WO2021040440A1 - Composition pharmaceutique pour le traitement ou la prévention de la stéatohépatite non alcoolique (shna) - Google Patents

Composition pharmaceutique pour le traitement ou la prévention de la stéatohépatite non alcoolique (shna) Download PDF

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WO2021040440A1
WO2021040440A1 PCT/KR2020/011513 KR2020011513W WO2021040440A1 WO 2021040440 A1 WO2021040440 A1 WO 2021040440A1 KR 2020011513 W KR2020011513 W KR 2020011513W WO 2021040440 A1 WO2021040440 A1 WO 2021040440A1
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pharmaceutical composition
fibrosis
alcoholic steatohepatitis
treatment
nash
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PCT/KR2020/011513
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Korean (ko)
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김본중
남궁훈
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(주)셀트리온
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • 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
    • 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
    • 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 treating or preventing non-alcoholic steatohepatitis (NASH), and a method for treating or preventing the same.
  • NASH non-alcoholic steatohepatitis
  • Nonalcoholic Fatty Liver Disease is usually divided into two stages. First, the most common type is simple fatty liver (NAFL, Nonalcoholic Fatty Liver), which is literally a simple fatty liver symptom. The second type of disease is non-alcoholic steatohepatitis (NASH), which is a disease that causes inflammation of hepatocytes by fatty liver.
  • NASH non-alcoholic steatohepatitis
  • Non-alcoholic steatohepatitis is a common, often "silent" liver disease. It is very histologically similar to alcoholic liver disease, but occurs in people with no alcohol history who drink little or no alcohol. Three main features: abnormal fat accumulation or deposition in the liver (hepatic steatosis), liver inflammation (hepatitis), liver damage or liver tissue damage (liver fibrosis) characterizes NASH and distinguishes it from other liver diseases of metabolic origin. .
  • NASH can primarily classify suspected patients through commercial blood test panel tests, and further evaluations do not reveal any apparent reason for liver disease (e.g., excessive use of medications, viral hepatitis or alcohol) and x-rays of the liver or When imaging studies reveal fat, NASH is suspected.
  • the only means of actually diagnosing NASH and distinguishing between simple fatty liver and NASH is a liver biopsy.
  • a liver biopsy a small piece of the liver is removed by inserting a needle through the skin.
  • NASH is diagnosed when damage or fibrosis to inflamed fat and liver cells is confirmed as a result of histologic examination using a microscope.
  • An important part of the information learned from the biopsy is whether scar tissue (fibrotic tissue) has developed in the liver.
  • no blood test or scan can reliably provide this information. Therefore, diagnosis and treatment effect of NASH can be confirmed only by histopathological method in which the liver tissue is removed and confirmed through a microscope.
  • Thiazolidinedione is a group of drugs having a structure as shown in [Chemical Formula 1] below, and is generally referred to as a glitazone series, and it makes the muscle tissue sensitive to insulin so that glucose is absorbed into the muscle. It is known as a type 2 diabetes treatment as a drug that plays a role in lowering blood sugar and blood sugar.
  • Thiazolidinedione-based drugs are currently known such as pioglitazone, robeglitazone and rosiglitazone.
  • Pioglitazone is an analog in which a functional group is attached to the thiazolidinedione, and has the structure of [Chemical Formula 2]. This is a commercially available drug for the treatment of type 2 diabetes and acts to lower blood sugar. Pioglitazone is a potential agonist for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and its specific formula is as follows.
  • PPAR-gamma peroxisome proliferator-activated receptor-gamma
  • Pioglitazone activates the differentiation of adipocytes by acting on the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), which is widely distributed in adipose tissue. Through this, it lowers free fatty acids and inhibits the storage of fat and fatty acids in the liver by improving insulin resistance. Recent clinical studies have shown that these actions can prevent abnormal liver fat accumulation or deposition (hepatic steatosis) in NASH patients and further reduce liver inflammation (hepatitis) (Promrat et al., A pilot). study of pioglitazone treatment for nonalcoholic steatohepatitis, HEPATEOLOGY, January 2004).
  • PPAR-gamma peroxisome proliferator-activated receptor-gamma
  • pioglitazone causes unwanted side effects, including drug-drug interactions, cardiovascular effects, edema, weight gain and potential for bladder cancer (e.g. Kus et al., PLoS ONE 6(11): e27126 (2011)). Reference)). Therefore, it is not recommended to chronically administer pioglitazone at high doses, and it is necessary to develop a combination drug including an auxiliary drug that can reduce the side effects of pioglitazone while maintaining the effect.
