JP6702722B2 - Preventive and/or therapeutic agent for hepatocellular carcinoma - Google Patents

Description

The present invention relates to a preventive and/or therapeutic agent for hepatocellular carcinoma.

The number of deaths due to malignant neoplasms in Japan in 2011 was 357,000, which was the leading cause of death, of which more than 30,000 died of hepatocellular carcinoma.
As a main cause of hepatocellular carcinoma occurring in Japan, 90% or more of hepatitis B virus or hepatitis C virus (HCV: hereinafter sometimes referred to as “HCV” in the present specification) is persistent. It is said to be caused by infection (chronic hepatitis), and viral hepatitis is extremely important as a disease involved in the development of hepatocellular carcinoma. In addition, non-alcoholic steatohepatitis (Non-alcoholic steatohepatitis: hereinafter sometimes referred to as “NASH” in the present specification) is hepatitis caused by accumulation of fat in the liver. Oxidative stress, insulin resistance, inflammatory cytokines, etc. cause transition from fatty liver and worsening of pathology. In recent years, due to the increase in metabolic syndrome (visceral fat syndrome), it has been feared that the number of patients with the onset of NASH and subsequent fibrosis of liver tissue, liver cirrhosis, and hepatocellular carcinoma will increase. Together with hepatitis, it is important as a disease involved in the development of hepatocellular carcinoma.

Treatment of hepatocellular carcinoma includes surgical treatments such as hepatectomy and liver transplantation, percutaneous ethanol injection therapy, medical local therapy such as radiofrequency thermocoagulation therapy or percutaneous microwave coagulation therapy, and Examples include catheter arterial embolization or catheter therapy such as hepatic arterial infusion reservoir therapy, or chemotherapy such as molecular targeted drugs. However, even now that these therapies can be performed, the frequency of recurrence of hepatocellular carcinoma is high, and intrahepatic recurrence (secondary carcinogenesis) is observed in 28.8% within 2 years from the diagnosis (Non-Patent Document 1). ), has repeated recurrence and eventually killed many patients. Therefore, along with early detection and treatment of hepatocellular carcinoma, suppression of hepatocarcinogenesis from chronic hepatitis and suppression of recurrence after hepatocellular carcinoma treatment are mentioned as important issues in the future. It is considered extremely important to proactively treat the disease to suppress recurrence. However, there is no established therapeutic method for suppressing recurrence of hepatocellular carcinoma.

As a drug used for chemotherapy for hepatocellular carcinoma, for example, sorafenib (trade name Nexavar (registered trademark)), which is a molecular target drug, is used. This drug is used only as systemic chemotherapy for unresectable hepatocellular carcinoma and has been reported to cause various serious side effects. Furthermore, the efficacy and safety of this drug in adjuvant chemotherapy after surgical treatment or local medical treatment for hepatocellular carcinoma are not established at present, and surgical treatment or internal medicine for hepatocellular carcinoma has not yet been established. There is a strong demand for effective and safe drugs that can be used after topical local therapy.

(2E,4E,6E,10E)-3,7,11,15-Tetramethylhexadeca-2,4,6,10,14-pentaenoic acid (hereinafter referred to as "peretinoin" in the present specification) Is a compound that is classified as an acyclic retinoid, and clinically, long-term administration of this compound for one year significantly suppressed recurrence after curative treatment of hepatocellular carcinoma. It has been confirmed to have a recurrence suppressing effect. In addition, hepatic dysfunction and other side effects seen in other retinoids are scarcely observed, and it is a safe drug (Non-Patent Document 2).

On the other hand, an angiotensin II receptor antagonist (hereinafter, sometimes referred to as “ARB” (Angiotensin Receptor Blocker) in the present specification) antagonizes the pressor substance angiotensin II, and angiotensin II becomes an angiotensin II receptor. It is a drug that shows a blood pressure-lowering action by inhibiting binding, and losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan, azilsartan, etc. are clinically used as antihypertensive agents. ARB has various effects such as anti-inflammatory effect, endothelial function improving effect, cardiovascular remodeling suppressing effect, oxidative stress suppressing effect, growth factor suppressing effect, and insulin resistance improving effect as well as antihypertensive effect. It has been reported in clinical or basic tests that it is also useful for renal diseases, arteriosclerosis, etc. (Non-patent Documents 3 and 4).

