EP3442500A1 - Utilisation de l'acide fenofibrique dans le traitement des maladies hepatiques - Google Patents
Utilisation de l'acide fenofibrique dans le traitement des maladies hepatiquesInfo
- Publication number
- EP3442500A1 EP3442500A1 EP17717192.3A EP17717192A EP3442500A1 EP 3442500 A1 EP3442500 A1 EP 3442500A1 EP 17717192 A EP17717192 A EP 17717192A EP 3442500 A1 EP3442500 A1 EP 3442500A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- treatment
- composition
- liver diseases
- liver
- fenofibric acid
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
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Classifications
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
Definitions
- the present invention relates to the treatment and prevention of liver diseases, such as NAFLD, non-alcoholic steatohepatitis (NASH), liver fibrosis or cirrhosis.
- liver diseases such as NAFLD, non-alcoholic steatohepatitis (NASH), liver fibrosis or cirrhosis.
- the invention relates more particularly to the use of fenofibric acid in the treatment and prevention of NASH.
- the liver is the second largest organ of the human body. It performs many complex functions including: i) defense against diseases and infections, ii) elimination of toxins from the body (poisons), such as alcohol, iii) control of cholesterol levels, iv) help blood clotting; v) the release of bile which breaks down fat and aids digestion; and vi) the metabolism of foreign bodies, particularly oral drugs.
- Liver disease usually does not cause obvious signs or symptoms until they are advanced and the liver is damaged. They can be hereditary (genetic), or caused by a variety of factors which damage the liver, such as viruses and excessive alcohol consumption. Obesity is also associated with liver damage. Over time, the damage can cause scarification of the liver, which can lead to liver failure that may be life-threatening. Symptoms of liver diseases are weakness and fatigue, weight loss, nausea, vomiting and a yellowish discolouration of the skin (jaundice).
- NAFLD non-alcoholic fatty liver disease
- Non-alcoholic fatty liver disease NAFLD often causes no symptoms. Symptoms may include fatigue, weakness, weight loss or appetite, nausea, abdominal pain, yellowing of the skin and eyes (jaundice), itching, accumulation of fluid and swelling of the legs (edema) and abdomen (ascites), and also mental confusion.
- Non-alcoholic steatohepatitis causes swelling and damage to the liver. It develops in the same people at risk as for NAFLD although, here too, some people contract it without presenting any risk factors.
- Non-alcoholic steatohepatitis NASH is a complex disease that is only just beginning to be understood and whose definition as well as indices of disease progression (NAS scores) are likely to change with the evolution of scientific knowledge. It is the consequence of a metabolic disorder that finds its base in the "fat" liver.
- WO2015083164A describes pharmaceutical compositions of aramchol salts which are arachidic acid and 3-aminocholic acid conjugated amides, belonging to the family of FABAC (fatty acid synthesis molecules). conjugated bile acid).
- FABACs are known to be effective in reducing blood cholesterol levels and lipid levels in the liver (steatosis) but also in improving the metabolic parameters associated with "fatty" liver disease and steatosis. non-alcoholic hepatitis.
- Galmed Pharmaceuticals describes a selection of new aramchol salts that improves their solubility and absorption, and therefore, their bioavailability.
- Amino aramchol salts particularly the meglumine, lysine and tromethamine salts, were selected after a permeability study in rats.
- the present application does not disclose a result relating to the use of amino salts of aramchol in the treatment of NAFLD and NASH.
- Novo Nordisk application US2015 / 0374794A relates to a glucagon derivative used in the treatment of diabetes and hepatic steatosis.
- Novo Nordisk has achieved results in the regression of NASH with the corresponding drug, Victoza®. The results are published in a study of 52 patients, but the work was done with the old definition of reversion parameters of NASH, which accepts the removal of steatosis as a criterion.
- Intercept Pharmaceuticals with its drug OCA (Obstetric Acid), an analogue and agonist of choice for the Farnesoid Receptor X (FXR), demonstrated action on steatosis, inflammation, and fibrosis in a Mb phase study "FLINT” (performed out of 283 patients), without achieving a significant result in the reversion of NASH.