  • Carnitine (Carnitine, beta-hydroxy-gamma-N-trimethylaminobutyric acid, 3-hydroxy-4-N,N,N-trimethylaminobutyrate) has a chemical formula as shown in [Chemical Formula 3], and is also known as vitamin BT.
  • Carnitine is an amino acid derivative and acts as an essential cofactor in fatty acid metabolism. It is used for the treatment of primary or secondary carnitine deficiency, and although both L- and DL- isomers are used, only the L-type is recognized for its therapeutic effect.
  • L-carnitine When L-carnitine is administered orally, by injection, or by dialysis, it has the effect of reducing chronic intermittent hemodialysis by increasing the plasma concentration of triglycerides and lowering total cholesterol. It is also used to prevent carnitine deficiency due to hyperlipidemia and toxicity induced by anthra-cyclines and valproate.
  • Biphenyl dimethyl dicarboxylate is an artificial synthetic material similar to Schizandrin C, an active ingredient of Schisandra chinensis, which has been used as a folk remedy for a long time. It is a compound.
  • biphenyldimethyldicarboxylate has been proven to have an effect on various chronic and viral hepatitis by animal and clinical experiments, and thus is currently being applied in clinical practice.
  • biphenyldimethyldicarboxylate has an inhibitory effect on liver damage caused by carbon tetrachloride [Yu HuiQin: Diphenyl-dimethyl-dicarboxylate in treating and preventing hepatitis due drug poisoning, Chinese Medical Journal.
  • the problem to be solved by the present invention is to provide a pharmaceutical composition for the treatment or prevention of non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • Another problem to be solved by the present invention is to provide a method for treating or preventing non-alcoholic steatohepatitis comprising administering a pharmaceutical composition to a patient with non-alcoholic steatohepatitis.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of nonalcoholic steatohepatitis (NASH).
  • NASH nonalcoholic steatohepatitis
  • Nonalcoholic Steatohepatitis is a type of aggravated disease of nonalcoholic fatty liver disease (NAFLD), and refers to a condition in which inflammation of hepatocytes caused by fatty liver is induced. It is histologically very similar to alcoholic liver disease, but it is defined as NASH when it occurs in people with no alcohol history who drink little or no alcohol, and abnormal fat accumulation or deposition in the liver (hepatic steatosis), and liver inflammation (hepatitis ), liver damage or liver tissue damage (liver fibrosis) characterizes it and distinguishes it from other liver diseases of metabolic origin.
  • NASH nonalcoholic Steatohepatitis
  • Nonalcoholic Fatty Liver Disease When only fat accumulation is observed in the initial stage, it is diagnosed as Nonalcoholic Fatty Liver Disease (NAFLD), but when it develops and accompanies mesenchymal inflammation, liver cell damage, and liver fibrosis, it is classified as NASH.
  • NASH Nonalcoholic Fatty Liver Disease
  • Non-alcoholic steatohepatitis proceeds in the order of mesenchymal inflammation, liver cell damage, and liver fibrosis, and liver fibrosis is also a serious disease in NASH.
  • the pharmaceutical composition is
  • Biphenyldimethylcarboxylate a pharmaceutically acceptable salt, hydrate or crystalline form thereof may be included.
  • the pharmaceutical composition may include pioglitazone, L-carnitine, and biphenyldimethyldicarboxylate.
  • the “thiazolidinedion drug” is a group of drugs having a basic structure as shown in [Chemical Formula 5], and is generally referred to as a glitazone series, and makes the muscle tissue sensitive to insulin so that it becomes glucose into the muscle. It is known as a type 2 diabetes treatment as a drug that plays a role in lowering blood sugar by helping this absorption.
  • Thiazolidione drugs include pioglitazone, lobeglitazone, and rosiglitazone.
  • R represents a substituted benzyl group linked with an alkyl group.
  • R may be a substituted benzene linked with a methyl group, and more specifically, R may be as shown in [Chemical Formula 6].
  • the “carnitine” is 3-hydroxy-4-trimethylammonio-butytric acid and has a structure as shown in [Chemical Formula 3], and is also known as vitamin BT. As an amino acid derivative, it plays a role as an essential coenzyme in fatty acid metabolism. It is used for the treatment of primary or secondary carnitine deficiency, and both L- and DL-isomers can be used.