Although there are some reports on the therapeutic effect of ARB on cancers (Patent Documents 1 to 3), no example has been reported on the use of ARB in combination with a retinoid for the prevention and/or treatment of hepatocellular carcinoma.

JP 2001-002587 WO2002/087503 Pamphlet WO2010/061142 Pamphlet

18th National Primary Liver Cancer Follow-up Report, Japan Liver Cancer Research Association (2009) N. Eng. J. Med., 334(24), 1561-1567(1996) AMER. J. Hypertension, 18, 720-730 (2005) Current Hypertension Report, 10, 261-267 (2008)

An object of the present invention is to provide a drug useful for prevention and/or treatment of hepatocellular carcinoma.

As a result of intensive studies to solve the above problems, the present inventors used an acyclic retinoid such as peretinoin and an angiotensin II receptor antagonist in combination to suppress carcinogenesis of both hepatocellular carcinomas. It was found that the combination of an acyclic retinoid and an angiotensin II receptor antagonist has a significant effect on the prevention and/or treatment of hepatocellular carcinoma, and thus the present invention is completed. I arrived.
That is, according to the present invention, the prevention and/or treatment of hepatocellular carcinoma obtained by combining an acyclic retinoid or a salt thereof or a solvate thereof, and an angiotensin II receptor antagonist or a salt thereof or a solvate thereof. A medicine for is provided.

That is, the present invention relates to the inventions described below.
[1] For the prevention and/or treatment of hepatocellular carcinoma, which comprises a combination of an acyclic retinoid or a salt thereof or a solvate thereof, and an angiotensin II receptor antagonist or a salt thereof or a solvate thereof. Medicine.
[2] The medicine according to the above [1], wherein the acyclic retinoid is peretinoin.
[3] The medicine according to the above [1] or [2], wherein the angiotensin II receptor antagonist is losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan or azilsartan.
[4] The medicine according to any one of [1] to [3] above, wherein the prevention and/or treatment of hepatocellular carcinoma is suppression of recurrence after the treatment of hepatocellular carcinoma.
[5] The medicine according to any one of [1] to [4], wherein the hepatocellular carcinoma is a hepatocyte cancer caused by hepatitis virus.
[6] The medicine according to the above [5], wherein the hepatitis virus is hepatitis C virus.
[7] The acyclic retinoid or a salt thereof or a solvate thereof, and the angiotensin II receptor antagonist or a salt thereof or a solvate thereof together in the form of a single preparation (combination drug). 1] to the pharmaceutical according to any one of [6].
[8] In the form of a kit preparation containing a combination of a preparation containing an acyclic retinoid or a salt thereof or a solvate thereof, and a preparation containing an angiotensin II receptor antagonist or a salt thereof or a solvate thereof The pharmaceutical according to any one of [1] to [6] above.
[9] An acyclic retinoid or a salt thereof or a solvent thereof for administration in combination with an angiotensin II receptor antagonist or a salt thereof or a solvate thereof for the purpose of preventing and/or treating hepatocellular carcinoma A medicine containing a Japanese medicine.
[10] The following (1) and (2);
(1) A medicament for preventing and/or treating hepatocellular carcinoma, which comprises an acyclic retinoid or a salt thereof or a solvate thereof;
(2) Instructions for instructing to administer the pharmaceutical agent in combination with an angiotensin II receptor antagonist, a salt thereof or a solvate thereof.
The medicament according to [9] above, which is in the form of a kit containing
[11] An angiotensin II receptor antagonist or a salt thereof, or a solvent thereof for administration in combination with an acyclic retinoid or a salt thereof or a solvate thereof for the purpose of preventing and/or treating hepatocellular carcinoma A medicine containing a Japanese medicine.
[12] The following (1) and (2);
(1) A medicament for preventing and/or treating hepatocellular carcinoma, which comprises an angiotensin II receptor antagonist, a salt thereof, or a solvate thereof.
(2) Instructions for instructing the administration of the pharmaceutical agent in combination with an acyclic retinoid or a salt thereof or a solvate thereof;
The medicament according to [11], which is in the form of a kit containing
[13] The medicine according to any one of [9] to [12], wherein the acyclic retinoid is peretinoin.
[14] The medicine according to any one of [9] to [13] above, wherein the angiotensin II receptor antagonist is losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan or azilsartan.
[15] The medicament according to any one of [9] to [14] above, wherein the prevention and/or treatment of hepatocellular carcinoma is suppression of recurrence after the treatment of hepatocellular carcinoma.
[16] The medicine according to any one of [9] to [15], wherein the hepatocellular carcinoma is hepatocyte cancer caused by hepatitis virus.
[17] The medicine according to the above [16], wherein the hepatitis virus is hepatitis C virus.

