WO2016085994A1 - Ibudilast et telmisartan pour le traitement de la stéatose hépatique non alcoolique, la stéatohépatite non alcoolique et la stéatohépatite non alcoolique avancée - Google Patents

Ibudilast et telmisartan pour le traitement de la stéatose hépatique non alcoolique, la stéatohépatite non alcoolique et la stéatohépatite non alcoolique avancée Download PDF

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WO2016085994A1
WO2016085994A1 PCT/US2015/062448 US2015062448W WO2016085994A1 WO 2016085994 A1 WO2016085994 A1 WO 2016085994A1 US 2015062448 W US2015062448 W US 2015062448W WO 2016085994 A1 WO2016085994 A1 WO 2016085994A1
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ibudilast
administered
pharmaceutically acceptable
acceptable salt
patient
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PCT/US2015/062448
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English (en)
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Kazuko Matsuda
Yuichi Iwaki
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Medicinova, Inc.
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Publication of WO2016085994A1 publication Critical patent/WO2016085994A1/fr

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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/08—Solutions
    • 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

  • This disclosure relates to methods of inhibiting or treating non-alcoholic steatohepatitis (NASH), advanced NASH, conditions leading to or arising from them, and/or negative effects of each of the above by administering ibudilast and telmisartan (or pharmacological equivalents of each thereof).
  • NASH non-alcoholic steatohepatitis
  • ibudilast and telmisartan or pharmacological equivalents of each thereof.
  • NASH is a common liver disease, which resembles alcoholic liver disease, but occurs in people who drink little or no alcohol.
  • the major feature in NASH is fat in the liver, along with inflammation and damage.
  • NASH can progress into advanced NASH, which is characterized, inter alia, by hepatic fibrosis. Advanced NASH and conditions leading to or arising from advanced NASH, are a growing problem worldwide, affecting people of every age.
  • a method of treating a patient suffering from and/or diagnosed with NAFLD or NASH comprising administering to the patient an effective amount of ibudilast or a pharmaceutically acceptable salt thereof in combination with an effective amount of telmisartan or an ester thereof or a pharmaceutically acceptable salt of each thereof, wherein ibudilast or the pharmaceutically acceptable salt thereof and telmisartan or the ester thereof or the pharmaceutically acceptable salt of each thereof are administered together or separately.
  • the patient is suffering from NAFLD.
  • the patient is suffering from NASH.
  • the patient is diagnosed with NAFLD.
  • the patient is diagnosed with NASH.
  • the patient's liver inflammation or lobular inflammation is reduced or inhibited.
  • a damage to the patient's liver cells is reduced or inhibited.
  • the patient's hepatic ballooning is reduced or inhibited.
  • the patient's steatosis is reduced or inhibited.
  • a method of treating a patient suffering and/or diagnosed with from advanced NASH comprising administering to the patient an effective amount of ibudilast or a pharmaceutically acceptable salt thereof in combination with telmisartan or an ester thereof or a pharmaceutically acceptable salt of each thereof, wherein ibudilast or the pharmaceutically acceptable salt thereof and telmisartan or the ester thereof or the pharmaceutically acceptable salt of each thereof are administered together or separately.
  • the patient is suffering from advanced NASH.
  • the patient is diagnosed with advanced NASH.
  • the advanced NASH patient exhibits one or more symptoms from ascites, asterixis, hepatocellular carcinoma (HCC), hepatic fibrosis, hepatic scarring, hard liver border, palmar erythema, portal hypertension, spider angiomata, splenomegaly, and cirrhosis.
  • HCC hepatocellular carcinoma
  • hepatic fibrosis is reduced.
  • hepatic scarring is reduced.
  • the patient is a pediatric patient.
  • the ibudilast is administered in a form selected from the group consisting of capsules, powders, tablets, granules, pellets, injections, liquid compositions, ointments and patches.
  • the ibudilast is administered orally or parenterally.
  • the ibudilast is administered orally, and wherein the ibudilast is administered in an amount of 10 mg to 200 mg per dose, and wherein 2 to 3 doses of ibudilast are administered per day.
  • the ibudilast is administered in an amount of 10 mg to 60 mg per dose.
  • the ibudilast is administered by injection, wherein the ibudilast is administered in an amount of 10 mg to 200 mg per dose, and wherein 2 to 3 doses of ibudilast are administered per day. In another embodiment, the ibudilast is administered in an amount of 10 mg to 60 mg per dose.
  • the telmisartan is administered orally in an amount of 20 mg to 80 mg per day in one or more administrations.
