosis (hemosiderosis), but if excessive iron deposition is accompanied by tissue damage, or if total body iron reaches 5g or more, it is called hemochromatosis (hemochromatosis). (see non-patent document 1)

Iron overload can be classified according to the cause. Specifically, the following can be roughly classified into: increased absorption of iron (iron food ) in food (hereditary hemochromatosis, chronic liver disease, delayed porphyria cutanea (porphyria cutanea tarda), transferrin-free blood disease, overdose with an oral iron-containing agent, etc.), iron overload caused by non-oral administration (excessive iron caused by blood transfusion, overdose with an intravenous iron-containing agent, etc.), and diseases caused by both (hereditary tyrosinemia, brain-liver-kidney syndrome (Zellweger's syndrome), neonatal hemochromatosis, idiopathic pulmonary iron-containing hemochromatosis (idiophatic pulmonary hypopyronierosis), Renal iron-containing hemosiderosis (Renal iron-containing hemosiderosis), etc.). As congenital diseases, idiopathic hemochromatosis and thalassemia (thalassemia) are common. In the latter diseases, iron excess due to overdosing or blood transfusion of an iron-containing agent for intravenous injection is exemplified. (see non-patent document 2)

If the iron overload continues to worsen, the internal organs with the liver, heart and pancreas as the center will be damaged, and the condition will further develop into a fatal disease. As general symptoms, there can be mentioned: an increase in the amount of iron stored in the whole body, a large amount of iron deposition in the form of ferritin and ferrihemoglobin in parenchymal cells (parenchymal cells) of the heart, pancreas, liver and other organs, and morphological and functional disorders of organs and parts where iron is deposited in excess. For example, as a therapeutic drug against iron overload after blood transfusion, an injection drug of an iron chelator is common. However, since this drug is an injectable drug, and is not suitable for administration to outpatient patients because it is not administered continuously for a long period of time over a plurality of days and hardly shows an effect, development of an iron chelator which can be orally administered has been recently advanced. Under these circumstances, it is desired to develop a drug which is effective against iron overload and has no side effects.

On the other hand, 22 β -methoxyolean-12-ene-3 β, 24(4 β) -diol is a compound represented by the following structure, and is known to have an effect of inhibiting hepatocyte damage and to be highly safe (see patent documents 1 and 2).

[ chemical formula 1]

Patent document 1: international publication No. 97/03088 pamphlet

Patent document 2: patent specification No. 3279574

Non-patent document 1: mark H.Beers et al 2 (ed.), good island Seattle (translation), "メルクマニユアル 17th Edition Japanese (Japanese Edition) (The Merck Manual, 17th Edition, InJapan), Nikkei BP, 12.10.1999, p.883-885

Non-patent document 2: gong 27211; "post-transfusion iron remanence disease and oral iron chelator" ("Yu Xue Hou Zi と a Ti-a キレ -a ト agent"), latest medicine, 3 months 2006, 61 Vol, No. 3, p.453-457

Disclosure of Invention

Problems to be solved by the invention

The present inventors have made intensive studies to solve the above-mentioned problems and as a result, have found that a serum ferritin value can be reduced by administering 22 β -methoxy olean-12-ene-3 β, 24(4 β) -diol, and thus a pharmaceutical composition excellent in the prevention or treatment of iron overload can be obtained, and have completed the present invention.

Means for solving the problems

Namely, the present invention relates to the following points:

[1] a prophylactic or therapeutic agent for iron overload comprising 22 β -methoxy-olean-12-en-3 β, 24(4 β) -diol or a pharmacologically acceptable salt thereof;

[2] the prophylactic or therapeutic agent according to [1], wherein the iron overload is hemochromatosis;

[3] use of 22 β -methoxyolean-12-ene-3 β, 24(4 β) -diol or a pharmacologically acceptable salt thereof in the manufacture of a prophylactic or therapeutic agent for iron overload;

[4] the use according to [3], wherein the iron overload disease is pigmentation;

[5] 22 β -methoxy-olean-12-en-3 β, 24(4 β) -diol or a pharmacologically acceptable salt thereof for use in the prevention or treatment of iron overload;

[6] the compound according to [5], wherein the iron overload is hemochromatosis;

[7] a method for preventing or treating iron overload comprising administering to a subject in need of prevention or treatment of iron overload an effective amount of 22 β -methoxy-olean-12-en-3 β, 24(4 β) -diol or a pharmacologically acceptable salt thereof;

[8] the method according to [7], wherein the iron overload disease is hemochromatosis.

