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WO2012144619A1 - Agent thérapeutique pour maladies hépatiques chroniques destiné à être administré par voie orale - Google Patents

Agent thérapeutique pour maladies hépatiques chroniques destiné à être administré par voie orale Download PDF

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Publication number
WO2012144619A1
WO2012144619A1 PCT/JP2012/060762 JP2012060762W WO2012144619A1 WO 2012144619 A1 WO2012144619 A1 WO 2012144619A1 JP 2012060762 W JP2012060762 W JP 2012060762W WO 2012144619 A1 WO2012144619 A1 WO 2012144619A1
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Prior art keywords
iron
dfo
diet
therapeutic agent
oral administration
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PCT/JP2012/060762
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English (en)
Japanese (ja)
Inventor
石崎　園子
しのぶ 西谷
友希 斎藤
真弓 堀江
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to a therapeutic agent for chronic liver disease for oral administration for treating chronic liver disease caused by hepatitis C virus (HCV) or non-alcoholic steatohepatitis (NASH).
  • HCV hepatitis C virus
  • NASH non-alcoholic steatohepatitis
  • Deferoxamine is the substance name N- (5-aminopentyl) -N-hydroxy-N '-[5- (N-hydroxy-3- ⁇ [5- (N-hydroxyacetamido) pentyl] carbamoyl ⁇ propanamido) pentyl] butanediamide which is also abbreviated as DFO or DFOA.
  • This compound is conventionally used as a therapeutic agent for iron overload and iron poisoning as one of the chelating agents used to remove excess iron from the body.
  • the mesylate salt is a drug marketed under the trade name “Desferal” for hemochromatosis (iron overload) as an iron chelator in the form of an injection.
  • DFO has actually been used in the form of an injection, but attempts to use it in an oral dosage form have already been made. For example, around 1960, attempts have been made to remove iron in the diet by oral administration of DFO in healthy individuals or patients with anemia or hemochromatosis (for example, Non-patent Document 1 below).
  • Patent Document 1 relating to a DFO substance patent also describes that oral administration may be used as a medicine. And, the trial of oral administration of DFO is roughly divided into the following three.
  • DFO administration is attempted for hepatitis C patients (for example, Non-patent Document 4), or hepatitis model animals are used, and DFO is administered intraperitoneally as a chelator to study the role of iron in hepatotoxicity.
  • Ip is performed (for example, Non-Patent Document 5).
  • intravenous administration iv
  • intramuscular administration im
  • subcutaneous administration sc
  • the present invention provides a therapeutic agent for chronic liver disease for oral administration for treating chronic liver disease caused by hepatitis C virus (HCV), alcoholic hepatitis, or non-alcoholic steatohepatitis (NASH).
  • HCV hepatitis C virus
  • NASH non-alcoholic steatohepatitis
  • Another object of the present invention is to provide an inhibitor of enteral absorption of heme iron in a form for oral administration.
  • Deferoxamine has an action of chelating with free iron (inorganic iron) existing in the bloodstream to promote excretion from urine, and iron in an iron complex of porphyrin (so-called heme iron)
  • the present inventors have surprisingly been able to inhibit the absorption of iron in the diet, including heme iron, when deferoxamine is administered orally.
  • the present invention has been made based on this finding.
  • the present invention is caused by hepatitis C virus (HCV), alcoholic hepatitis, or nonalcoholic steatohepatitis (NASH), which contains deferoxamine or a pharmaceutically acceptable salt thereof as an active ingredient.
  • HCV hepatitis C virus
  • NASH nonalcoholic steatohepatitis
  • a prophylactic or therapeutic agent for oral administration of chronic liver disease is provided.
  • the present invention also provides a heme iron enteral absorption inhibitor characterized by containing deferoxamine or a pharmaceutically acceptable salt thereof as an active ingredient and in a form for oral administration.
  • the effect of DFO on plasma iron elevation 0 to 4 hours after feeding with iron citrate-containing diet is shown.
  • the effect of 2.5 equivalents of DFO on plasma iron elevation 0-22 hours after feeding with iron citrate containing feed is shown.
  • Fig. 2 shows the effect of DFO on plasma iron elevation 0 to 4 hours after feeding pig iron-containing iron.
  • the effect of 2.5 equivalents of DFO on plasma iron elevation from 0 to 22 hours after the feeding of pig liver-containing food is shown.
  • the amount of iron in the liver (iron source: iron citrate) 5 weeks after DFO mixed feeding to normal rats is shown.