- OCA Oleric Acid
- FXR Farnesoid Receptor X
- Obetictic Acid could not confirm effects on NASH and fibrosis in the subsequent Mb phase study in Japan, which discredits the efficacy of the molecule in the treatment of NASH and fibrosis.
- OCA Obetictic Acid
- obetictic acid has been shown to have numerous side effects, including significant pruritus and in particular increased cholesterol, which is not acceptable for patients with cardiovascular risk.
- the patent US91 15073B2 highlights a molecule developed by Genfit, which has intrinsic agonist properties of the peroxisome proliferator activated receptors (in English, peroxisome proliferator-activated receptor - see details shortly thereafter). These receptors are proteins of the superfamily of nuclear receptors that naturally bind lipids and act as a transcription factor for the target genes involved in particular in metabolism and adipogenesis. The agonist properties of this molecule make it a candidate for the treatment of metabolic disorders and / or inflammatory diseases, and in particular the peripheral and central diseases associated with the metabolic syndrome, including nonalcoholic steatohepatitis.
- WO2015143367 discloses a new type of drug, cenicriviroc (or CVC), an HIV entry inhibitor that blocks access to the CCR5 receptor, as a candidate for the treatment of NASH in subjects adults with liver fibrosis.
- cenicriviroc or CVC
- the phase II study (“CENTAUR") is underway.
- Cenicriviroc is given orally at 150 mg, daily in the morning with food.
- US Pat. No. 8,658,787 B2 (Galectin Therapeutics) relates to a polysaccharide formulation containing galactose, in particular galacto-rhamnogalacturonate GR-MD-02.
- GR-MD-02 is administered in doses up to 8 mg / kg / week. Completion of the study is not expected until 2018.
- Application WO2015 / 175381 A1 (Conatus Pharmaceuticals) addresses chronic liver disease-related complications with caspase inhibitors, such as emricassan. Conatus Pharmaceuticals reports that apoptosis and caspase activity correlate with the stage of cirrhosis.
- the patent application WO2013 / 169648A relates to a pharmaceutical composition combining several active ingredients, in particular an inhibitor of DGAT1, in combination with a drug that lowers triglycerides in the blood, and one or more excipients.
- This application evokes the use of fenofibric acid in combination as a molecule for lowering the triglyceride level.
- use in the treatment of NAFLD is cited.
- the active ingredients are used in combination, in order to target a maximum of physiological mechanisms for decreasing the level of triglyceride in the blood, resulting in a difficult to implement composition, the realization of which is complex and expensive.
- DGAT1 catalyzes the synthesis of triglycerides, its inhibition thus decreases the synthesis of triglycerides
- the inhibitor of DGAT1 is associated with a drug decreasing the level of triglycerides in the blood.
- NAFLD is an accumulation of fatty acid in the liver.
- a hypertriglyceridemia is only a phenomenon associated with the disease and a drop of triglyceride in the blood does not equate to a cure of the disease.
- Patent application EP2296659 relates to the treatment of obesity, type 2 diabetes, heart disease and cancer. It relates to a combination of a DGAT1 inhibitor and a PPAR- ⁇ agonist. This application discusses the use of fenofibric acid in combination, and the treatment of NASH and NAFLD. However, no data or results relating to the use of the composition in the context of NASH are given.
- the patent application is intended only to reduce the level of triglyceride in the blood and treat dyslipidemia, which are only peripheral phenomena to the majority of liver diseases (including obesity) and does not target a method of treatment liver diseases, such as NAFLD or NASH.
- liver diseases such as non-alcoholic fatty liver, steatohepatitis non-alcoholic, liver fibrosis or cirrhosis.
- Fenofibric acid belongs to the family of fibric acids which are amphiphilic carboxylic acids characterized by the presence of a carboxyl end group (COOH), with polar and non-polar properties.