ADVANTAGEOUS EFFECTS OF INVENTION

The preventive or therapeutic agent of the present invention can achieve a high preventive or therapeutic effect on iron overload by administering 22 β -methoxyolean-12-en-3 β, 24(4 β) -diol or a pharmacologically acceptable salt thereof.

Drawings

Figure 1 is a graph showing the evolution (mean) of serum ferritin values after oral administration of 22 β -methoxyolean-12-en-3 β, 24(4 β) -diol (50mg, 200 mg/day).

Figure 2 is a graph showing the evolution of serum ferritin values (median) after oral administration of 22 β -methoxyolean-12-en-3 β, 24(4 β) -diol (50mg, 200 mg/day).

Detailed description of the invention

The term "iron overload" as used herein refers to a state in which deposited iron (storage) and serum iron are higher than normal values. Specific examples of the iron overload disease of the present invention include localized hemosiderosis, hereditary hemochromatosis, secondary hemosiderosis, secondary hemochromatosis, and iron excess of unknown cause (an increase in iron storage amount due to hepatic parenchymal disease, nonalcoholic fatty liver disease, and chronic hepatitis c), and hemochromatosis is preferable.

The term "hemochromatosis" as used herein means excessive iron deposition accompanied by tissue damage or total iron content of 5g or more. Hemochromatosis includes hereditary iron overload and non-hereditary iron overload. The non-hereditary iron overload is iron overload caused by excessive iron due to blood transfusion or reduced iron utilization due to erythropoiesis disorder, and is also called secondary hemochromatosis. Hemochromatosis is characterized by abnormal iron metabolism, excessive absorption of ingested iron, saturation of iron-binding proteins, and particularly, hemosiderin-containing deposits in the liver, pancreas, and skin. It may cause cirrhosis, diabetes (bronze diabetes), skin pigmentation (copper muscle), and cardiac insufficiency in the terminal phase. This also occurs in the case of ingestion of large quantities of iron, either orally or non-orally, or in the case of massive blood transfusions (Stedman's Medical Dictionary, 4th Edition, 1998, Medical View Co., Ltd.) (1998, 4th Edition)).

The 22 β -methoxyolean-12-en-3 β, 24(4 β) -diol used as an active ingredient of the prophylactic or therapeutic agent of the present invention is a known compound and can be obtained, for example, by the method described in example 22 (compound 27) of WO97/03088 pamphlet. The 22 beta-methoxy olean-12-ene-3 beta, 24(4 beta) -diol can be simply salified by the action of pharmaceutically acceptable alkali. Preferred bases include inorganic bases such as sodium hydroxide, potassium hydroxide, aluminum hydroxide, sodium carbonate, potassium carbonate and sodium hydrogencarbonate, and organic bases such as piperazine, morpholine, piperidine, ethylamine and trimethylamine.

The 22 β -methoxyolean-12-en-3 β, 24(4 β) -diol or a pharmacologically acceptable salt thereof may be generally administered orally in the form of a usual pharmaceutical preparation such as capsules, microcapsules, tablets, granules, powders and the like. Further, the pharmaceutical composition can be administered parenterally (for example, intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal administration, rectal administration, and transdermal administration) in the form of a commonly used pharmaceutical preparation such as an injection such as intravenous injection or intramuscular injection. The above-mentioned various preparations can be prepared by a conventional method using a commonly used excipient, a compatibilizer (extender), a binder, a wetting agent, a disintegrant, a surfactant, a lubricant, a dispersant, a buffer, a preservative, a solubilizer, a preservative, a flavoring agent, an analgesic, a stabilizer, etc. Examples of the nontoxic additives that can be used include lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methyl cellulose, carboxymethyl cellulose or a salt thereof, gum arabic, polyethylene glycol, syrup, vaseline, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, and sodium phosphate. As described above, 22 β -methoxy-olean-12-en-3 β, 24(4 β) -diol or a pharmacologically acceptable salt thereof may be administered in the form of a pharmaceutical composition comprising a pharmacologically acceptable carrier or diluent.