  • the amount of iron in the liver (iron source: pig liver) after 3 weeks of DFO mixed feeding to normal rats is shown.
  • Fig. 6 shows the effect of oral administration of DFO on plasma iron transition after food loading in phlebotomized dogs.
  • the effect of heme iron-induced plasma iron elevation suppression by DFO is shown. It shows the effect of DFO for ALT increase by CCl 4 administration (0.25ml / Kg). It shows the effect of DFO for ALT increase by CCl 4 administration (0.5ml / Kg).
  • the disease targeted by the therapeutic agent for oral administration of the present invention is a disease group in which suppression of increase in plasma iron or suppression or decrease in accumulation of iron in the liver is desired for treatment, specifically, hepatitis C virus ( HCV), alcoholic hepatitis, or non-alcoholic steatohepatitis (NASH) is a chronic liver disease.
  • HCV hepatitis C virus
  • NASH non-alcoholic steatohepatitis
  • hepatitis C virus HCV
  • alcoholic hepatitis alcoholic hepatitis
  • NASH non-alcoholic steatohepatitis
  • HCV chronic liver disease caused by hepatitis C virus
  • the chronic liver disease caused by the hepatitis C virus is an infection with hepatitis C virus (virus, hepatitis C virus, HCV), which has shifted to chronic hepatitis.
  • HCV targets hepatocytes and some lymphocytes.
  • phlebotherapy may be performed as iron in the blood causes liver damage.
  • DFO chronic liver disease caused by hepatitis C virus (HCV) can be easily prevented or treated.
  • HCV hepatitis C virus
  • liver disease caused by alcoholic hepatitis it is known that iron is deposited in the liver due to promotion of iron absorption from the digestive tract accompanying alcohol intake and increased iron uptake into the liver.
  • liver fibrosis is exacerbated when alcohol and iron are administered simultaneously.
  • Treatment for alcoholic liver disorder is not to continue drinking alcohol, but if a method that removes excess accumulated iron is used in combination, it is expected that the improvement of the impaired liver will be accelerated.
  • chronic liver disease caused by non-alcoholic steatohepatitis (NASH) is hepatitis caused by the accumulation of fat in the liver and may progress to cirrhosis or hepatocellular carcinoma.
  • the treatment is said to be based on dietary improvement and exercise therapy, but drugs for liver disease are administered. It is a new discovery that the therapeutic agent for oral administration of the present invention is effective in the treatment of chronic liver disease caused by NASH by suppressing the increase in plasma iron or suppressing or decreasing the accumulation of iron in the liver.
  • the enteral absorption inhibitor of heme iron of the present invention is a chronic disease caused by various diseases for which suppression of enteral absorption of heme iron is desired, that is, hepatitis C virus, alcoholic hepatitis, or nonalcoholic steatohepatitis. It is useful as an agent for preventing or treating liver diseases.
  • deferoxamine and / or a pharmaceutically acceptable salt thereof is used as an active ingredient of a therapeutic agent for chronic liver disease for oral administration and an enteral absorption inhibitor of heme iron.
  • Pharmaceutically acceptable salts of deferoxamine include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, citric acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, mesyl Examples thereof include salts with acids (methanesulfonic acid) and organic acids such as tosylic acid. Among them, deferoxamine mesylate is preferably used.
  • a single administration of the therapeutic agent for chronic liver disease for oral administration and the enteral absorption inhibitor of heme iron is performed in an amount of 20 to 500 mg / person of active ingredient, more preferably active ingredient.
  • the amount is 50 mg to 200 mg / person.
  • the preventive or therapeutic agent for chronic liver disease for oral administration of the present invention and the enteral absorption inhibitor of heme iron contain the above-mentioned deferoxamine and / or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Various components used in medicines for example, pharmaceutically and physiologically acceptable solid or liquid carriers, additives and the like may be contained.
  • the carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, gelatin, albumin, amino acid, water, and physiological saline. Water etc. are mentioned.
  • additives such as a stabilizer, a wetting agent, an emulsifier, a binder, and an isotonic agent can be appropriately added.
  • the additive is not particularly limited as long as it is usually used for the purpose depending on the purpose. Specifically, for example, flavoring, sugar, sweetener, dietary fiber, vitamins, sodium glutamate Amino acids such as (MSG), nucleic acids such as inosine monophosphate (IMP), inorganic salts such as sodium chloride, and water.
  • the therapeutic agent for chronic liver disease for oral administration and the enteral absorption inhibitor of heme iron of the present invention can be used in a form that can be administered orally without limitation on physical properties such as dry powder, paste, and solution.