- Fibrates have been used for 50 years in the therapy of many forms of hypercholesterolemia, in association or not with statins. Although less effective in lowering LDL cholesterol and triglycerides, the ability of fibrates to increase HDL (good) cholesterol and lower triglyceride levels appears to reduce resistance to cholesterol. insulin when dyslipidemia is associated with other features of the metabolic syndrome (hypertension and type 2 diabetes). Therefore, they are used in many hyperlipidemias. Fibrates are not suitable for patients with low levels of HDL.
- Peroxisome Proliferator Activated Receptors are members of the nuclear hormone receptor superfamily, which are transcription factors that transmit signals from soluble lipid factors (eg, hormones, vitamins, and fatty acids) to the genome. Nuclear receptors recognize and bind to the DNA at the response element (REs) and activate or repress the expression of a target gene.
- REs response element
- Peroxisome proliferator-activated receptors heterodimerize with the retinoid X receptor (RXR) and bind to the response elements, so-called peroxisome proliferator response elements (PPRE).
- RXR retinoid X receptor
- PPRE peroxisome proliferator response elements
- Peroxisome proliferator-activated receptors display distinct expression patterns, suggesting important functional differences.
- PPARa is mainly expressed in tissues that metabolize high levels of fatty acids, such as the liver, kidneys, heart and muscle.
- the expression of PPAR- ⁇ is high in adipose tissue, where it triggers the differentiation of adipocytes and induces the expression of genes critical for adipogenesis.
- PPAR- ⁇ is a nuclear transcription factor (NTF), potentially regulating hundreds of genes involved in energy expenditure: lipid and lipoprotein synthesis and catabolism, fatty acid regulation and vascular wall biology.
- NTF nuclear transcription factor
- the natural ligands for PPAR- ⁇ are various fatty acids and derivatives such as 8 (S) hydroxyéicosatétraéno ⁇ que acid, 8 (S) hydroxyeicosapentaenoic acid and leukotrienes B4, while fibrates are synthetic ligands PPAR-a.
- Some carboxylic acids have the ability to stimulate PPARs ( ⁇ , ⁇ and ⁇ ).
- fibrates have not yet demonstrated properties on selective receptors SPPARM, more recently identified and which have among others superior clinical benefits, including lesser side effects, as was observed on the molecule K877 developing Kowa Pharmaceutical (“Selective peroxisome proliferator-activated receptor modulators (SPPARMa): the next generation of peroxisome proliferator-activated receptor agonists" Fruchart, Cardiovascular Diabetology 2013, 12:82).
- SPPARMa selective peroxisome proliferator-activated receptor modulators
- the ability of fibrates to inhibit platelet function is recognized, thereby reducing cardiovascular and thrombotic risks (Arterioscler Thromb Vase Biol-2009-Al-706-1 1).
- Fibrates can also influence other nuclear transcription factors such as liver LXR receptors and ANGPTLs, which also play a key role in lipid biology.
- the process is extremely complex and very specific to the tissues; it also depends on the presence or absence of several other proteins that serve as co-activators or co-repressors of nuclear transcription factor.
- fenofibrate is an LXR antagonist (important in inhibiting triglyceride synthesis), whereas fenofibric acid (and not the ester form) does not have the Hepatic antagonism of LXRs in triglyceride synthesis but, on the other hand, has an LXR agonist activity to regulate the ABCA1 gene belonging to the family of ABC transporters and involved in the transport of cholesterol.
- esters such as fenofibrate are only PPAR ⁇ and not other isoform agonists, while the acidic bezafibrate is a panagonist of the 3 PPAR ⁇ , ⁇ / ⁇ and Y isoforms (Grygielen). Gergniak Nutrition Journal 2014, 13:17). The pharmacodynamic roles are therefore recognized as being different depending on whether there is esterification or amidation of the carboxylic group of the fib rate molecule (Mol and Cell Bioch Nov 2010, 344, 91-98).