[18] An effective amount of an acyclic retinoid or a salt thereof or a solvate thereof and an effective amount of an angiotensin II receptor antagonist or a salt thereof or a solvate thereof are simultaneously or simultaneously administered to a patient in need thereof. A method for preventing and/or treating hepatocellular carcinoma, which comprises the step of changing the dose and administering separately.
[19] The method according to the above [18], wherein the acyclic retinoid is peretinoin.
[20] The method according to the above [18] or [19], wherein the angiotensin II receptor antagonist is losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan or azilsartan.
[21] The method according to any one of [18] to [20] above, wherein the prevention and/or treatment of hepatocellular carcinoma is suppression of recurrence after the treatment of hepatocellular carcinoma.
[22] The method according to any one of [18] to [21] above, wherein the hepatocellular carcinoma is hepatocyte cancer caused by hepatitis virus.
[23] The method according to [22] above, wherein the hepatitis virus is hepatitis C virus.

[24] An acyclic retinoid or a salt thereof or a solvate thereof, and an angiotensin II receptor antagonist or a salt thereof, or a salt thereof for producing a medicament for preventing and/or treating hepatocellular carcinoma Use of a combination of solvates.
[25] The use according to the above [24], wherein the acyclic retinoid is peretinoin.
[26] The use according to the above [24] or [25], wherein the angiotensin II receptor antagonist is losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan or azilsartan.
[27] The use according to any one of [24] to [26] above, wherein the prevention and/or treatment of hepatocellular carcinoma is suppression of recurrence after the treatment of hepatocellular carcinoma.
[28] The use according to any one of [24] to [27], wherein the hepatocellular carcinoma is a hepatocyte cancer caused by hepatitis virus.
[29] The use according to [28] above, wherein the hepatitis virus is hepatitis C virus.

[30] An acyclic retinoid or a salt thereof or a solvent thereof for administration in combination with an angiotensin II receptor antagonist or a salt thereof or a solvate thereof for the purpose of preventing and/or treating hepatocellular carcinoma Japanese food.
[31] The acyclic retinoid or the salt thereof or the solvate thereof according to the above [30], wherein the acyclic retinoid is peretinoin.
[32] The acyclic retinoid or salt thereof or the solvent thereof according to the above [30] or [31], wherein the angiotensin II receptor antagonist is losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan or azilsartan. Japanese food.
[33] The acyclic retinoid or a salt thereof according to any one of [30] to [32], wherein the prevention and/or treatment of hepatocellular carcinoma is suppression of recurrence after the treatment of hepatocellular carcinoma. Or a solvate thereof.
[34] The acyclic retinoid or a salt thereof or a solvate thereof according to any one of the above [30] to [33], wherein the hepatocellular carcinoma is a hepatocyte cancer caused by hepatitis virus.
[35] The acyclic retinoid or the salt thereof or the solvate thereof according to the above [34], wherein the hepatitis virus is hepatitis C virus.