  • the patient is suffering from diabetes, such as type 2 diabetes.
  • the patient is suffering from hypertension.
  • an ester refers to a ester with a mono, di, or trihydroxy, or higher hydroxylated compound containing 1-20, preferably, 1-10 carbon atoms, optionally substituted with one or more, preferably 1-3, more preferably, a single amino group.
  • administering or "Administration of a drug to a patient (and grammatical equivalents of this phrase) includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug.
  • direct administration including self-administration
  • indirect administration including the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • “Combination” when referring to “administration in combination” or grammatical equivalents thereof of two agents refers to requiring both agents to have a pharmacological action at a same time, irrespective of co- or separate administration in time.
  • “Advanced NASH” refers to a progression of NASH that leads to one or more symptoms such as spider angiomata, ascites, splenomegaly, hard liver border, palmar erythema, asterixis, hepatic fibrosis, and hepatocellular carcinoma. Advanced NASH is also associated with symptoms such as cirrhosis and liver failure, and with liver transplantation.
  • NASH can worsen, to advanced NASH, causing scarring or fibrosis to appear and accumulate in the liver. As fibrosis worsens, cirrhosis may develop, and the liver becomes severely scarred, hardened, and unable to function normally. Once serious scarring or cirrhosis is present, few treatments can halt the progression. A person with cirrhosis can experience fluid retention, muscle wasting, bleeding from the intestines, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure, and transplantation is increasingly performed in people with advanced NASH. For example, NASH and advanced NASH ranks as one of the major causes of cirrhosis in the U.S.A., along with hepatitis C and alcoholic liver disease.
  • stigmata of chronic liver disease such as spider angiomata, ascites, splenomegaly, hard liver border, palmar erythema, or asterixis
  • patients can complain of jaundice or pruritus, or they might present with a complication of portal hypertension (e.g., ascites, variceal bleeding, or encephalopathy).
  • Cirrhosis in advanced NASH is a risk factor for development of hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • a prevalence of HCC in up to 2.8% in NASH patients over a 20-year period has been reported.
  • Data in Japanese patients report that the cumulative rate of HCC at 5 years may be as high as 15%.
  • Advanced NASH-associated cirrhosis is an increasing indication for liver transplantation.
  • compositions include the recited elements, but not exclude others.
  • Consisting essentially of when used to define methods and compositions shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transitional terms and phrases are within the scope of this disclosure.
  • Effective amount of a compound utilized herein is an amount that, when administered to a patient treated as herein, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the medical condition in the patient.
  • the full therapeutic effect does not necessarily occur by administration of one dose (or dosage), and may occur only after administration of a series of doses. Thus, an effective amount may be administered in one or more administrations.
  • an ester thereof refers to an ester of the carboxyl group of telmisartan or a pharmacological equivalent thereof.
  • An ester of the carboxylic acid can include, without limitation, as the corresponding alcohol, a compound of formula R A -OH, wherein R A is wherein R A is Ci-Ce alkyl, aryl, heteroaryl, C3-C 12 cycloalkyl, or C 2 -C8 heterocyclyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl are optionally substituted with 1 -4 C1-C 3 alkyl, aryl, C0 2 H, amino, alkylamino, or dialkylamino groups.
  • R A is C 1 -C4 alkyl.
  • NASH Non-alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • the major feature in NASH is fat in the liver, along with inflammation and damage. NASH can lead to cirrhosis, in which the liver is damaged, scarred, and is no longer able to work properly. NASH affects 2 to 5 percent of the U.S. population. Currently, no specific therapies for NASH exist. An additional 10 to 20 percent of Americans have fat in their liver, but no substantial inflammation or liver damage, a condition called “non-alcoholic fatty liver disease” (NAFLD). Although having fat in the liver is not normal, by itself it probably causes little harm or permanent damage. If fat is suspected based on blood test results or scans of the liver, this problem is referred to as NAFLD. If a liver biopsy is performed in this case, it will show that some people have NASH while others have NAFLD.
  • NAFLD non-alcoholic fatty liver disease
  • NASH is usually first suspected in a person who is found to have elevations in liver tests that are included in routine blood test panels, such as alanine aminotransferase (ALT) or aspartate aminotransferase (AST). When further evaluation shows no apparent reason for liver disease (such as medications, viral hepatitis, or excessive use of alcohol) and when x rays or imaging studies of the liver show fat, NASH is suspected.
