WO2019098572A2 - Composition pharmaceutique pour soulager la fibrose hépatique induite par le virus de l'hépatite - Google Patents

Composition pharmaceutique pour soulager la fibrose hépatique induite par le virus de l'hépatite Download PDF

Info

Publication number
WO2019098572A2
WO2019098572A2 PCT/KR2018/012961 KR2018012961W WO2019098572A2 WO 2019098572 A2 WO2019098572 A2 WO 2019098572A2 KR 2018012961 W KR2018012961 W KR 2018012961W WO 2019098572 A2 WO2019098572 A2 WO 2019098572A2
Authority
WO
WIPO (PCT)
Prior art keywords
acceptable salt
pharmaceutically acceptable
pharmaceutical composition
day
ursodeoxycholic acid
Prior art date
Application number
PCT/KR2018/012961
Other languages
English (en)
Korean (ko)
Other versions
WO2019098572A3 (fr
Inventor
김희선
신현주
김창욱
Original Assignee
주식회사 대웅제약
가톨릭대학교 산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 주식회사 대웅제약, 가톨릭대학교 산학협력단 filed Critical 주식회사 대웅제약
Publication of WO2019098572A2 publication Critical patent/WO2019098572A2/fr
Publication of WO2019098572A3 publication Critical patent/WO2019098572A3/fr