[36] An angiotensin II receptor antagonist or a salt thereof or a solvent thereof for administration in combination with an acyclic retinoid or a salt thereof or a solvate thereof for the purpose of preventing and/or treating hepatocellular carcinoma Japanese food.
[37] The angiotensin II receptor antagonist, the salt thereof, or the solvate thereof according to the above [36], wherein the acyclic retinoid is peretinoin.
[38] The angiotensin II receptor antagonist or the salt thereof or the salt thereof according to the above [36] or [37], wherein the angiotensin II receptor antagonist is losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan, or azilsartan. Solvates.
[39] The angiotensin II receptor antagonist or the angiotensin II receptor antagonist according to any one of [36] to [38] above, wherein the prevention and/or treatment of hepatocellular carcinoma is suppression of recurrence after the treatment of hepatocellular carcinoma. A salt or solvate thereof.
[40] The angiotensin II receptor antagonist, the salt thereof, or a solvate thereof according to any one of [36] to [39], wherein the hepatocellular carcinoma is a hepatocyte cancer caused by hepatitis virus.
[41] The angiotensin II receptor antagonist, the salt thereof, or the solvate thereof according to the above [40], wherein the hepatitis virus is hepatitis C virus.

According to the present invention, an excellent drug for preventing and/or treating hepatocellular carcinoma can be provided. In particular, as described in detail in Examples below, the combination of an acyclic retinoid and an angiotensin II receptor antagonist dramatically improves the hepatocellular carcinoma carcinogenesis-suppressing action. Therefore, the drug of the present invention, which is used in combination with both, has an excellent effect that the recurrence rate of hepatocellular carcinoma having a poor prognosis can be reduced.

It is a typical example of a GST-P positive precancerous lesion in each group. It is the GST-P positive precancerous lesion area in each group. It is the number of GST-P positive precancerous lesions (per 1 cm ² ) in each group.

The definition of the term in this specification is as follows. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention, as one embodiment, a combination of an acyclic retinoid or a salt thereof or a solvate thereof, and an angiotensin II receptor antagonist or a salt thereof or a solvate thereof, for the prevention of hepatocellular carcinoma And/or a medicine for treatment (hereinafter, the medicine of the embodiment may be referred to as “combination medicine of the present invention”). That is, the combination drug of the present invention is a drug for the prevention and/or treatment of hepatocellular carcinoma, which is an acyclic retinoid or a salt thereof or a solvate thereof, and an angiotensin II receptor antagonist or its. It is a combination of salts or solvates thereof, and these components can be administered at the same time or at different times.

Retinoids are vitamin A (retinol) and its related compounds, and have actions such as morphogenesis, cell differentiation and growth control in vivo. Retinoids are classified into cyclic retinoids and acyclic retinoids according to their structural characteristics (Retinoid/Cartenoid, 14-20 (1997), Nanzando). Examples of the cyclic retinoid include retinal, all-trans retinoic acid (tretinoin), 9-cis retinoic acid (aritretinoin), 13-cis retinoic acid (isotretinoin), and the like, in addition to the above retinol. In a broad sense, a compound having a chemical structure that is completely similar to vitamin A is also called a retinoid, including a synthetic compound having a binding affinity with a retinoic acid receptor.

In the present invention, the “acyclic retinoid” means one having no ring structure in the molecule among the above-mentioned broadly defined retinoids. Specific examples of the acyclic retinoid include geranylgeranoic acid, peretinoin, 2,3-dihydrogeranylgeranoic acid, 4,5-didehydro-10,11-dihydrogeranylgeranoic acid, 4,5 and 5. 8,9-Tetradehydrogeranylgeranoic acid, 4,5-didehydro-10,11,14,15-tetrahydrogeranylgeranoic acid, 14,15-dihydrogeranylgeranoic acid, metopreic acid, hydroprenic acid, phytanic acid And the like, and these can be used alone or in combination of two or more. Geranylgeranoic acid, which is one of the acyclic retinoids, is a component contained in herbs and is expected to be a preventive and therapeutic drug for cancer because it increases the ceramide level of membrane lipids and causes apoptosis of liver cancer cells. It has been reported that this is possible (J. Lipid Res., 45 1092-1103 (2004)).