- fenofibric acid alone has an interesting potential in the prevention of liver diseases, in particular NAFLD, NASH, liver cirrhosis and liver fibrosis, but also that unlike fenofibrate , fenofibric acid has the advantage of not requiring hepatic metabolism to modify its structure and exert a PPAR ⁇ agonist activity.
- fenofibric acid or one of its pharmaceutically acceptable salts, is theoretically safer than fenofibrate because it does not require hepatic activation.
- the fenofibric acid which is a selective activator of PPAR ⁇ receptors is in this respect the only active ingredient which covers almost all the pathologies that make up NASH.
- the invention relates to a composition
- a composition comprising as sole active ingredient fenofibric acid or a pharmaceutically acceptable salt for use in the treatment of liver diseases.
- the pharmaceutically acceptable salt of fenofibric acid consists of a choline salt
- the choline salt improves the aqueous solubility of fenofibric acid, allowing in the case of oral administration a facilitated absorption, and in the case of intravenous administration obtaining a solution easier to inject.
- the pharmaceutically acceptable salt of fenofibric acid is the metformin salt.
- Metformin salt improves the efficacy of fenofibric acid.
- fenofibric acid salt form with metformin which is a new molecular entity, provides advantageous effects different from the sum of fenofibric acid and metformin taken individually.
- metformin salt allows a synergistic action of the active ingredients influencing in particular the efficacy in the treatment of liver diseases and in particular non-alcoholic steatohepatitis or non-alcoholic fatty liver disease associated with diseases of the metabolic syndrome such as than diabetes and obesity.
- the liver disease consists of a stéato non-alcoholic hepatitis.
- the liver disease consists of non-alcoholic fatty liver disease.
- the liver disease consists of liver fibrosis.
- the liver disease consists of cirrhosis.
- the mode of administration consists of a sublingual administration.
- the mode of administration consists of oral administration.
- the mode of administration consists of subcutaneous administration.
- the mode of administration consists of an intravenous administration.
- the sublingual, subcutaneous and intravenous modes of administration make it possible to reduce the first pass effect.
- the drug form consists of a ring.
- the ring shape has the advantage of having a larger contact area.
- the drug form consists of the form of sublingual ring, sublingual stick, bucco-adhesive ring, bucket stick, freeze-dried ring, soluble ring, orodispersible ring, effervescent ring or a single-dose oral solution.
- the distribution profile of the fenofibric acid comprises particles of fenofibric acid, at least 50% of the particles being of sizes less than 2000 nm and the set of particles being less than 5000 nm.
- micronization of fenofibric acid improves its solubility and its penetration through the mucous membranes.
- the drug form consists of a sublingual ring comprising particles of fenofibric acid, at least 50% of the particles being of sizes less than 2000 nm and the set of particles being less than 5000 nm.
- the unit dose of fenofibric acid administered is between 10 and 10 mg.
- the unit dose of fenofibric acid is between 10 and 50 mg.
- the daily dose of fenofibric acid is between 25 and 10 mg.
- the composition comprises at least one excipient, in particular at least one of binders, disintegrating agents, diluents, lubricants, surfactants, oral adhesion agents, absorption promoters / promoters, buffering agents. , flow agents, colorants, flavors, sweeteners, solvents or preservatives.
- the invention relates to a process for the preparation of a composition comprising as active ingredient fenofibric acid, characterized in that this active principle is mixed with excipients, in particular binding agents, by the wet granulation method. .
- the formed grains are then dried and sized, and then mixed with the remaining excipients of the composition prior to compression of the obtained powder mixture to present the desired shape (e.g., ring, stick).
- the invention relates to a use of a composition comprising, as sole active ingredient, fenofibric acid or a pharmaceutically acceptable salt thereof for obtaining a medicinal product intended for use in the treatment of liver diseases, in particular NAFLD, NASH, liver fibrosis, cirrhosis.
- the invention relates to a method of treating liver diseases, including NAFLD, NASH, liver fibrosis, cirrhosis comprising the use of fenofibric acid as the sole active ingredient.
- Figure 1 is a solubility versus pH curve.