Links

Images

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a pharmaceutical composition for the improvement of hepatitis virus-induced liver fibrosis caused by hepatitis virus. More particularly, the present invention relates to a pharmaceutical composition for improving hepatic fibrosis induced by hepatitis virus, which comprises ursodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Liver fibrosis refers to encapsulation or replacement by a collagenous scar of damaged liver tissue. Liver fibrosis progresses at various rates depending on the cause of liver disease, environmental and host factors. Liver cirrhosis is an advanced stage of liver fibrosis, involving a transformation of the liver vasculature. Hepatic fibrosis is caused by liver damage due to various causes, and the mechanism of hepatic fibrosis differs depending on the cause of liver injury such as alcohol, hepatitis virus, bile acid (Baek Yong Han, Clinical and Molecular Hepatology , Vol.14, No.2 (S), 2008).
  • hepatic fibrosis mechanisms are different in primary biliary cirrhosis (PBC), non-alcholic steatohepatitis (NASH), and chronic viral hepatitis,
  • PBC primary biliary cirrhosis
  • NASH non-alcholic steatohepatitis
  • chronic viral hepatitis The histological characteristics also differ.
  • PBC primary biliary cirrhosis
  • NASH non-alcholic steatohepatitis
  • chronic viral hepatitis The histological characteristics also differ.
  • PBC primary biliary cirrhosis
  • NASH non-alcholic steatohepatitis
  • chronic viral hepatitis The histological characteristics also differ.
  • Non- (Central vein) chronic viral hepatitis starts inflammation and fibrotic reaction centered on liver triad.
  • Ursodeoxycholic acid has a molecular weight of 392.58 and its molecular formula is C 24 H 40 O 4. It is a major component of umbellum used for liver and biliary diseases in Korea, China and Japan for a long time. Is a kind of bile acid that is found in.
  • UDCA is the action of releasing waste materials and toxic bile acids in the microbial in vivo, stabilizing the hepatic cell membrane and protecting the hepatocyte, increasing the hepatic blood flow, inhibiting the absorption and biosynthesis of cholesterol, dissolving and inhibiting the production of gallstones And has pharmacological activity to normalize immune activity, and thus has a major clinical indication for cholelithiasis, chronic liver disease and fatty liver.
  • UDCA is known to be a major component of bile acid and has antioxidative, dandruff, mitochondrial membrane stabilization, cell death and cell membrane protection.
  • UDCA has been shown to inhibit hepatic fibrosis from progressing to hepatic cirrhosis in patients with primary biliary cirrhosis (PBC), it is not clear that it is effective in improving liver fibrosis.
  • UDCA does not have improving activity against liver fibrosis in patients with non-alcoholic fatty liver disease (NASH).
  • UDCA has been shown to improve liver fibrosis induced by hepatitis virus Or hepatic fibrosis in patients with hepatitis B who have undergone liver fibrosis has not been reported.
  • ELF score, TIMP-1 concentration, PIIINP concentration, and HA concentration can be used as markers of liver fibrosis to compare the extent and degree of improvement of liver fibrosis.
  • NICE National Institute for Health and Care Excellence
  • NEF enhanced liver fibrosis
  • the ELF score (Enhanced Liver Fibrosis (ELF) score) was used to assess the association between TIMP-1 (tissue inhibitor of metalloproteinases 1), PIIINP (amino-terminal propeptide of type III procollagen) is a set of extracellular matrix markers that combine quantitative serum concentration measurements of hyaluronic acid into a single value.
  • TIMP-1 tissue inhibitor of metalloproteinases 1
  • PIIINP amino-terminal propeptide of type III procollagen
  • hepatic stellate cells involved in hepatic fibrosis are activated by hepatic injury to increase the production of extracellular matrix, thereby increasing the blood levels of TIMP-1, PIIINP, and HA .
  • S. Yilmaz et al. Found that HA levels were higher in patients with chronic hepatitis and cirrhosis than in those with severe hepatic fibrosis. The higher values were found in serum levels of each component. Y.Murawaki .
  • the level of TIMP-1 and PIIINP in the liver was higher than in the control group.
  • the present inventors have conducted multicenter clinical trials to confirm the effect of urdoximecholic acid (UDCA) in patients with chronic viral hepatitis, particularly patients with chronic hepatitis B virus infection. Surprisingly, the present inventors have found that UDCA effectively improves hepatic fibrosis induced by hepatitis virus.
  • UDCA urdoximecholic acid
  • UDCA UDCA or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for improving hepatic fibrosis caused by hepatitis virus which comprises, as an active ingredient, ursodeoxycholic acid or a pharmaceutically acceptable salt thereof.
  • the liver fibrosis induced by the hepatitis virus may be hepatic fibrosis induced by the hepatitis B virus.
  • the pharmaceutical composition of the present invention has a dosage form suitable for administering a therapeutically effective amount of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is 600 mg / day to 1,000 mg / day as ursodeoxycholic acid, day. < / RTI >
  • the dosage form may be in the form of an oral dosage form, and may be in the form of an oral dosage form, preferably twice a day.
  • the dosage form may have the form of a twice-a-day dosage form comprising from 200 mg to 600 mg of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof as ursodeoxycholic acid.