In the present invention, an acyclic retinoid salt may be used. Examples of the salt include inorganic acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (for example, when treating an acyclic retinoid as a basic compound). Formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Etc.) and acid addition salts and the like. When an acyclic retinoid is treated as an acidic compound, inorganic salts (eg sodium salt, potassium salt, lithium salt, barium salt, calcium salt, magnesium salt etc.) and organic salts (eg pyridinium salt, picolinium salt, triethyl). Ammonium salts).
Moreover, in the present invention, a solvate of an acyclic retinoid or a salt thereof may be used. As the solvent forming the solvate, a physiologically acceptable organic solvent such as ethanol, acetone, ethyl acetate, hexane, etc. can be used in addition to water, but the solvent is not limited thereto.
When a plurality of types of acyclic retinoids are used in combination, the types of salts and solvates of various retinoids may be the same or different.
The acyclic retinoid or a salt thereof or a solvate thereof, especially the above-mentioned compounds are all known compounds and can be produced by known methods. For example, peretinoin can be produced by the method described in JP-A-56-140949. Further, in the present invention, a commercially available acyclic retinoid may be used.

In the present invention, the “acyclic retinoid or a salt thereof or a solvate thereof” is preferably peretinoin or a salt thereof or a solvate thereof, and particularly preferably peretinoin.

In the present invention, examples of the “angiotensin II receptor antagonist” include losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan, azilsartan and the like.

In the present invention, a salt of angiotensin II receptor antagonist may be used. Examples of the salt include inorganic acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (when treating angiotensin II receptor antagonists as basic compounds). For example, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid , Glutamic acid, etc.) and the like. When treating angiotensin II receptor antagonists as acidic compounds, inorganic salts (eg sodium salt, potassium salt, lithium salt, barium salt, calcium salt, magnesium salt, etc.) and organic salts (eg pyridinium salt, picolinium salt) , Triethylammonium salt, etc.).
Further, in the present invention, a solvate of an angiotensin II receptor antagonist or a salt thereof may be used. As the solvent forming the solvate, a physiologically acceptable organic solvent such as ethanol, acetone, ethyl acetate, hexane, etc. can be used in addition to water, but the solvent is not limited thereto.
The angiotensin II receptor antagonist, a salt thereof, or a solvate thereof can be produced by a known method, or a commercially available angiotensin II receptor antagonist may be used.

In the present invention, "angiotensin II receptor antagonist or a salt thereof or a solvate thereof" means an angiotensin II receptor antagonist or a salt thereof selected from losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan or azilsartan, or Those solvates are preferable, and losartan, olmesartan or azilsartan is particularly preferably used.

The combination ratio of the acyclic retinoid or a salt thereof or a solvate thereof and an angiotensin II receptor antagonist or a salt thereof or a solvate thereof in the present invention is not particularly limited, and the desired hepatocellular carcinoma prevention and It can be appropriately selected so that the therapeutic effect is achieved.

In the present invention, "prevention and/or treatment of hepatocellular carcinoma" means prevention of development of hepatocellular carcinoma, suppression of progression of hepatocellular carcinoma, treatment of hepatocellular carcinoma, and treatment after hepatocellular carcinoma. Is a concept that includes the suppression of recurrence of. The medicament of the present invention can be suitably used as a medicament for suppressing recurrence after hepatocellular carcinoma treatment, particularly for suppressing recurrence after hepatocellular carcinoma curative treatment. Here, as a treatment method for hepatocellular carcinoma, for example, surgical treatment methods such as hepatectomy, whole liver transplantation or partial transplantation; percutaneous ethanol injection therapy (PEIT), percutaneous microwave coagulation therapy ( PMCT), percutaneous topical therapy such as radiofrequency coagulation therapy (RFA); hepatic arterial chemotherapy (TAI); gelatin sponge, porous gelatin particles, embossesphere (tris-acryl/gelatin spherical particles), superabsorbent polymer. hepatic arterial embolization therapy (TAE) for embolizing the inside of an artery with an embolizing substance such as microspheres (SAP-MS), HepaSphere, Embozone (special fluorine-coated acrylic hydrogel), polyvinyl alcohol; epirubicin hydrochloride, cisplatin, doxorubicin hydrochloride Hepato-arterial chemoembolization therapy, which is performed using the above-mentioned embolizing substance after lipidation using an anticancer agent such as salt or mitomycin C, or using drug-(anticancer agent) eluting beads (drug-eluting beads; DEB). TACE); Glycyrrhizic acid, Shosaikoto, interferon, peginterferon, ribavirin, 5-fluorouracil, cisplatin, oxaliplatin, doxorubicin hydrochloride, epirubicin hydrochloride, mitoxantrone hydrochloride, etoposide, irinotecan hydrochloride, gemcitabine hydrochloride, Docetaxel hydrate, sorafenib tosylate, erlotinib hydrochloride, pitavastatin calcium and the like drug therapy and the like can be mentioned.

