WO2014048511A1 - Métadoxine pour utilisation dans le traitement de maladies du foie, et formulations à libération prolongée de métadoxine - Google Patents

Métadoxine pour utilisation dans le traitement de maladies du foie, et formulations à libération prolongée de métadoxine Download PDF

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Publication number
WO2014048511A1
WO2014048511A1 PCT/EP2013/000183 EP2013000183W WO2014048511A1 WO 2014048511 A1 WO2014048511 A1 WO 2014048511A1 EP 2013000183 W EP2013000183 W EP 2013000183W WO 2014048511 A1 WO2014048511 A1 WO 2014048511A1
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WO
WIPO (PCT)
Prior art keywords
metadoxine
pharmaceutical composition
composition according
prednisone
treatment
Prior art date
Application number
PCT/EP2013/000183
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English (en)
Inventor
Frederick Van Gulik
Yamsani Madhusudan RAO
Shankar Bodapunti PRABHA
Original Assignee
Eurodrug Laboratories B.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eurodrug Laboratories B.V. filed Critical Eurodrug Laboratories B.V.
Priority to BR112015006642-9A priority Critical patent/BR112015006642B1/pt
Priority to MX2015003810A priority patent/MX2015003810A/es
Priority to KR1020157006050A priority patent/KR20150063040A/ko
Publication of WO2014048511A1 publication Critical patent/WO2014048511A1/fr
Priority to PH12015500353A priority patent/PH12015500353A1/en
Priority to PH12016501553A priority patent/PH12016501553A1/en

