MX2015003810A

MX2015003810A - Metadoxine for use in the treatment of liver diseases, and metadoxine extended release formulations.

Info

Publication number: MX2015003810A
Application number: MX2015003810A
Authority: MX
Inventors: Frederick Van Gulik; Yamsani Madhusudan Roa; Shankar Bodapunti Prabha
Original assignee: Eurodrug Lab B V
Priority date: 2012-09-26
Filing date: 2013-01-22
Publication date: 2015-07-17
Also published as: PH12016501553A1; PH12016501553B1; WO2014048511A1; BR112015006642A2; PE20151323A1; KR20150063040A; BR112015006642B1; PH12015500353A1

Abstract

The invention relates to the use of metadoxine in the prevention and in the treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH), in the improvement of the survival rate of patients with Severe Alcoholic Hepatitis and to a new extended release pharmaceutical formulations comprising metadoxine.

Description

METADOXINE FOR USE IN THE TREATMENT OF DISEASES HEPATIC? PROLONGED METADOXINE RELEASE FORMULATIONS FIELD OF THE INVENTION The present invention relates to a new therapeutic use and new indications of metadoxin and a new formulation comprising metadoxin, especially designed for administration once a day.

BACKGROUND OF THE INVENTION Metadoxin (5-oxo-L-proline compound with 5-hydroxy-6-methylpyridine-3,4-dirnethanol (1: 1), hereinafter also referred to as MTD) is a synthetic compound having the following chemical formula: Methadxine 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. The half-life of the drug is 1 hour, and for this reason several administrations during the 24-hour period, in the form of a tablet or solution for oral or parenteral administration.

Pharmaceutical techniques for obtaining prolonged release of drugs have been known for some time, but the prolonged release formulation of metadoxin is not known. In fact, the present inventors have observed that there are significant difficulties in the production of a metadoxin formula that can be administered only once a day and, in particular, have encountered problems correlated with bioequivalence. Several attempts to formulate metadoxine in sustained release systems with different known polymers have not provided the desired results, i.e., a composition that can be administered once a day, bioequivalent to the plasma concentration obtained with the traditional compositions currently on sale. . In fact, at present, dosage units containing 500 mg of active ingredient are currently administered two / three times a day for an average of approximately 1000 mg of active ingredient, a dose considered necessary to maintain the therapeutic blood levels of metadoxin.

In addition, the normal complaint of people who take Methadxine twice a day in a dose of 500 mg is the alteration of sleep at night. This may be attributable to the higher cumulative concentration of methadxine due to the second dose administered at night.

Methadxine has been investigated for its pharmacological effects on the liver, especially in hepatosteatosis. However, to date there is no clinical evidence to evaluate the possible efficacy of metadoxine in the prevention and / or treatment of Non-Alcoholic Liver Disease (NAFLD) and, in particular, Non-Alcoholic Steatohepatitis ( NASH), in which hepatosteatosis is present.

Hepatosteatosis in NAFLD and NASH occurs when fat is deposited in the liver due to factors other than prolonged excessive consumption of alcohol. NAFLD and NASH have been associated with insulin resistance and metabolic syndrome and may respond to treatments originally developed for other insulin resistant conditions (eg diabetes mellitus type 2), such as weight loss and oral antidiabetic agents . NASH is a leading cause of liver cirrhosis of unknown origin.

BRIEF DESCRIPTION OF THE INVENTION 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 metadoxine dosage regimen (MTD), especially in the treatment and / or prevention of NAFLD and NASH.

The third object of the invention is to provide a treatment with metadoxine (BAT) for the reduction of mortality in patients with Severe Alcoholic Hepatitis (SAH).

The fourth object of the invention is to provide a new oral formulation of metadoxin that eliminates the need to take several doses per day, thus improving patient compliance and eliminating the sleep disturbance at night that occurs with the 500 mg in administrations conventional daily multiples, as well as being used in therapy.

