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  • 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
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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• • A—HUMAN NECESSITIES
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  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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  • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

• Hepatic encephalopathy also known as portosystemic encephalopathy, is a severe complication of acute or chronic liver failure.
• hepatic encephalopathy negatively impacts patient survival. About 30% of patients dying of end-stage liver disease experience significant encephalopathy, approaching coma.
• Hepatic encephalopathies can be subdivided in type A, B and C depending on the underlying cause.
• Acute liver failure is a rapid deterioration (within days and weeks) of liver function in a person who had no preexisting liver disease.
• Acute liver failure is commonly caused by paracetamol (acetaminophen) overdose, idiosyncratic reaction to medication (e.g. tetracycline, troglitazone), autoimmune causes, viral hepatitis (hepatitis A or B), acute fatty liver of pregnancy, or can be idiopathic.
• the blood thus by-passes the liver, which therefore cannot metabolize and clear blood substances which can be toxic like ammonium.
• Type B usually occurs as a result of congenital abnormalities and/or as a result of an invasive procedure or trauma.
• Cirrhosis occurs in patients with cirrhosis. Cirrhosis is a late stage of chronic liver disease when scarring (fibrosis) develops. The major causes of cirrhosis are:
• NASH Non Alcoholic Steato Hepatitis alpha-1 -antitrypsin deficiency, galactosemia and glycogen storage disorders
• PBC primary biliary cholangitis
• PSC primary sclerosing cholangitis
• Type-C HE can be subdivided in episodic (return to normal neural state between episodes), persistent (no return to normal neural state) and minimal encephalopathy (Bajaj, Aliment Pharmacol Ther. 2010 Mar;31 (5):537-47).
• Minimal encephalopathy is an encephalopathy that does not lead to clinically overt cognitive dysfunction, but can be evidenced using neuropsychological tests, and has been demonstrated to impair quality of life and to increase the risk of involvement in road traffic accidents.
• HE may affect 30-70% of patients with cirrrhosis ; overt HE (either episodic or persistent) is observed in 30-45% of patients with cirrhosis during their lifetime. It is to be noted that HE, even minimal, is an independant risk of mortality.
• Ammonia may have a central key role, together with systemic inflammation and changes in specific carriers on the blood-brain barrier. Hepatic encephalopathy could be a consequence of accumulation in the bloodstream of toxic substances, in particular ammonia, that are normally cleared by the liver. Ammonemia is not sufficient to induce HE. It is hypothetized that a combination of both increased blood ammonia and inflammation is necessary for HE to occur, in particular by a modification of the blood-brain barrier leading to intracerebral accumulation of toxic substances and modulation of neurotransmission.
• lactulose (beta-galactosidofructose) or lactilol (beta-galactosidosorbitol) are given to patients to accelerate the transit and to inhibit intestinal ammonia production. These are nonabsorbable disaccharides that are degraded by intestinal bacteria to lactic acid and other organic acids. Lactulose is administered to patients at a dose of 30 mL orally, daily or twice daily, and the dose may be increased, or reduced, depending on the tolerance or adverse effect observed in the patients.
• Lactulose is given after the first episode of hepatic encephalopathy to prevent recurrence.
• Antiobiotics are also used, in order to decrease the ammoniagenic bacterial load.
• Antiobiotics are generally used if treatment with lactulose is not effective enough and in secondary prevention.
• Rifaximin a nonabsorbable derivative of rifampin with a broad spectrum antibacterial activity. It can reduce endotoxemia, including hyperammonemia, by reducing the intestinal translocation of bacteria. Used in a number of trials, rifaximin effect was equivalent or superior to the compared agents with good tolerability.
• the recommended posology is 550 mg twice a day.
• LOLA can also be used to increase ammonia clearance. It may be combined with lactulose and/or rifaximin.
• Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate, and glycerol phenylbutyrate may also be used for the treatment of hepatic encephalopathy.
• the oral doses of sodium benzoate are about 5 g twice a day, although lower doses (2.5 g three times a week) may also help patients recover from symptoms of hepatic encephalopathy.
• Glycerol phenylbutyrate may be used at an oral dose of 6 ml twice-daily.
• Nutritional intervention is necessary in case of malnutrition or insufficient dietary intake. Eating vegetables proteins rather than proteins derived from red meat, and chicken and fish proteins may be favourable. It is also advised to supplement the diet with branched-chain amino acids. Zinc administration can also be used, with the potential to improve hyperammonemia, with zinc sulfate and zinc acetate that can be administered at a dose of 600 mg orally every day. L-carnitine is also used to improve hepatic encephalopathy symptoms, in particular in patients with cirrhosis.