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Classifications

    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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 concerns a new therapeutic use and new indications of metadoxine and a new formulation comprising metadoxine, especially designed for once a day administration.
  • Metadoxine (5-oxo-L-proline compound with 5-hydroxy-6-methylpyridine-3,4- dimethanol ( 1 : 1 ); herein after also referred to as MTD) is a synthetic compound having the following chemical formula
  • Metadoxine is currently marketed for the treatment of chronic and acute alcohol intoxication and Alcoholic Liver Disease (ALD), in the form of conventional immediate release (IR) tablets containing 500 mg of active- ingredient.
  • ALD chronic and acute alcohol intoxication and Alcoholic Liver Disease
  • IR immediate release
  • the half-life of the drug is 1 hour and for this reason several administrations are required during the 24-hour period, in the form of a tablet or solution for oral or parenteral administration.
  • the normal complaint of people taking Metadoxine twice daily at 500 mg dose is the disturbed sleep in the night. This may be attributable to higher accumulated concentration of Metadoxine due to second dose administered in the night.
  • Metadoxine has been investigated for its pharmacological effects on the liver, especially on hepatosteatosis.
  • NASH Non-Alcoholic Fatty Liver Disease
  • NASH Non-Alcoholic Steatohepatitis
  • NAFLD and NASH Hepatosteatosis in NAFLD and NASH occurs when fat is deposited in the liver due to factors other than prolonged excessive alcohol use. NAFLD and NASH have been associated with insulin resistance and the metabolic syndrome and may respond to treatments originally developed for other insulin-resistant states (e.g. diabetes mellitus type 2) such as weight loss and oral antidiabetic agents. NASH is a major cause of cirrhosis of the liver of unknown origin.
  • the first object of the invention is to provide a new treatment for NAFLD and NASH.
  • the second object of the invention is to provide a new dosage regime of metadoxine (MTD), especially in the treatment and/or in the prevention of NAFLD and NASH.
  • MTD metadoxine
  • the third object of the invention is to provide a treatment with metadoxine (MTD) for the reduction of mortality in patients with Severe Alcoholic Hepatitis (SAH).
  • MTD metadoxine
  • SAH Severe Alcoholic Hepatitis
  • the fourth object of the invention is to provide a new oral formulation of metadoxine which eliminates the need to take several doses per day, thus improving patient compliance and eliminating the disturbed sleep in the night occurring with the conventional 500 mg multiple daily administrations, as well as its use in therapy.
  • the invention relates to a new use of metadoxine (MTD) for the prevention and the treatment of NAFLD and NASH.
  • metadoxine may be administered in the form of any pharmaceutical composition for oral administration (tablet, capsule, caplet, sachet or syrup), or solution for parenteral administration.
  • NAFLD and “NASH”, as used herein with reference to the use of metadoxine, do not include NAFLD and NASH derived, related or anyway associated to hepatic fibrosis.
  • Said pharmaceutical compositions are preferably administered in a daily amount varying from 250 to 2,500 mg, advantageously from 500 to 1 ,500 mg, most preferably in an amount of approx, 1 ,000 mg to 1 ,500 mg.
  • Different dosages may however be selected by the physician according to the age, sex, weight and general clinical conditions of the subject to be treated, as well as the diagnosed stages of NAFLD/NASH.
  • compositions preferably comprise one or more pharmaceutical acceptable carriers, and are prepared according to methods which are well known to the skilled in the art.
  • metadoxine may be used in the treatment of NAFLD and NASH and also in the prevention in NASH in subjects who are susceptible to develop it such as, for instance, those subjects suffering from the metabolic syndrome, obesity and diabetes, which are known to be contributing factors to the development of NAFLD which progresses to NASH if not treated, leading to cirrhosis and ultimately to death.
  • a method for the treatment of NAFLD and NASH and for the prevention of NASH is also provided, said method comprising administering, to a subject in need thereof, an effective amount of metadoxine.
  • subject refers to an animal, especially a mammal, more particularly to a human being.
  • the invention relates to a new dosage regime, which comprises orally adm inistering MTD once a day, especially for the treatment and/or for the prevention of NASH.
  • the MDT composition is administered once daily, in the morning, advantageously after breakfast.
  • the invention relates to the use of MTD to provide a new therapy for the treatment of Severe Alcoholic Hepatitis (SAH), whereby the survival rate of patients is significantly improved.
  • SAH Severe Alcoholic Hepatitis
  • These patients are classically treated with corticosteroids (such as prednisone) alone.
  • corticosteroids such as prednisone
  • corticosteroids such as prednisone
  • the combination therapy of MTD and corticosteroids improves the survival rate of patients at 90 days by over 300% compared to monotherapy with corticosteroids alone (68% vs 20%).
  • monotherapy with corticosteroids results in death in 80% of SAH patients at 90 days
  • concomittant therapy with MTD results in a marked reduction of death to only 32% at 90 days.
  • MTD is administered in the form of an oral composition according to a dosage regime which provides a once a day administration of approx. 1 ,000 mg to 1 ,500 mg of active ingredient, for instance 1 ,000 mg, 1 ,250 mg or 1 ,500 mg.
  • MTD is co-administered at a daily dose of 1 ,500 mg with a corticosteroid (e.g. prednisone) to patients with Severe Alcoholic Hepatitis (SAH) to improve the survival rate of these patients.
  • a corticosteroid e.g. prednisone
  • SAH Severe Alcoholic Hepatitis
  • metadoxine is administered in the form of an oral composition, especially a scored oral tablet or caplet, or coated pellets (microspheres) in a capsule, comprising approx. 750 mg to 1 ,500 mg, for instance 1 ,000 mg to 1 ,500 mg of active ingredient, in combination with at least one pharmaceutically acceptable carrier.
  • said oral composition is an extended release once daily pharmaceutical formulation, which may be prepared according to any known methods.
  • said concomitant treatment with MTD and prednisone is performed by means of combinations of 40 mg of prednisone and 1 ,000 to 1 ,500 mg of MTD, especially by means of a bilayered scored tablet or caplet, comprising of an immediate release layer containing the active ingredient prednisone 40 mg and an extended release layer containing 1 ,000 to 1 ,500 mg of MTD to be administered once a day.
  • these combinations are fixed dose combinations of 40 mg of prednisone and 1 ,000 of MTD, or 40 mg of prednisone and 1 ,500 mg of MTD.
  • These combinations are prepared according to the methods well known in the art and comprise pharmaceutically acceptable excipients.
  • said composition is administered once daily, preferably in the morning after breakfast.
  • said extended release pharmaceutical formulations may comprise 500 mg to 1000 mg of MTD, advantageously 750 mg of MTD, and they may be administered twice a day.
  • said extended release pharmaceutical formulations may comprise 500 mg to 1000 mg of MTD and approx. 20 mg of prednisone, advantageously 750 mg of MTD and 20 mg of prednisone, and they may be administered twice a day. It was surprisingly found out that these formulations, although they have to be administered twice a day, i.e. at 12 hours intervals, do not cause the typical disturbed sleep in the night, so they are more acceptable for the patients than the conventional formulations.
  • the invention relates to a new oral formulation of MTD and its use in therapy.
  • MTD is administered in the form of a new oral, extended release once daily pharmaceutical formulation, wherein approx. 1 ,000 mg up to 1 ,500 mg of metadoxine is formulated in combination with at least an excipient selected and a polymer selected from a pharmaceutically acceptable cellulose derivative, a pharmaceutically acceptable methacrylate derivative, and their mixtures.