  • the dosage form may have the form of a twice-a-day dosage form comprising 300 mg to 500 mg of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof as ursodeoxycholic acid.
  • the dosage form may have the form of a once-a-day dosage form comprising 500 mg of erxodeoxycholic acid or a pharmaceutically acceptable salt thereof as ursodeoxycholic acid.
  • compositions of the present invention may be administered in combination with a therapeutically effective amount of an anti-hepatitis virus agent.
  • the anti-hepatitis virus agent is selected from the group consisting of lamivudine or a pharmaceutically acceptable salt thereof, telbivudine or a pharmaceutically acceptable salt thereof, cleavudine or a pharmaceutically acceptable salt thereof, entecavir or a pharmaceutically acceptable salt thereof, A salt thereof, adefovir or a pharmaceutically acceptable salt thereof, terfenoviridisoproxyl or a pharmaceutically acceptable salt thereof, bissipovir dipivoxil or a pharmaceutically acceptable salt thereof, tenofovir alphenamide or A pharmaceutically acceptable salt thereof, and a peginterferon-alpha or a pharmaceutically acceptable salt thereof.
  • the anti-hepatitis virus agent can be tenofovir disiproxyl or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the above-mentioned tenofovir disoproxil or a pharmaceutically acceptable salt thereof is in the range of about 100 mg / day to about 500 mg / day, preferably about 200 mg / day as tenofovir disoproxyl fumarate / day to about 400 mg / day, more preferably about 300 mg / day.
  • the combination comprises a first composition and a second composition administered independently of each other, the first composition comprising ursodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient;
  • the second composition may contain an anti-hepatitis virus agent as an active ingredient.
  • ursodeoxycholic acid effectively improves liver fibrosis induced by hepatitis virus, in particular liver fibrosis induced by hepatitis B virus. Accordingly, the pharmaceutical composition of the present invention can not only return the hepatic fibrosis stage to a non-fibrosis stage but also effectively prevent progression to the hepatocyte stage in a viral hepatitis patient, particularly a type B viral hepatitis patient.
  • Figure 1 shows the results of measuring the levels of HA, PIIINP and TIMP-1 in the group of 300 mg qd + UDCA 500 mg bid, 300 mg qd + UDCA 300 mg bid, and 300 mg qd + UDCA bid bid group .
  • Figure 2 shows the results of measuring the improvement rate of hepatic fibrosis in the group administered with Taborpovir 300 mg qd + UDCA 500 mg bid, 300 mg qd + UDCA 300 mg bid group, and Tenofovir 300 mg qd + UDCA bid bid group based on ELF score .
  • Liver fibrosis can be defined as excessive deposition of extracellular matrix (ECM) due to inflammation in the intracranial tract.
  • ECM extracellular matrix
  • hepatic stellate cells are activated by various cytokines or oxidative stress secreted from damaged hepatocytes or kupffer cells.
  • Activated hepatic stellate cells are increased in response to various growth factors (PDGF, CTGF, TGF ⁇ ), transformed into myofibroblast-like cells, activated hepatic stellate cells proliferate, secrete vasoconstrictors It synthesizes and secretes collagen (COL1A1, COL1A2) and secretes various inflammatory cytokines.
  • TIMP is overexpressed to secrete MMP and its inhibitory substance, TIMP, thereby affecting the reduction of ECM removal, resulting in excessive accumulation of ECM, leading to fibrosis.
  • hepatic stellate cells are activated is specific for each disease, for example, hepatitis caused by virus, alcoholic liver disease, nonalcoholic fatty liver disease, PBC cholestasis, and the like.
  • Viral hepatitis by HBV and HCV induces inflammation in the liver, contributing to the cyclic process of inflammation, necrosis and regeneration.
  • immune cells and secreted inflammatory cytokines are constantly infiltrated, leading to liver damage Thereby promoting liver fibrosis.
  • NK cell cytotoxicity is increased and IL-10 and TGF-b are secreted, activated CD4 + T cells and hepatocyte dissolution occur, resulting in hepatic damage.
  • hepatitis virus-induced liver fibrosis refers to hepatic fibrosis that occurs in patients with chronic hepatitis caused by hepatitis virus.
  • hepatitis B virus-induced liver fibrosis refers to hepatic fibrosis developed in patients with HBV hepatitis.
  • improvement refers to either restoring the fibrotic stage to the non-fibrotic stage or inhibiting the progression of the fibrotic stage to the cirrhotic stage All actions that at least reduce the degree of symptom associated with the condition being treated, including, for example, the condition being treated.
  • the non-fibrosis stage refers to the presence of portal and periportal lesions without extensive fibrosis.
  • the curing step refers to exhibiting nodular cirrhotic formation.
  • the " improvement " may be defined as a decrease in the statistically significant ELF score (p value ⁇ 0.05) in an ELF test (enhanced liver fibrosis (ELF) test).
  • pharmaceutically acceptable salt in the present invention means a salt which is physiologically acceptable and does not cause serious irritation to the organism to which the compound is administered, and does not impair the biological activity and properties of the compound.
  • the present invention provides a pharmaceutical composition for improving hepatic fibrosis induced by hepatitis virus, which comprises ursodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the hepatic fibrosis induced by hepatitis virus includes hepatic fibrosis induced by hepatitis A virus, hepatitis B virus, hepatitis C virus, etc., and preferably by hepatitis B virus Induced liver fibrosis.