- the present invention relates to the use of fenofibric acid, or a pharmaceutically acceptable salt thereof, or a polymorphic crystalline form thereof, in the preparation of a medicament for the treatment and prevention of diseases hepatic, especially non-alcoholic steatatohepatitis (NASH), fatty liver disease or non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and cirrhosis.
- NASH non-alcoholic steatatohepatitis
- NAFLD non-alcoholic fatty liver disease
- liver fibrosis liver fibrosis
- cirrhosis cirrhosis
- the invention also relates to the use of 2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoic acid (C17H15ClO4) (below), from one of its pharmaceutically acceptable salts or one of its crystalline polymorphic forms, can be used in a pharmaceutical composition to prevent or treat liver diseases.
- polymorphic crystalline form is understood by way of example and non-exhaustively: the polymorphic form I (melting point at 175 ° C.), the polymorphic form II of fenofibric acid prepared in particular from a setting in suspension of fenofibrate in isopropanol (melting point of about 184 ° C).
- the pharmaceutical composition of the invention may be administered orally, mucosally, parenterally or topically.
- the composition is administered enterally, such as, for example, a sublingual ring, a sublingual breakable stick, an adhesive mouth ring or an adhesive mouth stick, a soluble ring, a lyophilized ring, a ring effervescent, a fast oral disintegrating ring or a single-dose oral fluid.
- the composition is administered via the oral mucosa.
- the oral mucosa There are three different categories of drug delivery in the oral cavity: sublingual, oral and local / localized administration.
- the sublingual mucosa is relatively permeable, giving rapid absorption and acceptable bioavailability for many active molecules; it is convenient, accessible, and generally well accepted (Drug delivery via the mucous membranes of the oral cavity, J. Pharm Sci, 81: 1-10, 1992).
- the oral mucosa is much less permeable than the sublingual area, but has the same benefits, including liver bypass: no hepatic first-pass effect, enzymatic degradation in the area of the gastrointestinal tract.
- Saliva is an aqueous fluid with 1% organic and inorganic matter.
- the salivary pH varies from 5.5 to 7 depending on salivary flow.
- the daily salivary volume is between 0.5 and 2 liters depending on the person and some physiological factors (stress, ... etc).
- the average volume available to hydrate and disintegrate the pharmaceutical forms present in the oral mucosa is about 10 ml.
- Formulations intended to be administered by the oral mucosa route contain absorption promoters and / or buffering agents, and / or surfactants well known to those skilled in the art to optimize absorption. oral medication.
- a non-exhaustive list is given here: 23-lauryl ether, aprotinine, azone, cyclodextrin, dextran sulfate, lauric acid, lauric acid and propylene glycol, lysophosphatidylcholine, menthol, methoxysalicylate, methyl oleate, oleic acid, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulphate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, etc.
- Formulations for oral mucosal delivery contain micronized fenofibric acid to improve solubility in saliva and penetration through the oral mucosa (paracellular and transcellular).
- the particle size distribution of micronized fenofibric acid is characterized in that more than 50% of the particles are less than or equal to 2000 nm, and all the particles are smaller than 5000 nm.
- the particles are measured using a Malvern type laser granulometer or equivalent, and a wet-validated method (wetting with a surfactant) is preferred.
- One of the preferred pharmaceutical compositions of the invention is a sublingual ring of micronized fenofibric acid, wherein the ring is maintained in the oral cavity, under the tongue, until the drug is dissolved and absorbed.
- the Applicant has decided to explore in vitro approaches to test fenofibric acid as a drug inhibitor of progression of fatty liver / non-alcoholic steatohepatitis.
- NASH / NAFLD using cell models
- models and means of research are more numerous and more studied.
- primary cell cultures and immortalized cell lines are widely used to develop in vitro models for research.
- the immortalized primary cells are candidate cells selected for the in vitro study because of their stable phenotype, but also because of a simple and standardized culture method to implement.
- Immortalized human cells were cultured in enriched medium containing increasing concentrations of fenofibric acid.