  • extended release once daily pharmaceutical formulation indicates a pharmaceutical formulation that retains the active ingredient for a longer period of time than the conventional compositions and releases it slowly in order to maintain at length the plasmatic concentrations of the drug over a 24-hour period sufficient to exert the desired therapeutic effect.
  • Said formulation is here also called “TEET” (Therapeutic Efficiency Enhancing Technology) formulation.
  • pharmaceutically acceptable cellulose derivative indicates a derivative suitable for prolonging the release time of the drug from the composition, such as pharmaceutically acceptable cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate, hydroxyproplylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, their mixtures and their salts.
  • pharmaceutically acceptable methacrylate derivative indicates a derivative suitable for prolonging the release time of the drug from the composition, for example the copolymer methacrylic acid/methyl methacrylate, the copolymer methacrylic acid/ethyl methacrylate, their mixtures and their salts.
  • a preferred release modulator polymer according to the invention is a pharmaceutically acceptable cellulose derivative, advantageously selected from methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose and their mixtures.
  • the release modulator polymers are used alone or mixed together, in quantities between 75 mg and 250 mg per tablet, preferably between 100 mg and 175 mg, for example, 100, 125, 150 or 1 75 mg, per dosage unit.
  • the new oral formulation is a scored tablet or caplet, comprising approx. 1 ,000 mg to 1 ,500 mg of metadoxine and 50 to 250 mg, preferably approx. 150 mg, of one or more cellulose derivatives, e.g. methylcelluloses and hydroxypropylmethylcelluloses.
  • the formulation of the invention preferably also comprises excipients useful for the processing thereof, for example lubricating agents, filling agent, agents aiding compression and, if necessary or desired, other excipients such as, glidants, disintegrants, granulating agents, adsorbents, plasticizers moisture protecting barriers, etc., well known to a person skilled in the art.
  • excipients useful for the processing thereof for example lubricating agents, filling agent, agents aiding compression and, if necessary or desired, other excipients such as, glidants, disintegrants, granulating agents, adsorbents, plasticizers moisture protecting barriers, etc., well known to a person skilled in the art.
  • Fillers or diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like.
  • Lubricants include, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, and magnesium stearate. stearic acid, hydrogenated vegetable oil, talc and the like.
  • Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and the like.
  • Disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, cross- linked sodium carboxymethylcellulose or croscarmellose sodium, cross-linked calcium carboxymethylcellulose;, guar gum and the like.
  • cross-linked polymers e.g., cross-linked polyvinyl pyrrolidone or crospovidone, cross- linked sodium carboxymethylcellulose or croscarmellose sodium, cross-linked calcium carboxymethylcellulose;, guar gum and the like.
  • Granulating agents include, but are not limited to, polyvinylpyrrolidone, microcrystalline cellulose and the like.
  • the preferred formulation of the invention advantageously also comprises one or more filing agents, such as talc, lactose or microcrystalline cellulose, for example in total quantities of between 5 and 200 mg, for example between 10 and 150 mg, advantageously 10, 50, 70 or 100 mg, per dosage unit.
  • the formulation may also comprise an anti-fibrotic and/or one or more antioxidant agents.
  • the preferred formulation of the invention is preferably in the form of a tablet and can be prepared by mixing the active ingredient, the release modulator polymer (or the mixture of polymers) and any other components and compressing them to an appropriate hardness, according to the methods known in the art.
  • the new formulation is made of an intragranular part and an extragranular part.
  • the intragranular part the active ingredient, the cellulose derivative and one or more further excipients are present, while the extragranular part may comprise for instance a filler and a glidant or lubrificant agent, such as talc and magnesium stearate.
  • the invention comprises a process for preparation of the formulation of the invention, in the form of tablets, which comprises:
  • phase (e) Compressing the mixture (d).
  • in phase (b) compressing is performed to obtain a tablet hardness of between 7 and 9 Kg/cm 2 .
  • phase (d) in phase (d) a lubricating agent and/or a filling agent are mixed.
  • the formulation of the invention can also be formulated in the form of coated pellets (microspheres) in a capsule.
  • the formulations of the invention have undergone various tests to assess their dissolution profile and stability, as well as their in vivo bioavailability.
  • the tests conducted enabled us to conclude that the formulation of the invention, in particular the preferred formulation in the form of a tablet, as defined above, is stable and has an optimal dissolution profile for maintaining the haematic concentration of metadoxine effective for 24 hours.
  • the bioavailability tests conducted on the preferred formulation in the form of a tablet, as defined above provided excellent results and, when compared with the conventional formulations (for example 500 mg two times a day) of metadoxine, they showed improvement in therapeutic efficiency.
  • the formulations of the invention are therefore suitable for administration once a day only instead of the two to three times daily dosage of the conventional formulations.
  • the same extended release pharmaceutical formulations above may comprise 500 mg to 1000 mg of MTD, advantageously 750 mg of MTD, and they may be administered twice a day.
  • All the new extended release formulations above may further comprise a corticosteroid agent, preferably prednisone, advantageously in a 40 mg per day amount, i.e. they may comprise approx. 40 mg of prednisone when administered once a day or approx. 20 mg of prednisone when administered twice a day.
  • a corticosteroid agent preferably prednisone, advantageously in a 40 mg per day amount, i.e. they may comprise approx. 40 mg of prednisone when administered once a day or approx. 20 mg of prednisone when administered twice a day.
  • the new formulation of the invention may be used in the treatment and in the prevention of liver degeneration of any origin, i.e. in the treatment of NAFLD, in the treatment and in the prevention of NASH, as a life-saving drug to significantly increase the survival rate of SAH patients, as well as in the treatment of chronic alcohol intoxication.
  • the new formulation may be used to improve liver functions, to accelerate fatty liver recovery and to reduce steatosis, irrespective of the etiology of the pathology.
  • the new formulation may also be administered to prevent NAFLD and NASH in a subject suffering from metabolic syndrome and/or obesity and/or diabetes.
  • the Applicant carried out an extensive clinical study and found out that metadoxine is extremely effective in the treatment of NASH. Details of the clinical protocol and of the outcomes are reported in the experimental section of this description.
  • Mean change from baseline is -0.76 ⁇ 0.92 grade for metadoxine compared to 0.00 ⁇ 0.76 grade for placebo (p ⁇ 0.01 ).
  • Median change from baseline is - 1 .00 [- 1 .0, 0.0] grade for metadoxine compared to 0.00 [-0.75, 0.0] grade for placebo (p ⁇ 0.01 ).
  • Table lc Baseline distribution of Laboratory Parameters Serum HDL Cholesterol (mg/dL) 43.2 ⁇ 25.3 44.9 ⁇ 22.0
  • Serum Creatinine (mg %) 0.96 ⁇ 0.22 1.00 ⁇ 0.30
  • Insulin resistance was calculated using the homeostasis model assessment for insulin resistance (HOMA-IR) according to the following formula: [glucose (mg dL) x insulin (uU/mL)]/405.
  • ITT analysis includes 50 liver biopsy not cases and 17 lost to follow up cases were replaced with worst outcome at baseline. 1 case been excluded since histology grade unknown at baseline.
  • Severe Alcoholic Hepatitis is a disease with high mortality of up to 50% in two months without treatment.
  • the standard treatment is with a corticosteroid, e.g. prednisone 40 mg daily.
  • a randomized, open clinical trial has been performed to investigate the clinical benefit of Metadoxine in improving the survival rate in SAH patients.
  • Metadoxine also reduced the development or progression of complications (encephalopathy and hepatorenal syndrome).