  • NASH is diagnosed and separated from NAFLD by a liver biopsy. For a liver biopsy, a needle is inserted through the skin to remove a small piece of the liver. NASH is diagnosed when examination of the tissue with a microscope shows fat along with inflammation and damage to liver cells. A biopsy can provide information about scar tissue has development in the liver.
  • “Pharmaceutically acceptable” refers to non-toxic and suitable for administration to a patient, including a human patient.
  • “Pharmaceutically acceptable salts” refer to salts that are non-toxic and are suitable for administration to patients.
  • Non-limiting examples of cationic salts include alkali metal, alkaline earth metal, and various primary, secondary, and tertiary ammonium salts.
  • Non- limiting examples of cationic salts include sodium, potassium, and calcium salts.
  • Certain examples of anionic salts include various carboxylic acid, sulfonic acid, and mineral acid salts. Examples of mineral acids include without limitation, sulfuric, phosphoric, nitric, acid salts.
  • an ester of a relevant compound when an ester of a relevant compound includes a cationic portion, for example, when the ester includes an amino acid ester, the salts thereof can include various carboxylic acid, sulfonic acid, and miner acid salts.
  • anionic salts include halide salts, such as without limitation, chloride salts,
  • polybasic, such as di or tri basic acids can form 2 or three different kinds of salts.
  • “Pharmacological equivalent” of an agent refers to a prodrug, such as an ester, thereof or a pharmaceutically acceptable salt of each thereof.
  • Telmisartan refers to a compound of formula:
  • Treating" a medical condition or a patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, reduction, alleviation, or amelioration of one or more manifestations of or negative effects of NASH or advanced NASH, improvement in one or more clinical outcomes, diminishment of extent of NASH or advanced NASH, delay or slowing of NASH or advanced NASH progression, amelioration, palliation, or stabilization of the fibrosis state, and other beneficial results described herein.
  • composition utilized herein may optionally contain one or more additional components as described below.
  • compositions may further comprise one or more pharmaceutically acceptable excipients or carriers.
  • suitable excipients include, without limitation, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophors, carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders/fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like.
  • PEG polyethylene glycol
  • HCO hydrogenated castor oil
  • cremophors carb
  • starches e.g., corn starch
  • inorganic salts e.g., antimicrobial agents, antioxidants, binders/fillers
  • surfactants e.g., calcium or magnesium stearate
  • glidants such as talc, disintegrants, diluents
  • a composition may include one or more carbohydrates such as a sugar, a derivatized sugar such as an alditol, aldonic acid, an esterified sugar, and/or a sugar polymer.
  • carbohydrate excipients include, for example: monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.
  • compositions of the disclosure are potato and corn- based starches such as sodium starch glycolate and directly compressible modified starch.
  • excipients include inorganic salt or buffers such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.
  • a composition may also include an antimicrobial agent, e.g., for preventing or deterring microbial growth.
  • antimicrobial agents suitable for the present disclosure include benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimersol, and combinations thereof.
  • a composition may also contain one or more antioxidants.
  • Suitable antioxidants for use in the present disclosure include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.
  • Additional excipients include surfactants such as polysorbates, e.g., "Tween 20" and “Tween 80,” and pluronics such as F68 and F88 (both of which are available from BASF, Mount Olive, N.J.), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, and phosphatidylethanolamines), fatty acids and fatty esters, steroids such as cholesterol, and chelating agents, such as EDTA, zinc and other such suitable cations.
  • a composition may optionally include one or more acids or bases.
  • Non-limiting examples of acids that can be used include those acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.
  • suitable bases include, without limitation, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumarate, and combinations thereof.
  • the amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active agent components, and particular needs of the composition. Typically, the optimal amount of any individual excipient is determined through routine experimentation, i.e., by preparing compositions containing varying amounts of the excipient (ranging from low to high), examining the stability and other parameters, and then determining the range at which optimal performance is attained with no significant adverse effects.
  • the excipient will be present in the composition in an amount of about 1% to about 99% by weight, preferably from about 5% to about 98% by weight, more preferably from about 15 to about 95% by weight of the excipient.
  • the amount of excipient present in an ibudilast composition of the disclosure is selected from the following: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 95% by weight.
  • a compositions can be formulated to improve stability and extend the half-life of the pharmacologically active component (such as ibudilast and telmisartan).
  • Controlled or sustained-release formulations include a carrier or vehicle such as liposomes, nonresorbable impermeable polymers such as ethylenevinyl acetate copolymers and Hytrel® copolymers, swellable polymers such as hydrogels, or resorbable polymers such as collagen and certain polyacids or polyesters such as those used to make resorbable sutures.