The medicament of the present invention can be administered before, after, or at the same time as the method for preventing or treating hepatocellular carcinoma. Here, the method for treating hepatocellular carcinoma is not particularly limited, and the above methods can be applied, or two or more kinds can be used in combination. In the present invention, surgical treatment or local medical treatment is preferred.

The background of hepatocellular carcinoma in the present invention is not particularly limited, and examples thereof include chronic hepatitis or liver cirrhosis (viral, alcoholic, fatty liver, non-alcoholic, mycotoxin, etc.), and the present invention is preferable. Is hepatocellular carcinoma caused by hepatitis virus (preferably hepatitis virus positive hepatocellular carcinoma), more preferably hepatocytes caused by one or more viruses selected from hepatitis B virus and hepatitis C virus. (Preferably hepatocellular carcinoma positive for one or more viruses selected from hepatitis B virus and hepatitis C virus), particularly preferably hepatocellular carcinoma caused by hepatitis C virus (preferably C type). Hepatitis virus-positive hepatocellular carcinoma). As specifically disclosed in Examples below, the pharmaceutical agent of the present invention exerts an excellent recurrence-suppressing action on patients after treatment of hepatocellular carcinoma caused by hepatitis C virus, and improves prognosis. Became clear. Therefore, the medicament of the present invention can be particularly suitably used as a medicament for suppressing recurrence after treatment of hepatocellular carcinoma caused by hepatitis C virus.
Further, since the medicament of the present invention can suppress recurrence after the treatment of hepatocellular carcinoma, it can avoid re-invasion in the retreatment of recurrent hepatic cancer, and the medicament of the present invention can be treated after the treatment of hepatocellular carcinoma. It can be preferably used as a medicine for suppressing the recurrence of

The form of the combination drug of the present invention is not particularly limited, and specific examples thereof include the following forms (I) and (II).
(I) Form of a single preparation (compounding agent) containing both acyclic retinoid or a salt thereof or a solvate thereof and an angiotensin II receptor antagonist or a salt thereof or a solvate thereof.
(II) A form having a preparation containing an acyclic retinoid or a salt thereof or a solvate thereof and a preparation containing an angiotensin II receptor antagonist or a salt thereof or a solvate thereof as separate preparations ..
In the case of the form according to (II), each preparation may be administered at the same time or may be administered separately at appropriate time intervals to prevent and/or treat the desired hepatocellular carcinoma. Appropriate dosage regimens may be employed to achieve the effect. Further, in the case of the form (II), it can be provided as a kit preparation of a combination containing both preparations in a single package.

The administration route of the medicament of the present invention is not particularly limited, and it may be either oral administration or parenteral administration. In the form according to (II), one may be an oral administration preparation and the other may be a parenteral administration preparation. Examples of the oral administration preparation include tablets, capsules, granules, powders and syrups. Examples of the preparation for parenteral administration include injections, suppositories, inhalants, transdermal agents, external skin preparations, eye drops, nasal drops and the like. Of these dosage forms, the preferred dosage form is an oral preparation, and tablets, capsules, granules, powders, syrups and the like are particularly preferable.
The preparation for oral administration and the preparation for parenteral administration can be produced by using known preparation additives, for example, based on a known method described in the 15th Revised Japanese Pharmacopoeia General Rules for Preparation and the like.

The dose of the medicament of the present invention is not particularly limited, and the dose can be appropriately increased or decreased according to various conditions such as age, body weight, symptoms of patients, administration form, and number of administrations. When the retinoid is peretinoin, it is preferable to administer 10 mg to 10 g, preferably 100 mg to 5 g, more preferably 300 mg to 1 g, particularly preferably 500 mg to 900 mg per day as a free form of peretinoin to an adult. .. The angiotensin II receptor antagonist is preferably administered at 0.1 mg to 200 mg, preferably 1 mg to 100 mg per day. As the administration interval, the above-mentioned dose can be administered once a day or divided into a plurality of times.