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  • Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

L'invention concerne l'utilisation de métadoxine dans la prévention et dans le traitement de la stéatose hépatique non alcoolique (NAFLD) et la stéatohépatite non alcoolique (NASH), l'amélioration du taux de survie de patients atteints d'hépatite alcoolique sévère et une nouvelle formulation pharmaceutique à libération prolongée comprenant de la métadoxine.
PCT/EP2013/000183 2012-09-26 2013-01-22 Métadoxine pour utilisation dans le traitement de maladies du foie, et formulations à libération prolongée de métadoxine WO2014048511A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
BR112015006642-9A BR112015006642B1 (pt) 2012-09-26 2013-01-22 Composição farmacêutica de liberação prolongada compreendendo metadoxina e prednisona
MX2015003810A MX2015003810A (es) 2012-09-26 2013-01-22 Metadoxina para usarse en el tratamiento de enfermedades hepaticas y formulaciones de liberacion prolongada de metadoxina.
KR1020157006050A KR20150063040A (ko) 2012-09-26 2013-01-22 간 질환의 치료에 사용하기 위한 메타독신 및 메타독신 연장 방출성 제제
PH12015500353A PH12015500353A1 (en) 2012-09-26 2015-02-18 Metadoxine for use in the treatment of liver diseases, and metadoxine extended release formulations
PH12016501553A PH12016501553A1 (en) 2012-09-26 2016-08-05 Metadoxine for use in the treatment of liver diseases, and metadoxine extended release formulations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP2012004028 2012-09-26
EPPCT/EP2012/004028 2012-09-26

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WO2014048511A1 true WO2014048511A1 (fr) 2014-04-03

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KR (1) KR20150063040A (fr)
BR (1) BR112015006642B1 (fr)
MX (1) MX2015003810A (fr)
PE (1) PE20151323A1 (fr)
PH (2) PH12015500353A1 (fr)
WO (1) WO2014048511A1 (fr)

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Cited By (1)

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CN103976970A (zh) * 2014-06-06 2014-08-13 程奉平 美他多辛缓释片的制备方法

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