  • ibudilast can be encapsulated, adsorbed to, or associated with, particulate carriers.
  • particulate carriers include those derived from polymethyl methacrylate polymers, as well as microparticles derived from poly(lactides) and poly(lactide-co-glycolides), known as PLG. See, e.g., Jeffery et al, Pharm. Res. (1993) 10:362-368; and McGee et al., J. Microencap. (1996).
  • Suitable oral dosage forms useful herein include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules, and pellets.
  • Alternative formulations include aerosols, transdermal patches, gels, creams, ointments, suppositories, powders or lyophilates that can be reconstituted, as well as liquids.
  • suitable diluents for reconstituting solid compositions e.g., prior to injection, include bacteriostatic water for injection, dextrose 5% in water, phosphate-buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.
  • solutions and suspensions are contemplated.
  • Tablets can be made by compression or molding, optionally with one or more accessory ingredients or additives.
  • Compressed tablets are prepared, for example, by compressing in a suitable tableting machine, the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) and/or surface-active or dispersing agent.
  • a binder e.g., povidone, gelatin, hydroxypropylmethyl cellulose
  • lubricant e.g., inert diluent
  • preservative e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose
  • disintegrant e.g., sodium starch glyco
  • Molded tablets are made, for example, by molding in a suitable tableting machine, a mixture of powdered compounds moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored, and may be formulated so as to provide slow or controlled release of the active ingredients, using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with a coating, such as a thin film, sugar coating, or an enteric coating to provide release in parts of the gut other than the stomach. Processes, equipment, and toll manufacturers for tablet and capsule making are well-known in the art.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredients, generally in a flavored base such as sucrose and acacia or tragacanth and pastilles comprising the active ingredients in an inert base such as gelatin and glycerin or sucrose and acacia.
  • a pharmaceutical composition for topical administration may also be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.
  • the formulation may be in the form of a patch (e.g., a transdermal patch) or a dressing such as a bandage or adhesive plaster impregnated with active ingredients and optionally one or more excipients or diluents.
  • Topical formulations may additionally include a compound that enhances absorption or penetration of the ingredients through the skin or other affected areas, such as dimethylsulfoxidem bisabolol, oleic acid, isopropyl myristate, and D-limonene, to name a few.
  • the oily phase is constituted from known ingredients in a known manner. While this phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat and/or an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifier(s) with or without stabilizer(s) make up the so- called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of cream formulations.
  • Illustrative emulgents and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • Formulations for rectal administration are typically in the form of a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration generally take the form of a suppository, tampon, cream, gel, paste, foam or spray.
  • Formulations suitable for nasal administration include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns. Such a formulation is typically administered by rapid inhalation through the nasal passage, e.g., from a container of the powder held in proximity to the nose.
  • a formulation for nasal delivery may be in the form of a liquid, e.g., a nasal spray or nasal drops.
  • Aerosolizable formulations for inhalation may be in dry powder form (e.g., suitable for administration by a dry powder inhaler), or, alternatively, may be in liquid form, e.g., for use in a nebulizer.
  • Nebulizers for delivering an aerosolized solution include the AERxTM (Aradigm), the Ultravent® (Mallinkrodt), and the Acorn II® (Marquest Medical Products).
  • a composition of the disclosure may also be delivered using a pressurized, metered dose inhaler (MDI), e.g., the Ventolin® metered dose inhaler, containing a solution or suspension of a combination of drugs as described herein in a pharmaceutically inert liquid propellant, e.g., a chlorofluorocarbon or fluorocarbon.
  • MDI pressurized, metered dose inhaler
  • a pharmaceutically inert liquid propellant e.g., a chlorofluorocarbon or fluorocarbon.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile solutions suitable for injection, as well as aqueous and non-aqueous sterile suspensions.
  • Parenteral formulations of the disclosure are optionally contained in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
  • sterile liquid carrier for example, water for injections
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the types previously described.
  • a sustained release composition may also be utilized such that each of the drug components is released or absorbed slowly over time, when compared to a non-sustained release formulation.
  • Sustained release formulations may employ pro-drug forms of the active agent, delayed-release drug delivery systems such as liposomes or polymer matrices, hydrogels, or covalent attachment of a polymer such as polyethylene glycol to the active agent.
  • compositions may optionally include other agents conventional in the pharmaceutical arts and particular type of formulation being employed, for example, for oral administration forms, the composition for oral administration may also include additional agents as sweeteners, thickeners or flavoring agents.