  • Such forms that can be administered orally include solid forms such as tablets, granules, powders and capsules, liquid forms such as solutions, suspensions and emulsions, and forms such as lyophilization agents. Can be mentioned. These preparations can be prepared by conventional means on the preparation.
  • the preventive or therapeutic agent for chronic liver disease for oral administration and the enteral absorption inhibitor of heme iron according to the present invention include other liver protectants (for example, urso, strong neominophagen, Sho-saiko-to, etc.) Administration of a drug that suppresses iron absorption (for example, proton pump inhibitor, tannin, phthalic acid, etc.), and can also be used in combination with hemoptysis therapy.
  • a drug that suppresses iron absorption for example, proton pump inhibitor, tannin, phthalic acid, etc.
  • the number of phlebotomy and the amount of phlebotomy can be reduced by the action of iron absorption suppression in the diet by DFO.
  • the enteral absorption inhibitor of heme iron of the present invention can be used in a form in which the above-mentioned deferoxamine and / or a pharmaceutically acceptable salt thereof is blended with various foods and drinks such as foods, beverages and seasonings. You may use in the form which mix
  • the deferoxamine and / or a pharmaceutically acceptable salt thereof may be stored in granules, tablets or gelatin capsules used in supplements.
  • Example 1 Evaluation of single plasma iron efficacy by oral administration of DFO in normal rats
  • A The extent to which DFO can suppress the absorption of iron from the diet of normal rats was evaluated from the transition of plasma iron after feeding by the following method.
  • Method The animals used were 7-10 week old Wistar rats (male), fasted for 22 hours, then weighed and grouped into groups of 5 animals. 4 g of ready-to-eat food was freely fed for 1 hour. The DFO amount was equivalent to the iron amount of each bait, mixed with each bait and administered as a diet.
  • an iron-free dietary Fe0 diet (AIN93G composition (Oriental Yeast Co., Ltd.) and iron citrate 0.029 mg / 100 g diet included) was prepared and used for the test.
  • an Fe14 diet was provided in which iron citrate was mixed with Fe0 diet to 14 mg / 100 g diet. After the end of feeding, blood was collected over time from the tail vein using a heparin tube, and after plasma separation, plasma iron was measured using Plasma Iron Test Wako (Wako Pure Chemical Industries).
  • the results are shown in FIG.
  • FIG. 4 shows the results of measuring blood plasma collected from the tail vein after 2, 4, 6, 8, 10, and 22 hours. From these results, not only when iron citrate is used as the iron source, but also when pig liver that is usually eaten by humans is used as the iron source, the plasma iron inhibitory action of DFO is recognized from 0.625 equivalents, In 2.5 equivalent, it turned out that the effect equivalent to an iron-free food is shown. In addition, when 2.5 equivalents are converted into a person, the iron content in one person's meal is about 3.3 mg (according to the 2010 National Nutrition Survey). About 100 mg.
  • Example 2 Efficacy evaluation of long-term intrahepatic iron accumulation by oral administration of DFO in normal rats (A) It was evaluated by the following method whether DFO could suppress the absorption of iron from the diet of normal rats and reduce the amount of iron accumulation in the liver.
  • Method The animals used were 7-week-old Wistar rats (male), were weighed and divided into groups, and each group consisted of 8 animals. Group 1 Fe0 diet, Group 2 Fe14 diet, Group 3 Fe14 diet + DFO 0.625 equivalent, Group 4 Fe14 diet + DFO 1.25 equivalent, Group 5 Fe14 diet + DFO 2.5 equivalent were prepared and allowed to eat freely for 5 weeks. Five weeks later, after exsanguination from the inferior vena cava under anesthesia, the liver was removed, crushed and freeze-dried.
  • each group consisted of 6 animals, and the pork liver diet was prepared by replacing all the casein protein component with pork liver during the preparation of the Fe0 diet (the iron content is 11 mg / 100 g diet).
  • the group composition was 1 group Fe0 diet, 2 group liver diet, 3 group liver diet + DFO 2.5 equivalent, 4 group liver diet + DFO 5 equivalent, 5 group liver diet + DFO 7.5 equivalent, and allowed to eat freely for 3 weeks. Three weeks later, after exsanguination from the inferior vena cava under anesthesia, the liver was removed, crushed and freeze-dried. After the ashing treatment, the amount of Fe was measured by AES-ICP (Hitachi), and the result is shown in FIG.