• WO 201 1 /124571 describes the use of biotin at a high dose (in the range of 100 to 600 mg/day) for the treatment of visual impairments, in particular related to optic atrophy. It should be noted that the visual impairments actually described in this application are symptoms related to a particular leukoencephalopathy, i.e. an involvement of the white matter of the brain. This document neither describes nor suggests that biotin could be used for the treatment of HE.
• WO 2014/016003 describes the use of biotin at a high dose (of the order of 100 to 600 mg/day) for the treatment of multiple sclerosis (MS), stroke and X-linked adrenoleukodystrophy (X-ALD), in particular adrenomyeloneuropathy (AMN).
• MS multiple sclerosis
• X-ALD X-linked adrenoleukodystrophy
• APN adrenomyeloneuropathy
• WO 2014/177286 provides evidence that biotin is useful for treatment of AMN.
• WO2016151 132 provides evidence that biotin is useful for treating amyotrophic lateral sclerosis (ALS).
• ALS amyotrophic lateral sclerosis
• JPH01226814A the biotin is provided as a signle intraperitoneal shoot of 1 mg of biotin. Results are reported for human, with doses used therein in the range of a few mg (about 5-1 Omg) per day. The results reported for the patients are, however, not conclusive. Indeed, there is a high natural variability of the general state and of the ammonia level in the serum of patients with HE. Tables 7 and 8 only report data obtained during 10 days, without any control or information about other treatments that the patients received. From patient 2, it can be seen that there is a high variability in the ammonia level (rising and decreasing) for the first 5 days, even tough this patient did not receive any biotin during this timespan.
• biotin in the context of the present invention, it is proposed to use biotin, at a much higher dose, in order to improve the condition of patients suffering from hepatic encephalopathy.
• biotin at a high dose (a higher dose than the one presented in the prior art) can be useful for hepatic encephalopathy treatment and could ultimately limit the evolution of the disease, and even revert some symptoms thereof is particularly novel and surprising.
• the invention therefore relates to biotin for use thereof in the treatment or prevention of hepatic encephalopathy, wherein the biotin is very preferably used a a high dose, i.e. at least 100 mg per day. It is preferably used at a daily dose higher than 100 mg.
• compositions containing biotin for the use thereof in the treatment of hepatic encephalopathy and also the use of biotin for the production or manufacture of a drug intended for the treatment of hepatic encephalopathy.
• the drug shall contain more than 20 mg, more preferably more than 40 mg, more preferably more than 50 mg, more preferably more than 70mg, more preferably about or exactly 100 mg of biotin, in particular when used by oral administration.
• the teachings of the invention thus make it possible to implement treatment methods comprising the administration of biotin to patients suffering from hepatic encephalopathy.
• the invention thus also relates to a method for treating a patient suffering from hepatic encephalopathy, comprising the step of administering biotin to said patient. Examples of dosage of biotin, and treatment regimen are disclosed below.
• Biotin can be used alone or in combination with another compound used for treating hepatic encephalopathy (or symptoms thereof).
• the invention therefore covers a composition containing biotin and also another medicament, as listed above, against hepatic encephalopathy, for simultaneous, separate or sequential (spread out over time) use in the treatment of a hepatic encephalopathy.
• the invention also describes and relates to a method of treating a patient suffering from hepatic encephalopathy, comprising the steps of providing biotin to said patient, and optionally (but preferably) another drug useful for providing relief to said patients with regards to the symptoms of hepatic encephalopathy.
• Biotin can, in particular, be used to improve cognitive and psychomotor processing speed, memory and motor control and coordination.
• biotin Treatment with biotin can also lead to increase of the weight of the patient.
• the biotin is preferably used for treating type C hepatic encephalopathy, whether persistent, episodic or minimal.
• biotin may be used in patient with type A or type B hepatic encephalopathy to decrease the symptoms before the situation comes back to normal.
• Administration of biotin to type A patients would allow these patients to wait for a longer time before receiving a liver graft and/or to be in a better condition when receiving it.
• Biotin can also be used for preventing episodes of hepatic encephalopathy. In particular such prevention is useful in patients with diagnosed cirrhosis, whether they have already presented an episode of HE (i.e. whether they have episodic or persistent HE) or whether they have not been diagnosed with HE (they have not presented any episode of HE symptoms, or no clinical sign of HE), and thus have minimal HE or no HE at all.
• HE hepatic encephalopathy
• Biotin at a high dose is particularly interesting to prevent secondary episodes of HE, in patients that have already presented an episode of HE.