- the objective of the study was to measure the level of intracellular lipid droplets.
- the entire staining procedure is conducted at room temperature, protecting the samples from direct light.
- the images were acquired with a fluorescence microscope.
- fenofibric acid exhibited pharmacological activity when administered orally in a validated mouse model of NASH.
- the Applicant has chosen a mouse model used and validated for non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) because it is well suited to study the efficacy of the drug candidate which exhibits LXR agonist activity, unlike fenofibrate (ester).
- NASH non-alcoholic steatohepatitis
- HCC hepatocellular carcinoma
- Fenofibric acid is studied in 2 doses and administered orally once a day.
- the positive control is telmisartan and the fenofibrate (ester) is retained as a negative control, more specifically as a comparator (according to the respective reference articles Liver Int 2009 Aug; 29 (7): 988-96 and Eur J Pharmacol 2016 Feb 5; 772: 22-32).
- mice Male mice number 60 for the curative part of the study. They follow the cycle of normal light, and are distributed in ventilated and enriched cages, after a period of one week of acclimation.
- mice are fed high-fat diet and fructose-enriched tap water.
- the mice are treated with the references or with the test formulation in 2 doses, with daily oral administration for approximately 2 months.
- mice that do not show sufficient weight gain or conforming biochemical parameters are discarded for the rest of the study and the mice incorporated in the curative part of the study are randomized.
- blood is collected to measure blood glucose, insulin, total cholesterol and triglyceride levels, as well as ALT and AST levels.
- the mice are sacrificed to measure hepatic total cholesterol, triglycerides, and fatty acid levels.
- Liver samples are also collected for histological analysis and the NAS score / index.
- fenofibric acid prevented the development of hepatic steatosis.
- Fenofibric acid also significantly reduced the plasma concentration of ALT, which is a marker of liver dysfunction.
- fenofibric acid could significantly inhibit the increase in liver weight and triglyceride levels. Moreover, among biochemical parameters, ALT levels have decreased significantly.
- fenofibric acid could significantly inhibit the increase in the hepatic steatosis activity score and areas of fibrosis.
- One of the preferred modes of administration is the oral mucosal route.
- the applicant has prepared solutions of fenofibric acid from samples submitted by the supplier Harman Finochem (India).
- the in vitro penetration of the formulation of fenofibric acid is evaluated using Franz-type diffusion cells at 37 ° C, a system commonly used to evaluate the in vitro penetration of compounds through the skin, but with the oral mucosa as a membrane in this case.
- the Applicant has chosen a porcine oral tissue because it has a non-keratinized morphology, fairly close to the human oral epithelium (Gandhi, R. B. and Robinson, Adv Drug Deli Rev, 13: 43-74, 1994).
- the membranes of the oral mucosa are separated by removing the underlying connective tissues using surgical scissors, to ensure that the basement membrane is still present.
- the tissue sections therefore have a thickness of at least 500 ⁇ and an approximate area of about 4 to 5 cm 2.
- Each membrane used is mounted between the donor and recipient compartments of Franz's cell system.
- the receptor compartment is filled with pH 7.4 buffer at 37 ° C and the donor compartment of micronized fenofibric acid solution at 37 ° C of different concentrations (from 0.2 mg / ml) with a pH also adjusted to pH 7 , 4 or a solution of fenofibric acid (0.5 mg / ml) in pH buffer solutions different (4.5, 6.0, 6.8 and 7.4). Samples are taken from the receiving compartment at a predetermined time interval (2, 5, 10, 15, 30, 60, 90, 120, 150 and 180 minutes), replaced by the same volume of buffer and subsequently analyzed by method HPLC.
- the amount of fenofibric acid present in the donor compartment is determined as a function of time.
- the coefficient of permeability (P) can be calculated from the linear part of the measurements made on the first times (regression).
- the solubility of fenofibric acid increases with pH and is highest at the pH closest to neutral.
- the results show a significant penetration of fenofibric acid through the porcine oral mucosa, from the first samples, with faster kinetics at higher concentrations and higher pHs.