  • additional agents as sweeteners, thickeners or flavoring agents.
  • Example 1 Therapeutically Beneficial effects of Ibudilast and Telmisartan in STAM model of Non-alcoholic Steatohepatitis
  • STAMTM is a model for non-alcoholic steatohepatitis (NASH), symtoms thereof, and related liver disorders, created by the combination of chemical and dietary interventions in C57BL/6 mice.
  • NASH non-alcoholic steatohepatitis
  • a combination of 1, 10, 50, or 100 mg/kg of ibudilast and 10 mg/kg of telmisartan is used in the study.
  • NASH is induced in 50 male mice by a single subcutaneous injection of 200 ⁇ g streptozotocin (STZ, Sigma-Aldrich, USA) solution 2 days after birth and feeding with high fat diet (HFD, 57 kcal% fat, cat#: HFD32, CLEA Japan, Japan) after 4 weeks of age.
  • STZ streptozotocin
  • HFD high fat diet
  • Vehicle, and ibudilast and Telmisartan are administered by oral route.
  • C57BL/6 mice (15-day-pregnant female) are obtained from Charles River Laboratories Japan (anagawa, Japan).
  • the animals are maintained in a SPF facility under controlled conditions of temperature (23 ⁇ 2°C), humidity (45 ⁇ 10%), lighting (12-hour artificial light and dark cycles; light from 8:00 to 20:00) and air exchange.
  • a high pressure (20 ⁇ 4 Pa) is maintained in the experimental room to prevent contamination of the facility.
  • mice are housed in polycarbonate cages K -600 (Natsume Seisakusho, Japan) with a maximum of 4 mice per cage. Sterilized ⁇ 8 ⁇ (Material Research Center, Japan) is used for bedding and replaced once a week.
  • Sterilized solid HFD is provided ad libitum, being placed in the metal lid on top of the cage. Pure water is provided ad libitum from a water bottle equipped with a rubber stopper and a sipper tube. Water bottles are replaced once a week, cleaned and sterilized in autoclave and reused.
  • mice are identified by numbers engraved on earrings. Each cage is labeled with a specific identification code.
  • Non-fasting blood glucose is measured in whole blood using LIFE CHECK (EIDIA, Japan).
  • LIFE CHECK EIDIA, Japan
  • blood is collected in polypropylene tubes with anticoagulant
  • Plasma ALT and AST levels are measured by FUJI DRI-CHEM 7000 (Fujifilm, Japan).
  • liver hydroxyproline content frozen liver samples (32-40 mg) are processed by an alkaline-acid hydrolysis method as follows. Liver samples are defatted with 100% acetone, dried in the air, dissolved in 2N NaOH at 65°C, and autoclaved at 121°C for 20 minutes. The lysed samples (400 ⁇ are acid-hydrolyzed with 400 ⁇ , of 6N HC1 at 121°C for 20 minutes, and neutralized with 400 of 4N NaOH containing 10 mg/mL activated carbon. AC buffer (2.2M acetic acid/0.48M citric acid, 400 ⁇ ) is added to the samples, followed by centrifugation to collect the supernatant.
  • AC buffer 2.2M acetic acid/0.48M citric acid, 400 ⁇
  • a standard curve of hydroxyproline is constructed with serial dilutions of trans-4-hydroxy-L-proline (Sigma- Aldrich) starting at 16 ⁇ g/mL.
  • the prepared samples and standards (each 400 ⁇ ) are mixed with 400 chloramine T solution (Wako Pure Chemical Industries) and incubated for 25 minutes at room temperature.
  • the samples are then mixed with Ehrlich's solution (400 ⁇ ) and heated at 65°C for 20 minutes to develop the color. After samples are cooled on ice and centrifuged to remove precipitates, the optical density of each supernatant is measured at 560 nm.
  • the concentrations of hydroxyproline are calculated from the hydroxyproline standard curve. Protein concentrations of liver samples are determined using a BCA protein assay kit (Thermo Fisher Scientific, USA) and used to normalize the calculated hydroxyproline values. Liver hydroxyproline levels are expressed as ⁇ g per mg protein.
  • HE staining sections are cut from paraffin blocks of left lateral liver tissue prefixed in Bouin's solution and stained with Lillie- Mayer's Hematoxylin (Muto Pure Chemicals, Japan) and eosin solution (Wako Pure Chemical Industries).
  • NAS is calculated according to the criteria of Kleiner (Kleiner DE. et ai, Hepatology, 2005;41 :1313).