Further, the present invention, as another aspect, for administration in combination with an angiotensin II receptor antagonist or a salt thereof or a solvate thereof for the purpose of preventing and/or treating hepatocellular carcinoma, an acyclic It is intended to provide a medicine containing a retinoid or a salt thereof or a solvate thereof. The medicament of the aspect contains an acyclic retinoid or a salt thereof or a solvate thereof as a component, and is an angiotensin II receptor antagonist or a salt thereof for the purpose of preventing and/or treating hepatocellular carcinoma. Alternatively, these solvates are administered at the same time or at different times. A specific aspect of the pharmaceutical agent of the aspect is, for example, a kit for preventing and/or treating hepatocellular carcinoma, which comprises the following (1) and (2);
(1) A medicament for preventing and/or treating hepatocellular carcinoma, which comprises an acyclic retinoid or a salt thereof or a solvate thereof;
(2) Instructions for instructing to administer the pharmaceutical agent in combination with an angiotensin II receptor antagonist, a salt thereof or a solvate thereof.
A kit including is included. Specific examples of the instruction sheet include a so-called statement sheet (attachment document) that describes explanatory items regarding efficacy and effects, usage, dosage, and the like.
The meaning of each wording in the embodiment, the amount of each component used, the items for formulation, and the like are the same as above.

Furthermore, the present invention provides, as another aspect, angiotensin II receptor antagonism for administration in combination with an acyclic retinoid or a salt thereof or a solvate thereof for the purpose of preventing and/or treating hepatocellular carcinoma. It is intended to provide a medicine containing a drug, a salt thereof or a solvate thereof. The medicament of the aspect contains an angiotensin II receptor antagonist or a salt thereof or a solvate thereof as a component, and is an acyclic retinoid or a salt thereof for the purpose of preventing and/or treating hepatocellular carcinoma. Alternatively, these solvates are administered at the same time or at different times. A specific aspect of the pharmaceutical agent of the aspect is, for example, a kit for preventing and/or treating hepatocellular carcinoma, which comprises the following (1) and (2);
(1) A medicament for preventing and/or treating hepatocellular carcinoma, which comprises an angiotensin II receptor antagonist, a salt thereof, or a solvate thereof.
(2) Instructions for instructing the administration of the pharmaceutical agent in combination with an acyclic retinoid or a salt thereof or a solvate thereof;
A kit including is included. Specific examples of the instruction sheet include a so-called statement sheet (attachment document) that describes explanatory items regarding efficacy and effects, usage, dosage, and the like.
The meaning of each wording in the embodiment, the amount of each component used, the items for formulation, and the like are the same as above.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to the following Examples.

Example 1
[Used drug]
Peretinoin produced by a known method was used as the acyclic retinoid, and losartan (Manyu Pharmaceutical Co., Ltd.) was used as the angiotensin II receptor antagonist.
[Method]
As a rat liver carcinogenesis model, a diethylnitrosamine (DEN) + partial hepatectomy model was used. Specifically, 200 mg/kg DEN or physiological saline (control) was intraperitoneally administered to 6-week-old male F344 rats, and 2/3 hepatectomy was performed 3 weeks after the administration, and 8 weeks later. Evaluated to. Soybean oil (control), which was a drug or a solvent, was orally administered from the second week, that is, one week before hepatectomy. The group composition is a single administration group of peretinoin (2 doses of 40 mg/kg/day and 10 mg/kg/day), a single administration group of losartan (30 mg/kg/day), a combination of both groups (2 groups depending on the dose of peretinoin), A total of 7 groups (n=7), a vehicle administration group and a DEN non-administration control group (negative control), were prepared, and the effects of these drugs on glutathione S-transferase placental form (GST-P) positive precancerous lesions were examined.