DETAILED DESCRIPTION OF THE INVENTION Thus, according to the first aspect, the invention relates to a new use of metadoxin (MTD) for the prevention and treatment of NAFLD and NASH. As for the first aspect of the invention, the metadoxin can be administered in the form of any pharmaceutical composition for oral administration (tablet, capsule, oblong tablet, sachet or syrup), or solution for parenteral administration.

The terms "NAFLD" and "Nash", as used herein with reference to the use of metadoxin, do not include derivatives of NAFLD and NASH, related or in any way associated with liver fibrosis.

Said pharmaceutical compositions are preferably administered in a daily amount ranging from 250 to 2500 mg, advantageously 500 to 1500 mg, more preferably in an amount of approximately 1000 to 1500 mg. Different dosages can however be selected by the doctor according to the age, sex, weight and general clinical conditions of the subject to be treated, as well as the stages diagnosed of NAFLD / NASH.

Said pharmaceutical compositions preferably comprise one or more pharmaceutically acceptable carriers, and are prepared according to methods that are well known to those skilled in the art.

Thus, according to the invention, metadoxin can be used in the treatment of NAFLD and NASH and also in the prevention of NASH in subjects who are susceptible to developing it such as, for example, those subjects suffering from metabolic syndrome, obesity and diabetes, which are known to be the factors that contribute to the development of NAFLD that progresses to NASH if left untreated, leading to cirrhosis and ultimately death.

According to this first aspect of the invention, a method for the treatment of NAFLD and NASH and also for the prevention of NASH are provided, said method comprising the administration, to a subject in need thereof, of an effective amount of metadoxin.

The term "subject", as used herein, refers to an animal, especially a mammal, more particularly to a human being.

According to the second aspect, the invention relates to a new dosage regimen, comprising the oral administration of MTD once a day, especially for the treatment and / or prevention of NASH.

According to a preferred embodiment of this second aspect of the invention, the MDT composition is administered once a day, in the morning, advantageously after breakfast.

According to the third aspect, the invention relates to the use of BAT to provide a new therapy for the treatment of severe alcoholic hepatitis (SAH), whereby the survival rate of patients is significantly improved. These patients are treated classically with corticosteroids (such as prednisone) alone.

Combination therapy of BAT and corticosteroids improves the survival rate of patients at 90 days by more than 300% compared to monotherapy with corticosteroids alone (68% vs 20%). Thus, monotherapy with corticosteroids results in death in 80% of patients with SAH at 90 days, while concomitant therapy with BAT results in a marked reduction in death of only 32% at 90 days.

Although it is well known that once-daily administration improves patient compliance and, as a consequence, leads to better therapeutic results, many medications, including BAT, are often administered two or three times a day, as it is not at all predictable if a single administration is capable of producing the same clinical effect, especially considering that patients who have the metabolic syndrome are subject to multi-drug therapy.

According to the second aspect of the invention, MTD is administered in the form of an oral composition according to a dosage regimen that provides a once-a-day administration of about 1000 to 1500 mg of active ingredient, for example 1000 mg, 1250 mg or 1500 mg.

According to the third aspect of this invention, BAT is coadministered at a daily dose of 1500 mg with a corticosteroid (e.g., prednisone) for patients with severe alcoholic hepatitis (SAH) to improve the survival rate of these patients. It has been shown that 30 days of concomitant treatment with 1500 mg of MTD daily and prednisone significantly improves the survival rate of patients at 90 days compared to monotherapy with prednisone (68% vs 20%). Therefore, it can be concluded that BAT is a life-saving medication, increasing the survival rate by more than 300% at 90 days According to a preferred embodiment of this aspect of the invention, metadoxin is administered in the form of an oral composition, especially an oral scored tablet or capsule, or coated granules (microspheres) in a capsule comprising approximately 750 to 1500 mg, for example 1000 a 1500 mg of active ingredient, in combination with at least one pharmaceutically acceptable carrier.

According to another preferred embodiment of this aspect of the invention, said oral composition is a pharmaceutical formulation of prolonged release once a day, which can be prepared according to any known method.