- the yield of the study is close to 100%, taking into account the analytical margin of error, compared to the initial theoretical concentration, which validates the test.
- fenofibric acid is rapidly absorbed through the oral mucosa under the various conditions tested.
- the molecule is a good candidate for a formulation with absorption in the oral cavity.
- This example aims to determine the solubility characteristics of different crystalline forms and salts of fenofibric acid, for oral mucosal administration, in order to treat or prevent patients from liver diseases, such as hepatic steatosis. .
- the solubilization kinetics is determined by placing in excess of samples of fenofibric acid in a buffered aqueous solution at pH 6.0, corresponding to the salivary pH. Samples are taken after 0.5, 1, 2, 4, 6, 12 and 24 hours. They are analyzed by HPLC after centrifugation and filtration of the samples on PTFE filter 0.45 m.
- Form II of fenofibric acid is obtained from suspension of fenofibrate (ester) in isopropanol.
- fenofibrate has a melting point of 80 ° C.
- the Applicant has studied the dissolution profile of several batches of fenofibric acid received from several suppliers.
- the batches of raw materials have different granulometric characteristics, including a standard grade (non-micronized) and several micronized batches.
- Fenofibric acid batches were prepared in various pharmaceutical forms including the following excipients: hypromellose, milk protein concentrate, corn starch, lactose monohydrate (0.4 mg / 50 mg of active ingredient), sodium lauryl sulfate as as surfactant, magnesium stearate, and talc as a flow agent necessary during manufacture.
- Cutting stick 25/50/75/100 mg ++ Micronized Dissolution tests were performed on most formulations in media such as pH 6.0 acetate buffer, pH 4.5 phosphate buffer and purified water. Likewise, the rings were tested in the simulated stomach conditions simulating fed conditions and fed with enzymes (media called respectively FeSSIF and FaSSIF) were also tested after doses of 50 and 100 mg.
- the USP type II vane system was selected for testing with 1000 ml volume, 37 ° C and samples taken at 0, 2, 5, 10, 15, 20, 30, 45 and 60 minutes were analyzed by HPLC without renewal of the media.
- micronized fenofibric acid alone is completely dissolved after 60 minutes and dissolution kinetics is faster for the most highly micronised batch (100% of particles below 5000 nm and> 53% of particles below 2000 nm). ).
- the dissolution kinetics is the slowest for the "compressed" form which has the lowest specific exchange surface.
- FaSSIF and FeSSIF media more than 80% of the fenofibric acid is dissolved after 10 minutes and the whole after 30 minutes. There are no differences between the two environments.
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Abstract
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR1653378A FR3050112B1 (fr) | 2016-04-15 | 2016-04-15 | Utilisation de l'acide fenofibrique dans le traitement des maladies hepatiques |
PCT/EP2017/059025 WO2017178630A1 (fr) | 2016-04-15 | 2017-04-13 | Utilisation de l'acide fenofibrique dans le traitement des maladies hepatiques |
Publications (1)
Publication Number | Publication Date |
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EP3442500A1 true EP3442500A1 (fr) | 2019-02-20 |
Family
ID=56611347
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17717192.3A Withdrawn EP3442500A1 (fr) | 2016-04-15 | 2017-04-13 | Utilisation de l'acide fenofibrique dans le traitement des maladies hepatiques |
Country Status (4)
Country | Link |