• biotin may be used as follows.
• the biotin is preferentially administered at a therapeutically effective amount, which is generally a high dose, i.e. at a dose of at least or about or exactly 100 mg per day. Even if a maximum dose is not really envisaged, the latter should not generally exceed 500 mg, 600 mg or 700 mg per day. This makes it possible to observe improvement in the condition of the patient, and/or stop or decrease of the worsening of the condition of the patient.
• the physician may determine the dose according to the weight of the patient.
• a dose at least equal to 1 mg/kg/day, preferably 3 mg/kg/day, preferably 5 mg/kg/day, or at least equal to 7.5 mg/kg/day, or even around 10 mg/kg/day, is administered to the patient.
• biotin per day are thus preferably administered to the patients, generally between 100 and 500 mg per day, or between 100 and 600 mg per day, more preferably between 100 and 300 mg per day, generally around or exactly 300 mg per day.
• the biotin is in a form suitable for oral administration.
• a composition for oral administration which will contain at least or about or exactly 20 mg, preferably at least or about or exactly 40 mg of biotin, or even at least or about or exactly 50 mg, at least or about or exactly 75 mg, at least or about or exactly 100 mg, at least or about or exactly 150 mg or at least or about or exactly 250 mg of biotin, or at least or about or exactly 300 mg of biotin.
• This composition is preferentially for pharmaceutical use, and is therefore a medicine.
• each unit dose of this composition contains at least or about or exactly 20 mg, preferably at least or about or exactly 40 mg, or even at least or about or exactly 50 mg, at least or about or exactly 100 mg, at least or about or exactly 150 mg or at least or about or exactly 250 mg of biotin or about or exactly 300 mg of biotin, as active ingredient.
• the total dose of biotin may be administered once a day, or through multiple intakes. In particular, biotin may be taken through two or three intakes a day. It is preferred when biotin is taken around meal times, and when the amount of biotin is substantially the same for each intake.
• the diseases herein described are chronic diseases, with worsening over time. It is thus preferable that treatment with biotin is performed in the long run, in order to be the most effective, to prevent the occurrence of new HE episodes and to stabilize any improvement that it will bring. Consequently, it is preferred when said treatment with biotin has a duration of at least 3 months. It is even preferred when said treatment with biotin has a duration of at least 6 months. As indicated, such treatment may be extended as long as possible in order to prevent the occurrence of new HE episodes, increase the improvement that could bring biotin, and stabilize the therapeutic effects. In particular, said treatment with biotin has a duration of at least one year. There is no envisioned end for the treatment and it is expected that the patient will take biotin as long as it is needed and will stabilize or improve the condition of the patient.
• this composition for oral administration contains biotin as sole active ingredient, and also excipients, without any other active ingredient.
• excipient should be understood to mean any compound being part of the formulation which is intended to act as a simple support, i.e. which is not intended to have a biological activity.
• composition can be in any form known in the art.
• it is in the form of gel capsules, tablets (optionally film-coated), pills or lozenges.
• it is in the form of a syrup.
• Said syrup contains an amount such that it contains at least or about or exactly 20 mg, preferably at least or about or exactly
• biotin per unit dose 40 mg, or even at least or about or exactly 50 mg, at least or about or exactly 75 mg or at least or about or exactly 100 mg of biotin per unit dose.
• concentration of biotin in this syrup depends on the unit dose that it is desired to give to the patient. Excipients which can be used by those skilled in the art are well known in the art. Talc (E553b), microcrystalline cellulose, lactose, mannose, starch (in particular corn starch), magnesium stearate (E572) and stearic acid (E570) can thus be chosen. This list is not exhaustive.
• a preferred excipient is microcrystalline cellulose.
• said film-coating may be formed from any substance known in the art, such as hypromellose (E464), ethylcellulose, macrogol, talc (E553b) titanium dioxide (E171 ) or iron oxide (E172).
• the active ingredient may also be colored (by any acceptable coloring, such as cochineal), thereby making it possible to verify that the biotin is well dispersed in the excipient.
• a slow release (or slow sustained) form may also be envisaged given the fact that plasma half life of biotin is short (about 2 hours).
• said slow release compositions are known in the art and described in particular in WO 201 1/077239.
• said slow release compositions may comprise a slow release matrix comprising biotin alone or with one or more active ingredient(s).
• the slow release composition comprises a matrix allowing immediate release, wherein said matrix comprises biotin alone or with one or more other active ingredient(s) and the slow release is achieved by a release modifying matrix or coating.
• the slow release composition may provide immediate release and differed (slow) release of biotin.
• slow release may be achieved through an osmotically driven release system.