  • To visualize collagen deposition Bouin's fixed left lateral liver sections are stained using picro-Sirius red solution (Waldeck, Germany).
  • RNA is extracted from liver samples using RNAiso (Takara Bio, Japan) according to the manufacturer's instructions.
  • RNAiso Takara Bio, Japan
  • One ⁇ g of RNA is reverse-transcribed using a reaction mixture containing 4.4 mM MgCl 2 (Roche, Switzerland), 40 U RNase inhibitor (Toyobo, Japan), 0.5 mM dNTP (Promega, USA), 6.28 ⁇ random hexamer (Promega), 5 x first strand buffer (Promega), 10 mM dithiothreitol (Invitrogen) and 200 U MMLV-RT (Invitrogen) in a final volume of 20 ⁇ .
  • the reaction is carried out for 1 hour at 37°C, followed by 5 minutes at 99°C.
  • Real-time PCR is performed using real-time PCR DICE and SYBR premix Taq (Takara Bio). To calculate the relative mRNA expression level, the expression of each gene is normalized to that of reference gene 36B4 (gene symbol: RplpO).
  • mice are fed with a normal diet ad libitum without any treatment until 9 weeks of age.
  • mice are orally administered vehicle in a volume of 10 mL/kg once daily from 6 to 9 weeks of age. Study Groups
  • mice are administered various combinations of ibudilast and telmisartan in the amounts as described above.
  • mice are refed with standard diet (CE-2, CLEA Japan, Inc.) after 30 minutes of the oral administration after fasting periods of 48 hours, and the mice are anatomized after refeeding periods of four hours.
  • the content of triglyceride and biosynthesis of fatty acid in isolated liver are measured.
  • Triglyceride can be extracted from the liver by using the method of Folch et al. (Folch, J., et al. 1957. J. Biol. Chem., 226: 497-509). Tissues are homogenized by using chloroform-methanol mixture 2:1 (v/v). [0088] The obtained homogenate is shaken for one hour to extract a lipid fraction, followed by obtaining the supernatant by centrifugation to dry. The extraction is carried out twice in the same procedure from sediment of the tissues and the obtained supernatant is mixed together to dry.
  • the dried extract is dissolved to 4% (v/v) of Triton X-100 and the triglyceride concentration is measured using Liquitech TG-II reagent (Roche Diagnostics K. K.). The result is shown by the mean value ⁇ the standard error. A statistical analysis is performed using Williams' multiple comparison test where the level of statistical significance is less than 5%.
  • the fatty acid synthesis in the liver is measured using the fatty acid synthesis from acetic acid.
  • the tissue is incubated in 95% (v/v) 0 2 , 5% (v/v) C0 2 , 0.5 mM acetic acid (0.25 ⁇ /mL, [l- 14 C]acetic acid) and Krebs-Ringer phosphate HEPES buffer (pH 7.4) containing 0.2% (v/v) BSA for two hours at 37° C.
  • the ethanol solution containing 15% (w/v) of potassium hydroxide is added, and incubated for two hours at 85° C. to saponify.
  • the ether layer as the upper layer obtained by centrifugation is removed. After the same procedure is carried out twice, the aqueous layer is adjusted using hydrochloric acid to pH 1. After adding petroleum ether and shaking for 30 minutes, the ether layer as the upper layer obtained by centrifugation is collected. The same procedure is carried out twice. After mixing the collected ether layer together, obtained solution is dried over. After the dried extract is dissolved to chloroform, purified water is added thereto followed by shaking for 30 minutes.
  • the chloroform layer is obtained as the lower layer.
  • the scintillation cocktail is mixed with the obtained solution to measure radioactivity using liquid scintillation counter (Tri-Crab 1900CA, PerkinElmer). The result is shown as the mean value ⁇ the standard error. A statistical analysis is performed using Williams' multiple comparison test where the level of statistical significance is less than 5%.
  • Example 3 Inhibitory Effect of a Combination of Ibudilast and Telmisratan on Fatty Liver (Evaluation Using Obesity-Related Fatty Liver Model) [0092] The effect of ibudilast on fatty liver is evaluated using B6.V-Lep° /J mice (ob/ob; Charles River Laboratories Japan, Inc.), a model of obesity-related insulin resistance and fatty liver.
  • mice Male ob/ob mice (Charles River Laboratories Japan, Inc.) at seven weeks of age are used.
  • vehicle group 2% (v/v) of PEG-60 hydrogenated castor oil (NIKKOL HCO-60, Nikko Chemicals Co., Ltd.) is orally administrated twice a day.