According to another form of preferred embodiment of this aspect of the invention, said concomitant treatment with MTD and prednisone is carried out by means of combinations of 40 mg of prednisone and 1000 to 1500 mg of MTD, especially by means of a slotted tablet or oblong tablet of two layers, comprising of an immediate release layer containing the active ingredient prednisone 40 mg and a prolonged release layer containing 1000 to 1500 mg of MTD to be administered once a day. Advantageously, these combinations are fixed combinations of doses of 40 mg of prednisone and 1000 mg of MTD, or 40 mg of prednisone and 1500 mg of MTD. These combinations are prepared according to methods well known in the art and comprise pharmaceutically acceptable excipients. According to another form of preferred embodiment of this aspect of the invention, said composition is administered once a day, preferably in the morning after breakfast.

Alternatively, said sustained release pharmaceutical formulations may comprise 500 to 1000 mg of MTD, advantageously 750 mg of MTD, and may be administered twice a day.

As a further alternative, said prolonged-release pharmaceutical formulations may comprise 500 mg to 1000 mg of MTD and about 20 mg of prednisone, advantageously 750 g of MTD and 20 mg of prednisone, and can be administered twice a day. Surprisingly, it has been found that these formulations, although they have to be administered twice a day, that is, at 12-hour intervals, do not cause the typical sleep disturbance at night, so they are more acceptable for the patients. patients than conventional formulations.

According to the fourth aspect, the invention relates to a new oral formulation of BAT and to be used in therapy.

Regarding this fourth aspect of the invention, BAT is administered in the form of a new oral prolonged-release pharmaceutical formulation, once a day, wherein approximately 1000 mg to 1500 mg of methadxine is formulated in combination with at least one excipient selected and a polymer selected from a pharmaceutically acceptable cellulose derivative, a pharmaceutically acceptable derivative of methacrylate, and mixtures thereof.

According to the present invention, "sustained-release pharmaceutical formulation once a day" indicates a pharmaceutical formulation that retains the active ingredient for a longer period of time than conventional compositions and releases it slowly in order to maintain plasma concentrations of the drug. along a 24 hour period, enough to exert the desired therapeutic effect. Said formulation is also here called "TEET" formulation (Teenology of Improvement of Therapeutic Efficiency).

The term "pharmaceutically acceptable cellulose derivative" denotes a suitable derivative for prolonging the time of release of the drug from the composition, such as pharmaceutically acceptable cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate (CAP), trimellitate cellulose acetate. (CAT), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, their mixtures and their salts.

The term "pharmaceutically acceptable methacrylate derivative" denotes a suitable derivative for prolonging the time of release of the drug from the composition, for example, the copolymer of methacrylic acid / methyl methacrylate, methacrylic acid / ethyl methacrylate copolymer, mixtures thereof and its salts.

A preferred release modulator polymer according to the invention is a pharmaceutically acceptable cellulose derivative, advantageously selected from methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and mixtures thereof.

The release modulatory polymers are used alone or in mixtures with each other, in amounts between 75 and 250 mg per tablet or, preferably between 100 mg and 175 mg, for example, 100, 125, 150 or 175 mg, per dosage unit.

According to a mode of advantageous embodiment of this aspect of the invention, the new oral formulation is a labeled tablet or oblong tablet, comprising approximately 1000 to 1500 mg of metadoxin and 50 to 250 mg, preferably approximately 150 mg, of one or more derivatives of cellulose, for example methylcelluloses and hydroxypropylmethylcelluloses.

The formulation of the invention preferably also comprises excipients useful for the treatment thereof, for example, lubricating agents, fillers, compression aids and, if necessary or desired, other excipients such as glidants, disintegrants, granulating agents, adsorbents, moisture protection barriers plasticizers, etc., well known to a person skilled in the art.

Fillers or diluents include, but are not limited to, icing sugar, compressible sugar, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talcum, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic calcium sulfate, 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.