  • Example 3 Evaluation of pharmacological effects on long-term intrahepatic iron accumulation by oral administration of DFO in rats with intrahepatic iron accumulation It has been reported that chronic hepatitis C patients have mild iron accumulation in the liver. Therefore, DFO was administered over a long period of time using rats in which iron was slightly accumulated in the liver, and the effect of suppressing the accumulation of iron in the liver was examined by the following method.
  • Method The experiment was conducted using a 7-week-old Wistar rat (male). In group 1, rats fed with animal feed CRF-1 (Oriental Yeast Co., Ltd.) for 2 weeks were fed a diet (Fe14) containing 14 mg / 100 g diet of iron citrate for 4 weeks.
  • CRF-1 Oriental Yeast Co., Ltd.
  • Groups 2-5 were fed a diet containing 2.5% Carbonyl iron for 2 weeks, causing mild accumulation of iron in the liver.
  • Groups 2-5 were fed a diet containing 2.5% Carbonyl iron for 2 weeks, then grouped by body weight and plasma iron, group 2 was Fe14 diet, group 3 was iron-free (Fe0) and group 4 was 5 groups of Fe14 meal + 5 equivalents of DFO were fed freely with Fe14 meal for 4 weeks.
  • group 5 once a week, 5 ml / kg of blood was collected from the tail vein without anesthesia, and blood was collected.
  • Six weeks after the start of the test after exsanguination from the inferior vena cava under anesthesia, the liver was removed, crushed and freeze-dried.
  • Example 4 Inhibition of postprandial plasma iron by oral administration of DFO in phlebotomized dogs
  • iron citrate and pork liver have been used as the iron source.
  • no increase in plasma iron was observed after feeding 200 g of iron-rich food (iron content: 17.3 mg). Therefore, 5 ml / kg of phlebotomy was performed 7 times once every 2 weeks to enhance iron absorption. The test was performed in the state.
  • a beagle dog with a body weight of 16-18Kg was allowed to freely ingest 200g of the diet of the composition shown in Table 1, 1, 2, 4, 6 and 8 hours after the meal, blood was collected from the brachial vein, and after plasma separation, Plasma Iron Test Wako (Wako Pure Chemical) was used to measure plasma iron.
  • Plasma Iron Test Wako (Wako Pure Chemical) was used to measure plasma iron.
  • DFO DFO was dissolved in distilled water 1 hour after feeding and was orally administered by gavage using an intragastric sonde, or was administered orally with a small amount of water in a gelatin capsule.
  • FIG. 8 shows the transition of plasma iron after 200 g of food having the composition shown in Table 1 was given to the phlebotomized dog. The iron absorption was increased by phlebotomy, and a marked increase in plasma iron was observed after meal loading. It can be seen that when 1 equivalent of DFO is administered orally, the increase in plasma iron can be significantly suppressed in both powder administration and solution administration.
  • Example 5 Inhibitory effect of oral administration of DFO on plasma iron elevation due to heme iron load in normal rats
  • foods such as iron citrate, which is inorganic iron as an iron source, and pork liver containing inorganic iron and heme iron
  • DFO is known to chelate inorganic iron, it has been reported that heme iron cannot be chelated.
  • DFO shows a very strong medicinal effect not only when inorganic iron is used as the iron source but also when food is used as the iron source. The effect of DFO on the suppression of plasma iron was verified by the following method.
  • the animals used were 7-10 week old Wistar rats (male), fasted for 22 hours, then weighed and grouped into groups of 5 animals.
  • 1 group is Fe0 diet
  • 2 groups and 3 groups are Fe25 diet mixed with Fe0 diet to iron citrate 25mg / 100g diet
  • 4 groups and 5 groups are hemoglobin added to Fe0 diet as iron 25mg / 100g diet Hem was 25 meals, and each meal was 4 g which could be completely eaten and allowed to eat freely for 1 hour.
  • 5 equivalents of DFO was dissolved in water and 2 ml / 1 animal was forcibly administered orally.
  • Plasma iron elevation by hemoglobin was almost the same as plasma iron elevation by iron citrate.
  • Example 6 Inhibition of hepatitis by oral administration of DFO in carbon tetrachloride-induced hepatitis model Carbon tetrachloride (CCl 4 ) is a very frequently used inflammatory substance as a hepatitis-inducing substance, but CCl 4 is administered intraperitoneally.