  • PEG-60 hydrogenated castor oil NIKKOL HCO-60, Nikko Chemicals Co., Ltd.
  • combination groups 10, 30 or 100 mg/kg of ibudilast and 4-20 mg/kg of telmisartan, dissolved in 2% (v/v) of PEG-60 hydrogenated castor oil are orally administered twice a day.
  • mice At 15 to 21 hours after the end of two weeks administration period, the mice are dissected in the fed state. The content of triglyceride in isolated liver is measured.
  • Triglyceride is extracted from the liver by using the method of Folch et al. (Folch, J., et al. 1957. J. Biol. Chem., 226: 497-509). Tissues are homogenized by using chloroform methanol mixture 2:1 (v/v).
  • the obtained homogenate is shaken for one hour to extract a lipid fraction, followed by obtaining the supernatant by centrifugation to dry.
  • the extraction is carried out twice in the same procedure from sediment of the tissues and the obtained supernatant is mixed together to dry over.
  • the dried extract is dissolved to 4% (v/v) of Triton X-100 and the triglyceride concentration is measured using Liquitech TG-II reagent (Roche Diagnostics K. K.). The results are shown as the mean value ⁇ the standard error.
  • a statistical analysis is performed using Williams' multiple comparison test where the level of statistical significance is less than 5%.
  • Example 4 Inhibitory Effects of a Combination of Ibudilast and Telmisartan on Hepatic Inflammation and Hepatic Fibrosis
  • the MCD diet (Oriental Yeast Co., Ltd.) produced in accordance with the previous report by Okumura et al. (Okumura, K., et al. 2006, Hepatol. Res., 36: 217-228) is administered to male C57BI/6J mice (CLEA Japan, Inc.) at ten weeks of age for six weeks.
  • TNFa, MCP-1, IL- ⁇ , TGFp, and collal mRNA expressions in isolated liver are measured using the quantitative real-time PCR method.
  • the 18S rRNA mRNA expression is used as an internal standard of the quantitative real-time PCR method and similarly measured.
  • Liver RNA is extracted using TRIzol reagent (Invitrogen).
  • the DNAase treatment of extracted RNA is performed using RNase-Free DNase Set (Qiagen) and RNeasy mini kit (Qiagen).
  • the reverse transcription of RNA is performed using High- Capacity cDNA Reverse Transcription kit with RNase inhibitor (Applied Biosystems).
  • the quantitative real-time PCR is performed using TaqMan Fast Universal PCR Master Mix (Applied Biosystems) and Applied Biosystems 7500 Fast Real-Time PCR System (Applied Biosystems).
  • TaqMan probes and primers are obtained as assay sets for each target mRNA (TaqMan Gene Expression Assays, Applied Biosystems, Inc.), specifically, TNFa (Mm00443258_ml), MCP-1 (Mm99999056_ml), IL- ⁇ (Mm00434228_ml), TGF (MmOl 178819_ml) and collal (Mm00801666_gl) of mouse, and 18s rRNA (Hs99999901_sl).
  • Each operation relating to the quantitative real-time PCR is carried out in accordance with the manual attached to each reagent, kits and device.
  • the mRNA expression of gene of interest (target) is shown as a relative value in which 18S rRNA is defined as an internal standard.
  • the results are shown as the mean value ⁇ the standard error.
  • a statistical analysis is carried out using Williams' multiple comparison test where the level of statistical significance is less than 5%.
  • NAFLD fatty liver on ultrasonography
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • Treatment is taken daily at the same hour in the morning, with no concomitant medication or alcohol consumption allowed. All patients receive dietary instructions using a meal-exchange plan from nutritionists.
  • the ideal dietary caloric intake for each patient is calculated as the ideal body weight (kg) x 25 kcal/kg. It is confirmed by questionnaire that the physical activity level is almost constant in each subject throughout the study period. The patients are followed for 12 months, with two-monthly visits.
  • FPG Fasting plasma glucose
  • HbAlc Hemoglobin Ale
  • NGSP National Glycohemoglobin Standardization Program
  • HOMA-IR Homeostasis model assessment-insulin resistance
  • TC total cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • TG triglyceride
  • FFAs free fatty acids
  • AST As biochemical parameters, AST, ALT, gamma glutamyl transpeptidase (yGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine (CR), uric acid (UA), sodium (Na), potassium (K), ferritin, and creatine phosphokinase (CPK) are measured.