Slippers 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, for example, cross-linked polyvinyl pyrrolidone or crospovidone, cross-linked sodium carboxymethyl cellulose or croscarmellose sodium, crosslinked calcium carboxymethyl cellulose, 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 presentation agents, such as talcum, microcrystalline cellulose or lactose, for example in total amounts 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 antifibrotic 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 modulating polymer (or the polymer mixture) and any other component and compression at an appropriate hardness, in accordance with methods known in the art.

According to a preferred embodiment of this aspect of the invention, the new formulation is made up of an intragranular part and an extragranular part. In the intragranular part, the active ingredient, the cellulose derivative and in addition one or more excipients are present, while the extragranular part may comprise, for example, a filler and a lubricating or sliding agent, such as talc and magnesium stearate.

According to another of its aspects, the invention comprises a process for the preparation of the formulation of the invention in the form of tablets, comprising: to. Mix the methadxine with the release modulator polymer and optionally a filler; b. Pre-compress the mixture (a); c. Grind the compressed mixture in (b); d. Optionally mix the ground mixture in (c); with the other desired excipients; and. Compress the mixture (d).

According to another preferred aspect, in the compression phase (b) is carried out to obtain a tablet hardness of between 7 and 9 Kg / cm2.

According to a further preferred aspect, in step (d) a lubricating agent and / or a filler are mixed.

The formulation of the invention can also be formulated in the form of coated granules (microspheres) in a capsule.

The formulations of the invention have been the object of various tests to evaluate their profile and dissolution stability, as well as their bioavailability in vivo.

The tests carried out allowed 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 a dissolution profile optimal for the maintenance of the effective concentration of metadoxine for 24 hours.

In addition, the bioavailability tests carried out on the preferred formulation in the form of a tablet, as defined above, gave excellent results and, compared to conventional formulations (for example 500 g twice a day) of methadxine, showed improvement in therapeutic efficiency. The formulations of the invention are therefore suitable for administration once a day instead of two to three times daily dosing of conventional formulations.

Alternatively, the same sustained release pharmaceutical formulations above may comprise 500 mg to 1000 mg of MTD, advantageously 750 mg of MTD, and may be administered twice a day.

As stated before, these formulations surprisingly do not cause the typical sleep disturbance, even when administered at night.

All of the new sustained release formulations above may further comprise a corticosteroid agent, preferably prednisone, advantageously in an amount of 40 mg per day, i.e., which may comprise about 40 mg of prednisone when administered once a day or approximately 20 mg of prednisone when administered twice a day.

Representative formulations according to a preferred embodiment of this aspect of the invention are presented in the experimental section of this description.

The new formulation of the invention can be used in the treatment and prevention of liver degeneration of any origin, that is, in the treatment of NAFLD, in the treatment and prevention of NASH, as a drug that saves lives to significantly increase the survival rate of patients with SAH, as well as in the treatment of chronic alcohol intoxication.

So the new formulation can be used to improve the functions of the liver, to accelerate the recovery of fatty liver and reduce steatosis, regardless of the etiology of the pathology.

The new formulation can 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 learned that methadxine is extremely effective in the treatment of NASH. The details of the clinical protocol and the results are reported in the experimental section of this description.

As can be seen, the daily oral administration of 1000 mg of metadoxine, significantly improved the conditions of the treated subjects, in terms of hepatosteatosis and necro-inflammation.

In another clinical study conducted in patients with Severe Alcohol Hepatitis (SAH), it has been shown that at 30 days of concomitant therapy with 1500 mg of MTD per day and 40 mg of prednisone per day, significantly improved the survival rate of patients compared to those who received monotherapy with Prednisone Survival was evaluated at 30 and 90 days. In the group that received BAT survival at 30 days, it was 74.3% compared to 45.7% (p = 0.02); and survival at 90 days was 68.6% vs 20% (p = 0.0001).