  • a hepatitis model was prepared and the efficacy of DFO was confirmed by the following method. Method : 7-week-old Wistar rat (male) was fed with 2.5% Carbonyl iron for 2 weeks, divided into 6 groups per group, 1 group CRF-1 (Fe amount of about 14 mg / 100 g diet), 2 groups CRF-1 Were freely fed with 2.5 equivalents of DFO for 6 weeks.
  • CCl 4 was diluted with olive oil to 0.25 ml / kg or 0.5 ml / kg and administered intraperitoneally once a week at 5 ml / kg.
  • Blood was collected from the tail vein 24 hours before and 48 hours before CCl 4 administration, and ALT, which is an index of hepatitis, was measured.
  • Result The results are shown in FIG. 10 and FIG. 11. From the results in FIG. 10, it can be seen that hepatitis induced with 0.25 ml / kg of CCl 4 can be suppressed by administration of a diet equivalent to 2.5 equivalents of DFO. Moreover, from the result of FIG. 11, it can be seen that early hepatitis induced by 0.5 ml / kg of CCl 4 can be suppressed by administration of a diet equivalent to 2.5 equivalents of DFO.

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Abstract

L'invention porte sur un agent prophylactique ou thérapeutique destiné à être administré par voie orale pour des maladies hépatiques chroniques associées à un virus de l'hépatite C (un VHC), une hépatite alcoolique ou une stéatohépatique non alcoolique (NASH), lequel agent prophylactique ou thérapeutique contient de la déféroxamine ou un sel pharmaceutiquement acceptable de celle-ci en tant que principe actif. L'agent prophylactique ou thérapeutique est efficace en tant qu'agent thérapeutique pour maladies hépatites chroniques destiné à être administré par voie orale.
PCT/JP2012/060762 2011-04-20 2012-04-20 Agent thérapeutique pour maladies hépatiques chroniques destiné à être administré par voie orale Ceased WO2012144619A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103736090A (zh) * 2014-01-27 2014-04-23 中国医学科学院医学生物学研究所 甲磺酸去铁胺佐剂及含甲磺酸去铁胺佐剂的疫苗
JP2023520709A (ja) * 2020-04-06 2023-05-18 ネミシス リミテッド 肝疾患と関連する鉄欠乏症の治療または予防における使用のためのカルボン酸塩リガンド修飾水酸化第二鉄組成物

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BRITTON,R.S. ET AL.: "Iron toxicity and chelation therapy", INT J HEMATOL, vol. 76, no. 3, 2002, pages 219 - 28 *
HEILMEYER, L. ET AL.: "Moderne hamochromatoseprobleme mit besonderer berucksichtigung der desferrioxaminbehandlung", DEUTSCHE MEDIZINISCHE WOCHENSCHRIFT, vol. 87, no. 52, 1962, pages 2661 - 7 *
JUNJI KATO: "Iron overload syndrome no Gen'in to Chiryo", THE CELL, vol. 34, no. 14, 2002, pages 579 - 82 *
KEISUKE HINO ET AL.: "Mansei Kanshogai ni Okeru Tetsu Taisha Ijo to Jotetsu Ryoho", THE JOURNAL OF THE JAPANESE SOCIETY OF INTERNAL MEDICINE, vol. 99, no. 6, 2010, pages 1248 - 54 *
STEWARD,A. ET AL.: "An improved animal model for studying desferrioxamine", BR J HAEMATOL, vol. 95, no. 4, 1996, pages 654 - 9 *
ZAREIFAR,S. ET AL.: "Efficacy of combined desferrioxamine and deferiprone versus single desferrioxamine therapy in patients with major thalassemia", ARCH IRAN MED, vol. 12, no. 5, 2009, pages 488 - 91 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103736090A (zh) * 2014-01-27 2014-04-23 中国医学科学院医学生物学研究所 甲磺酸去铁胺佐剂及含甲磺酸去铁胺佐剂的疫苗
CN103736090B (zh) * 2014-01-27 2016-03-02 中国医学科学院医学生物学研究所 甲磺酸去铁胺佐剂及含甲磺酸去铁胺佐剂的疫苗
JP2023520709A (ja) * 2020-04-06 2023-05-18 ネミシス リミテッド 肝疾患と関連する鉄欠乏症の治療または予防における使用のためのカルボン酸塩リガンド修飾水酸化第二鉄組成物
US12329736B2 (en) 2020-04-06 2025-06-17 NEMYSIS Ltd. Carboxylate ligand modified ferric iron hydroxide compositions for use in the treatment or prevention of iron deficiency associated with liver diseases

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