[result]
The results of drug administration for GST-P positive precancerous lesions are shown in FIGS. In the figure, DEN indicates diethylnitrosamine (DEN) + partial hepatectomy model, ARB administered losartan (30 mg/kg/day), ACR(10) administered peretinoin 10 mg/kg/day, ACR(40 ) Indicates 40 mg/kg/day administration of peretinoin, respectively. FIG. 1 shows typical examples of precancerous lesions in each group. As is clear from FIG. 1, precancerous lesions (DEN) caused by diethylnitrosamine (DEN) + partial hepatectomy were treated with losartan alone (DEN+ARB), peretinoin alone (10 mg/kg/day (DEN+ ACR( 10)), 40mg/kg/day (DEN+ACR(40)), and the combined administration of both (DEN+ACR(10)+ARB, DEN+ACR(40)+ARB) becomes single administration. 2 shows the average area of precancerous lesions, and FIG. 3 shows the number of lesions per 1 cm ^{2. As} is clear from FIGS. Precancerous lesion area and the number (control) caused by diethylnitrosamine (DEN) + partial hepatectomy, losartan alone administration (ARB), peretinoin alone administration (10 mg/kg/day (ACR(10)), 40 mg/kg /day (ACR(40)) significantly reduced and decreased, and a dose-response was observed after single administration of peretinoin.In addition, combined administration of both (ACR(10)+ARB, ACR(40)+ARB) Was found to be dose-dependently and significantly reduced and decreased as compared with each single administration.
From the above results, by combining acyclic retinoid or a salt or a solvate thereof, and an angiotensin II receptor antagonist or a salt or a solvate thereof, excellent prevention of hepatocellular carcinoma and / Alternatively, it has been found that the therapeutic effect is exerted.

The medicament of the present invention can be used as a medicament for the prevention and/or treatment of hepatocellular carcinoma, and thus has industrial applicability.

Claims (11)

A medicament for preventing and/or treating hepatocellular carcinoma, which comprises a combination of an acyclic retinoid or a salt thereof or a solvate thereof, and an angiotensin II receptor antagonist or a salt thereof or a solvate thereof. There
Wherein said acyclic retinoid is Bae retinoic,
Angiotensin II receptor antagonists, Ru losartan der, the pharmaceutical. The medicament according to claim 1 , wherein the prevention and/or treatment of hepatocellular carcinoma is suppression of recurrence after the treatment of hepatocellular carcinoma. The medicine according to claim 1 or 2 , wherein the hepatocellular carcinoma is hepatocyte cancer caused by hepatitis virus. The medicine according to claim 3 , wherein the hepatitis virus is hepatitis C virus. Acyclic retinoid or a salt thereof or a solvate thereof, and an angiotensin II receptor antagonist or a salt thereof, or any one of claims 1 to 4, solvate thereof is in the form of formulations which together contain The medicine according to. A kit formulation containing a combination of a formulation containing an acyclic retinoid or a salt thereof or a solvate thereof, and a formulation containing an angiotensin II receptor antagonist or a salt thereof or a solvate thereof. The medicine according to any one of claims 1 to 4 . An acyclic retinoid or a salt thereof or a solvate thereof for administration in combination with an angiotensin II receptor antagonist or a salt thereof or a solvate thereof for the purpose of preventing and/or treating hepatocellular carcinoma. A pharmaceutical containing:
Wherein said acyclic retinoid is Bae retinoic,
Angiotensin II receptor antagonists, Ru losartan der, the pharmaceutical. An angiotensin II receptor antagonist or a salt thereof or a solvate thereof for administration in combination with an acyclic retinoid or a salt thereof or a solvate thereof for the purpose of preventing and/or treating hepatocellular carcinoma A pharmaceutical containing:
Wherein said acyclic retinoid is Bae retinoic,
Angiotensin II receptor antagonists, Ru losartan der, the pharmaceutical. The medicament according to claim 7 or 8 , wherein the prevention and/or treatment of hepatocellular carcinoma is suppression of recurrence after the treatment of hepatocellular carcinoma. The medicament according to any one of claims 7-9 hepatocellular carcinoma is hepatocellular carcinoma caused by hepatitis virus. The medicine according to claim 10 , wherein the hepatitis virus is hepatitis C virus.