  • Pioglitazone is a thiazolidinedione-based drug having a structure as shown in the following [Chemical Formula 2], and is marketed for the treatment of type 2 diabetes and acts to lower blood sugar.
  • Pioglitazone is a potential agonist for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and its specific formula is as follows.
  • the pioglitazone of the present invention includes all pharmaceutically acceptable salts and crystal forms other than the hydrochloride and potassium salts thereof.
  • the pharmaceutically acceptable salts mentioned in the present invention mean salts commonly used in medicines, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, Salts from malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, tartaric acid, and trifluoroacetic acid.
  • L-Carnitine is an L isomer of carnitine, an amino acid derivative, and serves as an essential cofactor for fatty acid metabolism, and has the same structure as [Chemical Formula 7].
  • BDD biphenyl dimethyl dicarboxylate
  • the pharmaceutical composition may include pioglitazone, L-carnitine, and biphenyldimethyldicarboxylate in a weight ratio range of 1:5 to 30:25 to 60, preferably 1:15 to A weight ratio range of 25:35 to 55, more preferably a weight ratio range of 1:15 to 20:40 to 50, more preferably a weight ratio range of 1:15 to 17:40 to 45, most preferably 1: It can be included in the weight ratio range of 16.5:41.
  • the non-alcoholic steatohepatitis may include liver fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC), and the pharmaceutical composition of the present invention can treat, stabilize, reduce or Provides a preventive effect.
  • HCC hepatocellular carcinoma
  • hepatic fibrosis is formed by the accumulation of fat in the liver and eventually fibrosis as the damaged liver cannot decompose fatty acids, a compound that forms fat, and if it persists, it can develop into cirrhosis.
  • liver cirrhosis means that due to chronic inflammation, normal liver tissue is transformed into fibrous tissue such as regenerative nodules (a phenomenon in which small lumps are formed), and the function of the liver is degraded. Scar tissue has occurred throughout the liver, mainly due to irreversible necrosis caused by chronic liver inflammation.
  • hepatocellular carcinoma is the occurrence of cancer in hepatocytes and is the most common cause of death in patients with cirrhosis. It is a primary liver cancer with the highest frequency among liver cancers, and is the fifth most frequent malignant tumor in the world.
  • the pharmaceutical composition may reduce the NASH score.
  • non-alcoholic steatohepatitis diagnosis score (NASH score) is intended to quantify histological findings on liver tissue and use it as an index for diagnosing or measuring therapeutic effects of NASH, Microvesicular Vacuolation/Steatosis, It can be obtained by summing all the scores for each item for Lobular Inflammation and Ballooning of Hepatocyte. Specific evaluation methods for this can be confirmed in [Table 2] of the detailed description of the present invention.
  • diagnosis score for non-alcoholic steatohepatitis decreases, it is evaluated as having an effect of treating or preventing NASH.
  • the pharmaceutical composition is characterized in that it has a therapeutic, stabilizing, reducing or preventing effect on fibrosis or lobular inflammation in liver tissue of non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the pharmaceutical composition is effective in treating, stabilizing, reducing or preventing severe diseases of non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the severe disease of non-alcoholic steatohepatitis may be liver fibrosis, liver cirrhosis or hepatocellular carcinoma, and in one embodiment, it means a stage in which fibrosis in liver tissue has progressed.
  • the pharmaceutical composition has an effect of reducing the non-alcoholic steatohepatitis diagnostic score (NASH score).
  • NASH score non-alcoholic steatohepatitis diagnostic score
  • the pharmaceutical composition has an effect of treating or preventing fibrosis of non-alcoholic steatohepatitis.
  • the pharmaceutical composition is used to treat perisinusoidal fibrosis, Chicken-Wire Fibrosis, portal fibrosis, and bridging fibrosis among non-alcoholic steatohepatitis fibrosis. Can be prevented.
  • the fibrosis score (FIBROSIS score) is an index for indicating the degree of fibrosis of liver tissue in non-alcoholic steatohepatitis, and is a sum of scores for perivascular fibrosis, periportal fibrosis, and connected fibrosis. Specific evaluation methods can be confirmed in [Table 3] of the detailed description of the present invention. In general, when the FIBROSIS score is greater than 0, it is considered that fibrosis has progressed, and when the FIBROSIS score is no longer increased, it is recognized that there is an effect of preventing or treating or preventing fibrosis in non-alcoholic steatohepatitis. Therefore, if it shows a reduced value compared to the negative control group, it is considered to have a therapeutic or preventive effect.