  • the active ingredient may be urushodeoxycholic acid (UDCA), which may be used in the form of a salt, preferably a pharmaceutically acceptable salt.
  • the salt may be in the form of an acid addition salt formed by a pharmaceutically acceptable free acid, wherein the free acid comprises an organic acid and an inorganic acid.
  • the organic acids include, but are not limited to, citric, acetic, lactic, tartaric, maleic, fumaric, formic, propionic, oxalic, trifluroacetic, benzoic, gluconic, methanesulfonic, glycolic, succinic, Glutamic acid and aspartic acid.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid.
  • the above urushodeoxycholic acid is generally present in the bile of an animal and can be isolated from the bile of an animal or can be prepared by a chemical synthetic method known in the art. Urosodeoxycholic acid Can be used.
  • the pharmaceutical compositions of the present invention may have a dosage form suitable for administration of a therapeutically effective amount of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof.
  • the dosage form may be in the form of an oral dosage form.
  • a therapeutically effective amount of the above mentioned ursodeoxycholic acid or a pharmaceutically acceptable salt thereof is, for example, 300 mg / day to 1200 mg / day, for example, 400 mg as ursodeoxycholic acid when administered orally / day to 800 mg / day, or from 600 mg / day to 1,000 mg / day.
  • the therapeutically effective amount of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof can range, for example, from 600 mg / day to 1,000 mg / day as ursodeoxycholic acid when administered orally .
  • the therapeutically effective amount of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof can be, for example, about 1,000 mg / day as ursodeoxycholic acid when administered orally.
  • the therapeutically effective amount may be appropriately changed according to the progress of hepatic fibrosis of the subject to be administered, body weight health condition, route of administration, sex, and treatment period.
  • compositions of the present invention may be formulated in the form of preparations suitable for administration to a patient, preferably orally, of a therapeutically effective amount of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof.
  • Formulations suitable for oral administration i. E. Preparations for oral administration, contain 25 mg to 1,000 mg, such as from 50 mg to 500 mg, 200 mg, of a solution of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof per unit dosage form.
  • mg to 600 mg 100 mg to 500 mg, 300 mg to 500 mg, or 600 mg to 1,000 mg, and may be administered once or multiple times per day in consideration of a therapeutically effective amount.
  • the oral dosage form may comprise 100 mg, 200 mg, or 300 mg of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof per unit dosage, and may be administered multiple times .
  • the pharmaceutical compositions of the invention may be formulated in the form of pharmaceutical compositions for oral administration once to three times a day, preferably twice daily.
  • the pharmaceutical compositions of the present invention comprise from 200 mg to 600 mg, more preferably 300 mg to 500 mg of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof as ursodeoxycholic acid, May be in the form of preparations for oral administration.
  • the pharmaceutical composition of the present invention may have the form of a once-a-day oral dosage form comprising about 500 mg of ursodeoxycholic acid or a pharmaceutically acceptable salt thereof as ursodeoxycholic acid.
  • compositions of the present invention may be administered to mammals and formulated using techniques known in the art such that the active ingredient is either immediate release, sustained release or delayed release.
  • Formulations which may be used in the present invention include, but are not limited to, powders, granules, tablets, emulsions, syrups, aerosols, soft or hard capsules, sterile powders and the like.
  • compositions of the present invention may comprise a therapeutically effective amount of urushodeoxycholic acid or a pharmaceutically acceptable salt thereof alone or in combination with one or more pharmaceutically acceptable carriers, excipients or diluents commonly used in the art , And the like.
  • the carrier, excipient or diluent include a disintegrant, a binder, a lubricant, a fluidizing agent, a diluent, a stabilizer, a light shielding agent and the like.
  • the disintegrant include starch, crospovidone, sodium starch glycolate, croscarmellose sodium, crystalline cellulose, carboxymethylcellulose calcium and the like.
  • binder examples include hydroxypropylcellulose, glucose syrup, povidone, HPMC, gelatin solution and the like.
  • examples of the lubricant include polyethylene glycol, sodium lauryl sulfate, magnesium stearate, light silicic anhydride, talc, colloidal silicon dioxide, wax and the like.
  • the pharmaceutical compositions of the present invention includes a tablet or capsule which is commercially available, for example, Ursa TM 100mg tablets (Co. Daewoong, Republic of Korea), Ursa TM 200mg tablets (Co. Daewoong, Republic of Korea ), Ursa TM 300mg tablets (Co. Daewoong, Republic of Korea), Ursa TM 500mg tablets (Co. Daewoong, Republic of Korea), Daewoong Ursa TM ratio constant (Co.
  • the soft capsule (( Daewoong Pharmaceutical Co., Ltd., Korea).
  • the pharmaceutical compositions of the present invention may be administered in combination with a therapeutically effective amount of an anti-hepatitis virus agent.
  • the anti-hepatitis virus agent is an anti-hepatitis B virus agent.