Experimental section Example 1 Once-daily 1000 mg metadoxine extended-release tablet Example 2 Extended release tablet of 1500 mg of metadoxin Example 3 Long-Acting Tablets of 750 mg of metadoxin Example 4 Fixed-release combination of extended-release tablet of 750 mg metadoxin and 20 mg of prednisone Example 5 Clinical study in NASH A total of 134 patients were included in the randomized double-blind, placebo-controlled prospective study. Patients were randomized into two groups, receiving metadoxin (75) or placebo (59), and were treated for 16 weeks. 9 patients abandoned the treatment before the end of the study in the methadxine group and 8 stopped it in the placebo group. The analysis by protocol of the cohort of 82 patients who have paired biopsies (n = 82) before and after treatment show that 1000 mg / day of metadoxin is significantly effective in reducing hepatosteatosis (accumulation of fat in the liver). Reduction of hepatosteatosis is reported in 34 patients (73.9%) in the methadxine group compared to 25% of those in the placebo group (p <0.01). The mean change from the baseline is -0.76 + 0.92 degrees for metadoxin compared to 0.00 + 0.76 degrees for placebo (p <0.01). The mean change from the baseline is -1.00 [-1.0, 0.0] degrees for metadoxine compared to 0.00 [-0.75, 0.0] degrees for the placebo (p <0.01).

Reduction of necroinflammation was reported in 58.8% of patients in the Metadoxine group compared with 46.9% in the placebo group, a difference of 12%. Although the difference is not statistically significant (p = 0.331), there is a marked improvement in the Methadxine group, which indicates that the recovery takes longer, which requires a longer duration of therapy, possibly up to a year.

The analysis by intention to treat the whole group is presented in the following tables.

Table la: Baseline characteristics of the subjects Table 1 b: Baseline distribution of the symptoms Table: Baseline distribution of laboratory parameters Etadoxin factor (N = 75 Placebo (N = 59) WBC toral (cells / cmm) 8039.0 + 4488.0 7380.2 + 1612.0 7700. 0 [6400.0, 7200.0 [6300.0, 8550. 0] 8500.0] % P 55,419.5 55,219. 9 % L 37.0110.4 37,019. 9 % E 4.0412.4 3.92 13.4 4. 0 [2.0, 5.0] 3.0 [2.0, 5.0] % B 0.4111.28 0.31 + 0.84 % M 3.1713.5 3.5113.9 2. 0 [0.0, 7.0] 2.0 [0.0, 7.0] Hb (g / dL) 13,711.6 13. 911.7 Platelets (cells / 228753.4183229.1 230862.8177800.3 ALT (IU / L) 96.2159.3 101.9165.8 80. 0 [55.5, 128.0] 83.5 [55.5, 129.3] AST (IU / L) 67.5151.5 64.9135.8 54. 0 [38.0, 76.5] 62.0 [38.0, 80.5] SAP (IU / L) 139. 6190.3 148. 91121.2 112. 0 [71.5, 107.0 [69.5, 187. 5] 175.5] GGT (IU / L) 55. 6145.3 51. 9140.5 46. 5 [32.0, 64.4] 43.2 [34.1, 52.5] Serum bilirubin 1.1911.19 1.0210. 62 0. 86 [0.60, 1.15] 0.80 [0. 60, 1.39] Total protein (mg / 7.4810.70 7.6010.72 Serum albumin (gm / dL) 4.3710.54 4.2810.40 Blood glucose in 100. 6128.6 102.8131.5 fasting (mg / dL) Total serum cholesterol 193. 9144.7 201.4140.4 fasting (mg / dL) LDL cholesterol in serum in 121. 9139.3 125.4146.0 fasting (mg / dL) HDL cholesterol in serum 43. 2125.3 44.9122.0 (mg / dL) 39. 0 [32.0, 48.0] 40.8 [34.0, 47.8] Total Serum of fasting triglycerides 207.01138.6 196.41130.7 (mg / L d) 164. 5 [125.0, 163.0 [123.0, 228.8] 230.0] Serum Feritin 159.51114.0 247.01214,3 230. 0 [92.8, 120. 0 [82.2, 230] 320. 0] Insulin serum 15.6117.6 16.5116.9 11. 2 [8.2, 18.3] 10.8 [6.1, 17.8] Serum creatinine (mg%) 0.9610.22 1.0010.30 Serum Urea (mg%) 24,317.8 26,718.4 HOMA - IR 3.9314.21 4.0514.03 Table Id: Baseline distribution of vital signs and physical examination ; : Table: Baseline distribution of results ' Data presented as mean ± SD, median [25th, 75th percentiles] or N (%).