  • the pharmaceutical composition has an effect of reducing the fibrosis score (FIBROSIS score) of non-alcoholic steatohepatitis.
  • the pharmaceutical composition when administered to a steatohepatitis patient, has the effect of reducing the NASH score by 15% or more compared to the negative control group, and preferably 20 It has the effect of reducing by more than %.
  • the pharmaceutical composition when administered once daily for 12 weeks to patients with steatohepatitis, reduces the NASH score by 15% or more compared to the negative control group. There is, preferably there is an effect of reducing by 20% or more.
  • the pharmaceutical composition when administered to a steatohepatitis patient, has the effect of reducing the fibrosis score by 25% or more compared to the negative control group, preferably 30% or more, more preferably It has the effect of reducing by more than 35%.
  • the pharmaceutical composition when administered once daily for 12 weeks to patients with steatohepatitis, has the effect of reducing fibrosis score by 25% or more compared to the negative control group, and preferably There is an effect of reducing by 30% or more, more preferably by 35% or more.
  • the composition for improving liver function according to the present invention may be administered orally (eg, ingestion or inhalation) or parenterally (eg, injection, transdermal absorption, rectal administration), and injection may be performed, for example, It may be intravenous, subcutaneous, intramuscular, or intraperitoneal.
  • the pharmaceutical composition according to the present invention is formulated into tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, sprays, etc., depending on the route of administration. It can be angry.
  • the various types of pharmaceutical compositions according to the present invention may be prepared by known techniques using a pharmaceutically acceptable carrier commonly used in each formulation.
  • Examples of pharmaceutically acceptable carriers include excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweetening agents, solubilizing agents, bases, dispersing agents, wetting agents. , Suspending agents, stabilizers, colorants, and the like.
  • the composition for improving liver function may be a pharmaceutical composition.
  • the pharmaceutical composition may additionally contain pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances. It can be formulated in the form of a dosage or parenteral administration. In the case of parenteral administration, it can be administered topically to the skin, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.
  • the dose and frequency of administration of the pharmaceutical composition of the present invention may vary depending on the method of administration and the age, weight, or disease state of the patient, and when administered orally, the administrable range for each active ingredient is pioglitazone 0.01 to 200 mg/day, BDD 0.01 to 1600 mg/day, L-carnitine 0.01 to 4000 mg/day, preferably 0.1 to 100 mg/day, BDD 1 to 1000 mg/day, L-carnitine 1 to 2000 mg/day, more preferably 1 to 40 mg/day , BDD 10 ⁇ 800mg/day, L-carnitine 10 ⁇ 2000mg/day.
  • the range of the total administrable content of the composite composition is 0.01 to 6000 mg/day, preferably 0.01 to 4000 mg/day, more preferably 0.01 to 3000 mg/day.
  • the frequency of administration may be administered once a day to four times a day.
  • composition of the present invention may be used alone or in combination with one or more other therapeutic agent(s) (second active ingredient) depending on the severity of the disease to be treated.
  • a method for treating or preventing NASH disease by administering an effective amount of the pharmaceutical composition of the present invention to a NASH patient.
  • the administration may be administered orally (eg, ingestion or inhalation) or parenterally (eg, injection, transdermal absorption, rectal administration).
  • the pharmaceutical composition of the present invention has excellent therapeutic, stabilizing, reducing or preventing effects on non-alcoholic fatty liver disease (NAFLD), in particular, non-alcoholic steatohepatitis (NASH).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • FIG. 1 is a diagram showing and comparing scores and total scores for each item of the NASH score of the negative control group, the positive control group, Example 1, and Comparative Examples 1 to 3.
  • FIG. 1 is a diagram showing and comparing scores and total scores for each item of the NASH score of the negative control group, the positive control group, Example 1, and Comparative Examples 1 to 3.
  • FIG. 2 is a diagram showing and comparing the scores and total scores for each item of the negative control, positive control, Example 1, and Comparative Examples 1 to 3 of the FIBROSIS score.
  • the experimental animal was a 7-week-old male rat C57BL6 (Jackson Labs, US), and divided into a control group and an experimental group as shown in Table 1 below. High Fat Diet, HFD) was confirmed to induce NASH.