  • the anti-hepatitis virus agent may be selected from the group consisting of lamivudine or a pharmaceutically acceptable salt thereof, telbivudine or a pharmaceutically acceptable salt thereof, clevudine or a pharmaceutically acceptable salt thereof, A L-nucleoside analog such as Entecavir or a pharmaceutically acceptable salt thereof;
  • a pharmaceutical composition comprising adefovir or a pharmaceutically acceptable salt thereof, tenofovir disoproxil or a pharmaceutically acceptable salt thereof, besifovir dipivoxil or a pharmaceutically acceptable salt thereof, A salt thereof, a nucleotide analogue such as tenofovir alafenamide or a pharmaceutically acceptable salt thereof, or the like; Or peginterferon alfa or
  • the anti-hepatitis virus agent can be tenofovir disiproxyl or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the above mentioned tenofovir disoproxil or a pharmaceutically acceptable salt thereof is, for example, tenofovir disoproxil fumarate of about 100 day to about 500 mg / day, preferably in the range of about 200 mg / day to about 400 mg / day, more preferably about 300 mg / day.
  • the combination comprises a first composition and a second composition administered independently of each other, the first composition comprising ursodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient;
  • the second composition may contain an anti-hepatitis virus agent as an active ingredient.
  • Ursa ® 200 mg tablets (Co. Daewoong)
  • Ursa ® 300 mg tablet was used (Co. Daewoong)
  • the reference product has the same weight, shape purification except the active ingredient in the test product ( Placebo, Daewoong Pharmaceutical Co., Ltd.).
  • Patients with chronic hepatitis B who had decompensated liver disease requiring treatment with tenofovir were enrolled in the study for approximately 50 weeks (treatment period: 48 weeks) per patient.
  • a total of 75 subjects 25 subjects, 1: 1: 1) were randomly divided into two groups. Ten subjects were selected as subjects. And 90 patients were recruited for the clinical study.
  • the number of subjects per group is as follows.
  • the selection criteria of the subjects are as follows.
  • ALT level is more than twice the UNL level in the screening test or ALT level is over UNL in the screening test and ALT level is more than twice the UNL level within one month before screening.
  • the subjects performed screening, random assignment visits, about 9 visits including 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks and 48 weeks. And procedures were performed.
  • Liver fibrosis was evaluated by the ELF method in this study.
  • the ELF test is an early marker for hepatic fibrosis, which can be used to diagnose hepatic fibrosis with minimal blood.
  • HA, PIIINP, and TIMP-1 which are important markers for the progression of liver fibrosis, were analyzed by standardized tests and automatically calculated using scores.
  • Visit1 (visit screening) and Visit9 Changes in degree of fibrosis following administration were evaluated.
  • the data obtained from the subjects of this study are divided into safety set, full analysis set (FAS) and per protocol set (PPS).
  • FAS full analysis set
  • PPS per protocol set
  • FAS analysis was performed and PPS analysis was performed.
  • Safety data are analyzed for safety set.
  • Fibrosis improvement rate at 48 weeks of administration (remarkably improved, moderately improved, slightly improved, unchanged, deteriorated)
  • the viral resistance fraction The viral resistance fraction
  • the baseline values for the safety assessment parameters are based on the results of the last evaluation performed prior to the first administration of the clinical trial drug.
  • the descriptive statistics (number of subjects to be tested, the incidence and the number of expression) of the adverse reactions (TEAE), ADR, and SAE after administration of the drug by the administration group were presented and 90% confidence Provide a section. Differences in the ratios between the groups were compared by chi-square test or Fisher's exact test.
  • ELF score 2.278 + 0.851 ln (HA concentration) + 0.751 ln (PIIINP concentration) + 0.394 ln (TIMP-1 concentration)
  • the improvement rate of liver fibrosis was measured according to the criteria of Table 2. In other words, the proportion of patients who showed improvement of 'slightly improved', 'moderately improved', and 'remarkably improved' from the ELF score at 48 weeks was measured. The results are shown in FIG.
  • levels of HA, PIIINP, and TIMP-1 which are liver fibrosis markers, decreased in both test and placebo groups.
  • the UDCA 600 mg / day group showed a lower reduction rate than the placebo group, suggesting that the baseline value was significantly lower than the other groups.
  • the UDCA 1000 mg / day group showed a higher rate of reduction of liver fibrosis markers HA, PIIINP, and TIMP-1 compared to placebo.
  • UDCA hepatitis B virus
  • hepatitis virus which is the cause of hepatocyte damage
  • tenofovir May inhibit the expression of TGF-beta1
  • TGF-beta1 the most potent fibrotic cytokine of hepatic stellate cells
  • UDCA increased the expression of Smad7, which is known to reduce TGF-beta1, Smad2, and CBP expression and inhibit Smad signaling by TGF- have.
  • UDCA may be an improvement of liver fibrosis by a mechanism of decreasing TIMP-1 which increases and inhibits MMP, a proteolytic enzyme that degrades extracellular matrix.
  • UDCA improved hepatic fibrosis in patients with hepatitis B virus (HBV) infection, suggesting that this is a surprising effect not seen in liver fibrosis caused by other causes.
  • HBV hepatitis B virus