Insulin resistance was calculated using the homeostasis model assessment for insulin resistance (HOMD-IR) according to the following formula: [glucose (mg / dl) x insulin (uU / mL)] / 405.

Necroinflammatory stage, results in the metadoxine group ITT Analysis: 74 patients included in the analysis of the results > 34 baseline lines were submitted and biopsies at the end of the study • 1 unknown baseline biopsy 40 did not have a biopsy at the end of the study and were considered without "any improvement" taking the worst case. • 2 died during follow-up • 4 unanswered • 3 others 31 completed the study but without final biopsy PP Analysis: 34 patients included in the analysis of the results Necroinflammatory stage, results in the placebo group ITT Analysis: 59 patients included in the analysis of the results > 32 baseline lines were submitted and biopsies at the end of the study 27 did not have a biopsy at the end of the study and were considered without "any improvement" taking the worst case. • 1 died during follow-up • 5 unanswered • 2 other • 19 completed the study, but without final biopsy PP Analysis: 32 patients included in the analysis of the results Stage of steatosis, results in the methadxine group ITT Analysis: 75 patients included in the analysis of the results > 46 baseline lines were submitted and steatosis tests at the end of the study 29 patients did not have the biopsy at the end of the study and were considered without "no improvement" taking the worst case. • 2 died during follow-up • 4 unanswered • 3 Other • 20 completed the study, but without final biopsy PP Analysis: 46 patients included in the analysis of the results Stage of steatosis, results in the placebo group ITT Analysis: 59 patients included in the analysis of the results > 36 baseline lines were submitted and steatosis tests at the end of the study 23 did not have the biopsy at the end of the study and were considered without "no improvement" taking the worst case. • 1 deceased during follow-up • 5 Unanswered • 2 Other • 15 completed the study, but without final biopsy PP Analysis: 36 patients included in the analysis of the results Table 2: Primary efficacy analysis - average of -0.7110.76 -0.5010.67 0.249 0.0910.95 0.1010.87 0.965 base line Change of 0.0 [-1.0, 0. 0 [0.0, 0.0 [0.0, 0. 256 0.883 median of 0.0] Data presented as mean ± SD, median [25th, 75th percentiles] or N (%).

Change of mean of the midline, Change of median of the baseline were tested using the Student's T test of Independent Sample and the Mann Whitncy test respectively.

ITT analysis included 50 cases without liver biopsy and 17 deaths in the follow-up cases were replaced with worse outcome in the baseline.1 It has almost been excluded due to an unknown histological grade in the baseline.

The P values in% improvement were calculated using Pearson's chi-square.

Table 3: Adverse effects reported in each week due to the intervention Example 6 Clinical Study in SAH Severe alcoholic hepatitis (SAH) is a disease with a high mortality of up to 50% in two months without treatment. The standard treatment is with a corticosteroid, for example, 40 mg of prednisone per day. An open, randomized clinical trial has been conducted to investigate the clinical benefit of Metadoxin in improving the survival rate in patients with SAH.

A total of 217 patients were selected, of which 70 patients participated in the clinical study. The patients were randomly assigned to two treatment groups. The first group of 35 patients received standard monotherapy of 40 mg prednisone per day for 30 days. The second group of 35 patients received combination therapy of 40 mg of prednisone per day plus 500 mg of methadxine three times a day for 30 days. Survival was evaluated at 30 and 90 days respectively. A significant improvement was observed in the group of patients who received Metadoxin: • At 30 days, the survival rate was of 74.3% in the combination therapy group (prednisone plus methadxine), in comparison with 45.7% in the monotherapy group (prednisone alone) (p = 0.02), • At 90 days, the survival rate was 68. 6% in the combination therapy group (prednisone plus methadxine), compared to 20% in the monotherapy group (prednisone alone) (p = 0.0001), Methadxine also reduced the development or progression of complications (encephalopathy and hepatorenal syndrome).