  • the animals were bred in an environment set at a temperature of 22-26 degrees and a relative humidity of 30-70%, a dark cycle of 12 hours (lights on at 8 am to light off at 8 pm) and an illuminance of 150 to 300 Lux. , Health status was checked twice daily during the breeding period. In addition, 300uL of blood was collected once every 20 weeks after the start of the experiment.
  • the rats of the control group and the experimental group were euthanized with carbon dioxide, the liver was excised, washed with physiological saline, and stored in 10% Neutral Buffered Formalin (NBF) for a minimum of 24 hours and a maximum of 72 hours.
  • NBF Neutral Buffered Formalin
  • the left lateral lobe section of the liver tissues of the control and experimental mice stored in the formalin was retaken, fixed in Paraffin, hardened, and then sectioned into 5 um on a slide, and a FFPE (Formalin Fixed Paraffin Embedded) block was prepared. The section was stained with Sirius Red and then the tissue was analyzed under a microscope (Nikon E600).
  • NASH score Non-alcoholic steatohepatitis diagnosis score
  • FIBROSIS score fibrosis
  • NASH non-alcoholic steatohepatitis
  • Micro-foaming vacuole can be observed at all magnifications, but in this experimental example, it was performed at 20 magnification.
  • Item-1 Item-2 Judgment criteria score NASH score Microvesicular Vacuolation/Steatosis ⁇ 5% 0 5 ⁇ 33% One >33 ⁇ 66% 2 >66% 3 Lobular Inflammation No foci 0 ⁇ 2 foci per 20xfield One 2 ⁇ 4 foci per 20xfield 2 >4 foci per 20xfield 3 Ballooning of hepatocyte H&E stain 400x field None 0 Few balloon cells One Many cells/prominent ballooning 2
  • fibrosis in humans is divided into 4 stages, and the evaluation items are Perisinusoidal Fibrosis (Chick-Wire Fibrosis), Portal Fibrosis, and Bridging Fibrosis.
  • Perisinusoidal Fibrosis Choick-Wire Fibrosis
  • Portal Fibrosis Portal Fibrosis
  • Bridging Fibrosis the degree of each of the above items was scored, and in particular, perivascular fibrosis (0-3 points) according to the frequency of occurrence of fibrosis in the observed vessels, and context according to the type of fibrosis observed in the observed portal vein.
  • this FIBROSIS score reflects the principle of fibrosis evaluation in humans, and the higher the score, the higher the degree of fibrosis, so it is evaluated that NASH progressed more, and the lower the score, the better the treatment effect.
  • Item Item-2 Judgment criteria score FIBROSIS score Perisinusoidal Fibrosis (Chicken-Wire Fibrosis) No fibrosis 0 ⁇ 33% One >33 ⁇ 66% 2 >66% 3 Portal Fibrosis No portal fibrosis observed 0 Expanded portal areas One Periportal fibrosis 2 Periportal bridging fibrosis 3 Cirrhosis, widespread nodular remodeling 4 Bridging Fibrosis (any form) No bridging fibrosis observed 0 1 verified (1 focus) One 1 or more, no nodularity (>1 focus with no nodularity) 2 Bridging fibrosis with some nodular remodeling 3 Cirrhosis, widespred nodular remodeling 4
  • both the experimental group had a NASH score of 5 or more and a FIBROSIS score of 0 or more, and it was confirmed that NASH was induced at weeks 16 to 24 of HFD.
  • a pharmaceutical composition was prepared by mixing pioglitazone, BDD, and L-carnitine at a weight ratio of 1:16.5:41 based on the weight ratio of each free salt form.
  • pioglitazone is in the form of hydrochloride (manufacturer: Cipla Limited), BDD (manufacturer: Wanbangde pharmaceutical group Co., LTD.) and L-carnitine (manufacturer: Liaoning Nirvana Pharmaceutical co., Ltd.) as a free salt.
  • hydrochloride manufactured by Cipla Limited
  • BDD manufactured by mixing pioglitazone
  • L-carnitine manufactured by mixing pioglitazone, BDD, and L-carnitine at a weight ratio of 1:16.5:41 based on the weight ratio of each free salt form.
  • obeticholic acid Ocaliva, OCA
  • a placebo composition 5ml/kg was administered as a vehicle to the normal group and the negative control group.
  • a placebo composition 9% (v/v) Solutol HS-15 (Kolliphor) in PBS was used at a pH of 7.2.
  • the experimental groups were reared under the same conditions as the experimental examples except for drug administration. Health status was checked twice daily, and blood was collected once a week (0.6ul, twice).