  • Inflammatory markers such as hyaluronic acid (Hyal), 7S domain of type IV collagen (4Col7S), high-sensitivity C-reactive protein (hs-CRP), procollagen III peptide (P-3-P), zinc (Zn), total adiponectin, and interleukin (IL)-6 are analyzed at the Special Reference Laboratory (SRL, Tokyo, Japan).
  • SRL Special Reference Laboratory
  • BA bile acid
  • Subcutaneous and visceral fat distribution is determined by measuring a -150 Hounsfield unit (HU) to -50 HU area using the method of CT scanning at the umbilical level as described previously.
  • V/S ratio is calculated as visceral fat area (VFA)/subcutaneous fat area (SFA).
  • An index of fat deposition in the liver based on the liver-to-spleen (L/S) ratio according to CT attenuation values is also determined.
  • the mean HU values of the liver and spleen are determined in the parenchyma of the right (CT-L1) and left lobe (CT-L2) of the liver and approximately the same size area of the spleen (CT- Spleen), avoiding blood vessels, artifacts, and heterogeneous areas.
  • L/S ratio is calculated as [((CT-L1) + (CT-L2))/2]/(CT-Spleen).
  • a method of treating a patient suffering from non-alcoholic steatohepatitis comprising administering to the patient an effective amount of ibudilast or a pharmaceutically acceptable salt thereof in combination with an effective amount of telmisartan or an ester thereof or a pharmaceutically acceptable salt of each thereof, wherein ibudilast or the pharmaceutically acceptable salt thereof and telmisartan or the ester thereof or the pharmaceutically acceptable salt of each thereof are administered together or separately.
  • the method of Embodiment 1 wherein the patient's liver inflammation is reduced.
  • a method of treating a patient suffering from advanced NASH or a symptom thereof comprising administering to the patient an effective amount of ibudilast or a pharmaceutically acceptable salt thereof in combination with telmisartan or an ester thereof or a pharmaceutically acceptable salt of each thereof, wherein ibudilast or the pharmaceutically acceptable salt thereof and telmisartan or the ester thereof or the pharmaceutically acceptable salt of each thereof are administered together or separately.
  • Embodiment 13 wherein the advanced NASH symptom is one or more of ascites, asterixis, cirrhosis, hepatocellular carcinoma (HCC), hepatic fibrosis, hepatic scarring, hard liver border, palmar erythema, portal hypertension, spider angiomata, and splenomegaly.
  • HCC hepatocellular carcinoma
  • hepatic fibrosis hepatic scarring
  • hard liver border palmar erythema
  • portal hypertension spider angiomata
  • splenomegaly The method of any one of Embodiments 13-14, wherein the patient's hepatic fibrosis is reduced.
  • the method of any one of Embodiments 13-15 wherein the patient's hepatic scarring is reduced.
  • the method of any one of Embodiments 13-16 wherein the patient is a pediatric patient.
  • a method of treating a patient suffering from non-alcoholic fatty liver disease comprising administering to the patient an effective amount of ibudilast or a pharmaceutically acceptable salt thereof in combination with an effective amount of telmisartan or an ester thereof or a pharmaceutically acceptable salt of each thereof, wherein ibudilast or the pharmaceutically acceptable salt thereof and telmisartan or the ester thereof or the pharmaceutically acceptable salt of each thereof are administered together or separately.
  • NAFLD non-alcoholic fatty liver disease
  • telmisartan is administered orally in an amount of 20 mg to 80 mg per day in one or more administrations.

Abstract

La présente invention concerne des méthodes pour inhiber ou traiter la stéatose hépatique non alcoolique (NAFLD), la stéatohépatite non alcoolique (NASH), les formes avancées de la NASH, la stéatose hépatique non alcoolique, les affections menant à ces dernières ou en résultant et/ou les effets négatifs de chacune de ces dernières par l'administration d'ibudilast ou d'un sel pharmaceutiquement acceptable de ce dernier en association avec une quantité efficace de telmisartan ou d'un ester de ce dernier, ou d'un sel pharmaceutiquement acceptable de chacun de ces derniers.
PCT/US2015/062448 2014-11-26 2015-11-24 Ibudilast et telmisartan pour le traitement de la stéatose hépatique non alcoolique, la stéatohépatite non alcoolique et la stéatohépatite non alcoolique avancée WO2016085994A1 (fr)

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EP3538076A4 (fr) * 2016-11-08 2019-11-13 University of Louisville Research Foundation, Inc. Encapsulation d'inhibiteurs de phosphodiestérase pour traiter la maladie hépatique alcoolique

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