Claims

NOVELTY OF THE INVENTION Having described the present invention as above, it is considered as a novelty and, therefore, the content of the following is claimed as property: CLAIMS

1. Metadoxine for use in the prevention and treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH).

2. Metadoxine to be used in combination with a corticosteroid, to increase the survival rate of Severe Alcohol Hepatitis (SAH) in patients.

3. Metadoxin for use according to claim 2, wherein said corticosteroid is prednisone.

4. Metadoxin for use according to claims 1 to 3, characterized in that it is administered in a daily amount of 250 to 2500 mg.

5. Metadoxin for use according to claim 4, characterized in that it is administered in a daily amount of about 1000 to 1500 mg.

6. Metadoxin for use according to claim 5, characterized in that it is administered once a day, in the morning.

7. Metadoxine for use according to any of claims 1 to 6, for the prevention of NASH in a subject suffering from metabolic syndrome and / or obesity and / or diabetes.

8. A pharmaceutical composition comprising 1000 to 1500 mg of metadoxine in combination with at least one pharmaceutically acceptable excipient.

9. A prolonged release pharmaceutical composition comprising 750 to 1500 mg of metadoxine in combination with at least one excipient, a polymer selected from a pharmaceutically acceptable cellulose derivative, a pharmaceutically acceptable methacrylate derivative, their mixtures.

10. The pharmaceutical composition according to claim 9, characterized in that said cellulose derivatives are hydroxypropylmethylcelluloses.

11. The pharmaceutical composition according to any of claims 8 to 10, characterized in that said hydroxypropylmethylcelluloses are present in an amount of 50 to 250 rag.

12. The pharmaceutical composition according to any one of claims 8 to 11, characterized in that it further comprises one or more lubricating agents, filler, compression aids, glidants, disintegrants, granulating agents, adsorbents, protective barriers, moisture plasticizers.

13. The pharmaceutical composition according to any of claims 8 to 12, characterized in that it is a pharmaceutical formulation of prolonged release once a day.

14. The pharmaceutical composition according to any of claims 8 to 13, which has the following composition:

15. The pharmaceutical composition according to any of claims 8 to 13, which has the following composition:

16. The pharmaceutical composition according to any of claims 9 to 13, which has the following composition:

17. The pharmaceutical composition according to any of claims 8 to 16, characterized in that it comprises coated granules (microgranules) encapsulated in a capsule.

18. The pharmaceutical composition according to any of claims 8 to 16, characterized in that it further comprises an immediate release layer comprising a corticosteroid.

19. The pharmaceutical composition according to claim 14 or 15, characterized in that it also comprises 40 mg of prednisone.

20. The pharmaceutical composition according to claim 16, characterized in that it also comprises 20 mg of prednisone.

21. The pharmaceutical composition according to claim 19 or 20, which is a two-layered or oblong tablet, comprising an immediate release layer comprising prednisone and a second prolonged release layer comprising metadoxin, both layers optionally also they comprise pharmaceutically acceptable excipients.

22. A pharmaceutical composition according to any of claims 8 to 21, for use in the treatment and prevention of liver degeneration of any origin.

23. The pharmaceutical composition for use according to claim 22, for the treatment and / or prevention of NASH and Hepatic Alcohol Steatosis.

24. The pharmaceutical composition for use according to claim 23, for the prevention of NASH in a subject suffering from metabolic syndrome and / or diabetes.

25. The pharmaceutical composition for use according to claim 24, for improving the survival rate of patients with SAH, whereby the Methadxine is used as a combination therapy with a corticosteroid.

26. The pharmaceutical composition for use according to claim 25, wherein said corticosteroid is prednisone.

27. The pharmaceutical composition according to any of claims 8, 14, 15 and 19, characterized in that it is administered once a day.