  • mice of the 7 experimental groups were euthanized with carbon dioxide, the liver was excised, washed with physiological saline, and stored in 10% Neutral Buffered Formalin (NBF) for a minimum of 24 hours and a maximum of 72 hours.
  • NBF Neutral Buffered Formalin
  • livers of the 7 experimental groups were collected and tissue analysis was performed. It was confirmed that the invasion of immune cells around hepatocytes was reduced through high magnification under the microscope, and the degree of fibrosis was reduced by decreasing the bridge due to invasion of satellite cells and immune cells through the low magnification under the microscope.
  • Example 1 in which pioglitazone was administered alone and Comparative Example 3 in which L-carnitine was administered alone, fibrosis was somewhat relieved, and in the micrograph of Example 1 in which the composite composition was administered, a red line indicating connected fibrosis Little was observed. Accordingly, it can be seen that the composite composition administered in Example 1 has the best effect of treating or preventing NASH fibrosis.
  • Example 1 in terms of the NASH score and FIBROSIS score evaluation items, there was a tendency to be superior to Comparative Examples 1 to 3 in which each single component of the composite formulation of Preparation Example 1 was administered, and was positive. It was superior to the control OCA. In particular, it showed excellent effect on microvesicular vacuole, periportal fibrosis, and connected fibrosis.
  • Example 1 showed the lowest value in the overall NASH score, and in particular, in the FIBROSIS score, a significantly lower value compared to other comparative groups and positive controls was confirmed, and the NASH of the composition of Preparation Example 1 administered in Example 1, In particular, it can be seen that there is an excellent treatment or prevention effect for liver fibrosis.
  • Fibrosis is a symptom that appears in the most severe stage even in NASH, which is a deepening stage of non-alcoholic fatty liver disease (NAFLD), and it can be seen that the composite composition of the present invention has a more excellent effect in the treatment or prevention of severe NASH disease.
  • NASH non-alcoholic fatty liver disease

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour le traitement ou la prévention de la stéatohépatite non alcoolique (SHNA) comprenant 1) un médicament à base de thiazolidinédione ou un sel, un hydrure ou une forme cristalline pharmaceutiquement acceptable de celui-ci, 2) de la carnitine ou un sel, un hydrate ou une forme cristalline pharmaceutiquement acceptable de celle-ci, et 3) du biphényldiméthylcarboxylate ou un sel, un hydrate ou une forme cristalline pharmaceutiquement acceptable de celui-ci. La composition de la présente invention a un excellent effet de traitement ou de prévention de la stéatohépatite non alcoolique (SHNA).
PCT/KR2020/011513 2019-08-30 2020-08-27 Composition pharmaceutique pour le traitement ou la prévention de la stéatohépatite non alcoolique (shna) WO2021040440A1 (fr)

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CN202080061190.1A CN114340632A (zh) 2019-08-30 2020-08-27 用于治疗或预防非酒精性脂肪性肝炎（nash）的药物组合物

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KR20170102299A (ko) * 2015-01-09 2017-09-08 길리어드 아폴로, 엘엘씨 비-알콜성 지방간 질환의 치료를 위한 acc 억제제 조합 요법
KR20170102861A (ko) * 2014-10-20 2017-09-12 발비오띠스 식물 추출물의 혼합물 또는 상기 식물 속에 함유된 분자의 혼합물을 함유하는 조성물, 및 당질 및/또는 지질 대사를 조절하기 위한 용도
KR20190017690A (ko) * 2017-08-10 2019-02-20 주식회사 셀트리온화학연구소 약학 조성물 및 이의 제조방법
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KR20030041577A (ko) * 2001-11-20 2003-05-27 디디에스텍주식회사 난용성 약물과 치환된 시클로덱스트린을 함유하는고체분산체 및 이를 함유하는 약제학적 조성물
US20190169342A1 (en) * 2010-02-24 2019-06-06 Relypsa, Inc. Polyimidazoles for use as bile acid sequestrants
KR20170102861A (ko) * 2014-10-20 2017-09-12 발비오띠스 식물 추출물의 혼합물 또는 상기 식물 속에 함유된 분자의 혼합물을 함유하는 조성물, 및 당질 및/또는 지질 대사를 조절하기 위한 용도
KR20170102299A (ko) * 2015-01-09 2017-09-08 길리어드 아폴로, 엘엘씨 비-알콜성 지방간 질환의 치료를 위한 acc 억제제 조합 요법
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