---|---|
US (1) | US20190247343A1 (fr) |
EP (1) | EP3442500A1 (fr) |
FR (1) | FR3050112B1 (fr) |
WO (1) | WO2017178630A1 (fr) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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ES2927019T3 (es) | 2017-03-28 | 2022-11-02 | Gilead Sciences Inc | Combinaciones terapéuticas para el tratamiento de enfermedades hepáticas |
TWI814744B (zh) * | 2017-10-06 | 2023-09-11 | 美商基利科學股份有限公司 | 包含acc抑制劑之組合療法 |
WO2023022522A1 (fr) * | 2021-08-18 | 2023-02-23 | 제이투에이치바이오텍 주식회사 | Préparation complexe pour la prévention ou le traitement de la stéatohépatite, de la stéatose hépatique ou de la fibrose |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2774591B1 (fr) * | 1998-02-12 | 2000-05-05 | Lipha | Composition pharmaceutique comprenant l'association metformine et fibrate et son utilisation pour la preparation de medicaments destines a reduire l'hyperglycemie |
EP1424070A1 (fr) * | 2002-11-28 | 2004-06-02 | Fournier Laboratories Ireland Limited | Combinaison d'un agoniste de PPAR-alpha et de metformine pour la réduction du taux de triglycérides sériques |
US20080051411A1 (en) * | 2002-12-17 | 2008-02-28 | Cink Russell D | Salts of Fenofibric Acid and Pharmaceutical Formulations Thereof |
US20080152714A1 (en) * | 2005-04-08 | 2008-06-26 | Yi Gao | Pharmaceutical Formulations |
US7915247B1 (en) * | 2006-08-21 | 2011-03-29 | Mutual Pharmaceutical Company, Inc. | Methods of use of fenofibric acid |
WO2008046052A1 (fr) * | 2006-10-12 | 2008-04-17 | Abbott Laboratories | Formulations pharmaceutiques |
PE20140572A1 (es) | 2008-06-05 | 2014-05-16 | Janssen Pharmaceutica Nv | Combinaciones de drogas que comprenden un inhibidor de dgat y un agonista de ppar |
AU2011272782B2 (en) | 2010-07-02 | 2014-11-27 | Gilead Sciences, Inc. | Apoptosis signal-regulating kinase inhibitors |
ES2869884T3 (es) | 2011-09-16 | 2021-10-26 | Galectin Therapeutics Inc | Composiciones de galacto-ramnogalacturonato para el tratamiento de la esteatohepatitis no alcohólica y la enfermedad de hígado graso no alcohólico |
JP6140729B2 (ja) | 2011-12-28 | 2017-05-31 | ジェンフィットGenfit | 1,3−ジフェニルプロパン誘導体、その製造および使用 |
WO2013169648A1 (fr) | 2012-05-07 | 2013-11-14 | Novartis Ag | Combinaisons pharmaceutiques comprenant un inhibiteur de dgat1 et un médicament abaissant la teneur en triglycérides |
MX362275B (es) | 2013-04-18 | 2019-01-10 | Novo Nordisk As | Co-agonista de peptido similar a glucagon tipo 1 (glp-1) receptor de glucagon de larga duracion, estables para uso medico. |
US20160304553A1 (en) | 2013-12-04 | 2016-10-20 | Galmed Research & Development Ltd. | Aramchol salts |
MA39748A (fr) | 2014-03-21 | 2021-04-21 | Tobira Therapeutics Inc | Cenicriviroc pour le traitement de la fibrose |
RU2016148364A (ru) | 2014-05-12 | 2018-06-13 | Конатус Фармасьютикалз, Инк. | Лечение осложнений хронического заболевания печени |
WO2015187499A1 (fr) | 2014-06-03 | 2015-12-10 | Gilead Sciences, Inc. | Utilisation d'un inhibiteur d'ask1, éventuellement associé à un inhibiteur de loxl2, pour le traitement d'une maladie du foie |
-
2016
- 2016-04-15 FR FR1653378A patent/FR3050112B1/fr not_active Expired - Fee Related
-
2017
- 2017-04-13 WO PCT/EP2017/059025 patent/WO2017178630A1/fr active Application Filing
- 2017-04-13 EP EP17717192.3A patent/EP3442500A1/fr not_active Withdrawn
- 2017-04-13 US US16/094,183 patent/US20190247343A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
FR3050112B1 (fr) | 2020-09-04 |
WO2017178630A1 (fr) | 2017-10-19 |
FR3050112A1 (fr) | 2017-10-20 |
US20190247343A1 (en) | 2019-08-15 |
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