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour soulager la fibrose hépatique induite par un virus de l'hépatite, la composition comprenant de l'acide ursodésoxycholique ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif.
PCT/KR2018/012961 2017-11-15 2018-10-30 Composition pharmaceutique pour soulager la fibrose hépatique induite par le virus de l'hépatite WO2019098572A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2017-0152276 2017-11-15
KR1020170152276A KR101887561B1 (ko) 2017-11-15 2017-11-15 간염 바이러스에 의해 유발된 간 섬유화의 개선을 위한 약학 조성물

Publications (2)

Publication Number Publication Date
WO2019098572A2 true WO2019098572A2 (fr) 2019-05-23
WO2019098572A3 WO2019098572A3 (fr) 2019-07-11

Family

ID=63593798

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2018/012961 WO2019098572A2 (fr) 2017-11-15 2018-10-30 Composition pharmaceutique pour soulager la fibrose hépatique induite par le virus de l'hépatite

Country Status (2)

Country Link
KR (1) KR101887561B1 (fr)
WO (1) WO2019098572A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101887561B1 (ko) * 2017-11-15 2018-09-06 주식회사 대웅제약 간염 바이러스에 의해 유발된 간 섬유화의 개선을 위한 약학 조성물
KR20240002134A (ko) * 2022-06-28 2024-01-04 가톨릭대학교 산학협력단 테노포비르 알라페나미드를 포함하는 비알콜성 지방간염 예방, 개선 또는 치료용 조성물

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2755708A1 (fr) * 2009-03-17 2010-09-23 Axcan Pharma Inc. Procede de traitement d'une steatohepatite non alcoolique au moyen de doses elevees d'acide ursodesoxycholique
KR101887561B1 (ko) * 2017-11-15 2018-09-06 주식회사 대웅제약 간염 바이러스에 의해 유발된 간 섬유화의 개선을 위한 약학 조성물

Also Published As

Publication number Publication date
WO2019098572A3 (fr) 2019-07-11
KR101887561B1 (ko) 2018-09-06