The dosage form, administration method, administration amount, administration period and the like of 22 β -methoxyolean-12-en-3 β, 24(4 β) -diol in the prophylactic or therapeutic agent of the present invention can be appropriately set according to, for example, the body weight, age, degree of symptoms and the like of a patient. For example, 1 to 1000mg can be administered orally or non-orally 1 time or several times a day. Preferably, the dosage is 25-800 mg by oral or non-oral administration for 2 times per day.

As a result of examination useful for diagnosis of iron overload, a serum ferritin value, serum iron, Total Iron Binding Capacity (TIBC), and the like are known. As iron load increases, serum ferritin values will increase proportionally. Since the method of monitoring iron overload using serum ferritin values and liver MRI is simple and convenient and imposes little burden on patients, it is recommended to use (latest medical vol. 61, No. 3, 453-.

Examples

The present invention will be described in detail with reference to examples, which are not intended to limit the scope of the present invention.

Example 1

The oral administration of 22 beta-methoxyolean-12-en-3 beta, 24(4 beta) -diol was carried out for 24 weeks with patients with chronic hepatitis C as the subject. As the dose, 50 mg/day group and 200 mg/day group were provided. Each administration group was orally administered 22 β -methoxyolean-12-en-3 β, 24(4 β) -diol 2 times a day, that is, half of the daily dose was administered after breakfast and supper (for example, 50 mg/day of the administration group, 2 times a day, and 25mg after breakfast and supper, respectively). Serum samples were collected 2, 4, 8, 12, 16, 20, and 24 weeks after oral administration, and serum ferritin was measured (the number of serum sample collection persons: 49, 48, 47, 44, 45, 44, and 40 persons after 2, 4, 8, 12, 16, 20, and 24 weeks for the 50 mg/day group, and 45, 44, 43, 41, and 39 persons after 2, 4, 8, 12, 16, 20, and 24 weeks for the 200 mg/day group, respectively). Serum ferritin values were measured by chemiluminescence immunoassay (CLIA) [ measured according to the method described in the attached document of ChemiguACS-ferritin II (Bayer Medical Co., Ltd.) ].

The serum ferritin value before administration of 22 β -methoxyolean-12-ene-3 β, 24(4 β) -diol was defined as 0, and the serum ferritin value at each serum sample collection was expressed in% and the mean and median values were determined for all patients. The results are shown in fig. 1 and fig. 2, respectively.

From this result, it was confirmed that: by administering 22 β -methoxyolean-12-ene-3 β, 24(4 β) -diol, the serum ferritin value can be reduced, and thus a pharmaceutical composition excellent in the prevention or treatment of iron overload can be obtained.

Industrial applicability

According to the present invention, there is provided an agent for preventing or treating iron overload containing 22 β -methoxyolean-12-en-3 β, 24(4 β) -diol or a pharmacologically acceptable salt thereof.

The present invention has been described above with reference to specific embodiments, but variations or modifications obvious to those skilled in the art are also included in the scope of the present invention.

Claims (8)

1. A preventive or therapeutic agent for iron overload comprising 22 beta-methoxyolean-12-ene-3 beta, 24(4 beta) -diol or a pharmacologically acceptable salt thereof.

2. The prophylactic or therapeutic agent for iron overload according to claim 1, wherein the iron overload is hemochromatosis.

Use of 22 β -methoxy-olean-12-ene-3 β, 24(4 β) -diol or a pharmacologically acceptable salt thereof in the preparation of a prophylactic or therapeutic agent for iron overload.

4. The use according to claim 3, wherein the iron overload is hemochromatosis.

5. 22 beta-methoxy-olean-12-en-3 beta, 24(4 beta) -diol or a pharmacologically acceptable salt thereof for use in the prevention or treatment of iron overload.

6. The compound of claim 5 wherein the iron overload disorder is hemochromatosis.

7. A method for the prevention or treatment of iron overload comprising administering to a subject in need of prevention or treatment of iron overload an effective amount of 22 β -methoxy-olean-12-en-3 β, 24(4 β) -diol or a pharmacologically acceptable salt thereof.

8. The method of claim 7 wherein the iron overload condition is hemochromatosis.