Similar Documents

Publication Publication Date Title
WO2019190146A2 (fr) Nouvelle souche de lactobacillus fermentum lm1016 et composition pour la prévention ou le traitement de maladies cardiovasculaires
WO1998014181A1 (fr) Traitement et prevention des affections hepatiques
AU2016204909A1 (en) Treatment of multiple sclerosis with combination of laquinimod and interferon-beta
WO2019098572A2 (fr) Composition pharmaceutique pour soulager la fibrose hépatique induite par le virus de l'hépatite
EP2549997A2 (fr) Composition pharmaceutique pour la prévention ou le traitement d'une stéatose hépatique non alcoolique et procédé pour la prévention ou le traitement de la stéatose hépatique non alcoolique utilisant celle-ci
WO2020022708A1 (fr) Composition pharmaceutique pour la prévention ou le traitement de la stéatohépatite non alcoolique
WO2022131428A1 (fr) Composition comprenant de l'orlistat et une souche d'akkermansia muciniphila eb-amdk19
WO2022240035A1 (fr) Composition pharmaceutique destinée à la prévention ou au traitement de la fibrose
WO2023014113A1 (fr) Composition de gouttes oculaires comprenant de la récoflavone destinée au traitement de la xérophtalmie
RU2727142C2 (ru) Бисамидное производное дикарбоновой кислоты в качестве средства, стимулирующего регенерацию тканей и восстановление сниженных функций тканей
WO2018155921A1 (fr) Composition pharmaceutique destinée à prévenir et à traiter le cancer du pancréas, contenant du gossypol et de la phénformine à titre de principes actifs
WO2022114881A1 (fr) Composition pharmaceutique destinée à prévenir ou traiter une plaie ou une cicatrice, comprenant de la benzbromarone
WO2018021827A1 (fr) Compositions de traitement du cancer du foie comprenant un agent de destruction vasculaire
KR20230026396A (ko) 코로나바이러스감염증-19(covid-19) 치료용 조성물
WO2023140406A1 (fr) COMPOSITION PHARMACEUTIQUE COMPRENANT DU β-SITOSTÉROL POUR PRÉVENIR OU TRAITER LA SARCOPÉNIE
WO2024136185A1 (fr) Composition pharmaceutique pour la prévention ou le traitement d'une maladie cardiovasculaire, comprenant un inhibiteur du cotransporteur sodium-glucose-2 et un bloqueur du récepteur de l'angiotensine ii
WO2023200122A1 (fr) Composition pharmaceutique pour la prévention ou le traitement d'un accident vasculaire cérébral lié au diabète, contenant un antagoniste rage et un piégeur age
US20080254136A1 (en) Antiprotozoal Agent
WO2015050324A1 (fr) Utilisation du mélange d'un sel et d'un sucre dans la fabrication d'un médicament utilisé pour traiter le syndrome du vagin relâché ou la colpoxérose chez un mammifère
WO2022240036A1 (fr) Composition pharmaceutique pour la prévention ou le traitement de la fibrose
WO2023140407A1 (fr) Composition pharmaceutique comprenant du coumestrol pour la prévention ou le traitement de la sarcopénie
WO2023022522A1 (fr) Préparation complexe pour la prévention ou le traitement de la stéatohépatite, de la stéatose hépatique ou de la fibrose
WO2022139425A1 (fr) Procédé de diagnostic de maladies neurodégénératives par l'utilisation de l'hpma
WO2022045673A1 (fr) Composition comprenant un nouveau composé en tant que principe actif pour la prévention ou le traitement de l'insuffisance cardiaque consécutive à un infarctus du myocarde et utilisation associée
WO2012091425A2 (fr) Composition contenant, comme principe actif, un analogue de 4-hydroxytamoxifène ou un sel pharmaceutiquement acceptable de celui-ci, destinée à la prévention ou au traitement des maladies associées au syndrome métabolique

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18877363

Country of ref document: EP

Kind code of ref document: A2