• the slow release composition comprises a core comprising biotin, optionally one or more active ingredient(s), and optionally pharmaceutical excipient(s) and one or more outer layers, wherein the outer layers comprises one or more slow release agent(s).
• the biotin may be in the form which allows administration by injection: this then involves an injectable composition containing at least or about or exactly 20 mg, preferably at least or about or exactly 40 mg, or even at least or about or exactly 50 mg, at least or about or exactly 75 mg, at least or about or exactly 100 mg, at least or about or exactly 150 mg or at least or about or exactly 250 mg of biotin per unit dose.
• This injectable composition may be in the form of a vial containing the biotin, and also acceptable excipients.
• concentration of biotin is adjusted according to the envisaged volume of the vial. Certain excipients which improve biotin solubility can be used.
• the excipients that can be used for the production of injectable compositions are well known in the art. Mention may in particular be made of sodium dihydrogen phosphate, sodium bicarbonate (E550i), methyl para-hydroxybenzoate (E218) and propyl para-hydroxybenzoate (E216), which can be used together in proportions that those skilled in the art are capable of determining.
• the water used is water for injection. The injection is preferably carried out intramuscularly. It can also be carried out intravenously.
• Figure 1 levels of ASAT (A), ALAT (B), bilirubin (C) and albumin (D) in the serum of control (sham) or bile duct ligated (BDL) rats.
• Figure 2 6 minutes comportmental analysis of control and BDL rats without or with a water enriched in NH3.
• Figure 3 blood ammoniemia in control (sham) or BDL rats (A) or in rats injected with oil (control rats) or CCI 4 (B).
• Figure 4 levels of ASAT (A), ALAT (B), bilirubin (C) and albumin (D) in the serum of control (oil) or rats injected with CCI 4 .
• Figure 5 6 minutes comportmental analysis of control (oil) and rats injected with CCI 4 .
• Figure 6 blood ammoniemia in control or BDL rats fed wih placebo or with biotin (300 mg/kg in food, corresponding to a daily dose of 30mg/kg BW/day in rats or 300mg/day in humans).
• Figure 7 6 minutes comportmental analysis of control (sham) or BDL rats, with a diet without or with biotin (dose corresponding to 300 mg in human).
• Figure 8 6 minutes comportmental analysis of control and BDL rats without or with a diet enriched biotin (2 dosages corresponding to daily dose of 50 mg or 300 mg in human).
• Figure 9 blood-brain barrier permeability observed by penetration into the CNS of Texas red coupled todextran.
• Figure 10 blood-brain barrier permeability observed by penetration into the CNS of Texas red coupled to dextran.
• Figure 1 1 Mesure of serum IFN gamma (A) or TNF alpha (B) in control animals, BDL animals and CCI 4 animals with or without NH3-enriched water.
• HE+ animals showing comportmental signs of hepatic encephalopathy;
• HE- animals not showing signs of hepatic encephalopathy.
• Figure 12 Mesure of serum IFN gamma (A), TNF alpha (B) or IL 6 (C) in control animals, BDL animals with or without NH3-enriched water and/or biotin (300 mg/kg food) enriched diet.
• Example 1 Study in the rat bile duct ligation model plus hyperammonemic (NH3- enriched) water
• Rats with bile duct ligation is a model of cholestatic liver injury with associated oxidative stress and fibrogenesis. These rats develop progressive hepatic injury with the onset of fibrosis within 2 weeks and the development of biliary cirrhosis within 4-6 weeks. When given hyperammonemic supplements, more bile duct ligated rats develop encephalopathy.
• biotin is evaluated in bile duct ligated rats treated with hyperammonemic water regarding clinical efficacy in terms of orientation in open- field and body weight gain.
• sham-operated rats treated with either 1 ) control diet and control water; 2) control diet and hyperammonemic (NH3-enriched) water; 3) biotin-supplemented diet and control water; and 4) biotin-supplemented diet and hyperammonemic water.
• bile duct-ligated rats treated with either 1 ) control diet and water; 2) control diet and hyperammonemic water; 3) biotin- supplemented diet and control water; and 4) biotin-supplemented diet and hyperammonemic water.
• the dose of biotin used is 30 mg/kgBW/day which is equivalent to a human dose of 300 mg/day.
• Example 2 Another model of hepatic encephalopathy in rats is the model of liver fibrosis induced CCU plus hyperammonemic water
• Rats administered with CCI 4 have hepatotoxicity mediated by free radical production. These rats develop progressive hepatic injury with development of cirrhosis within 8 weeks.
• Bile duct ligation was used as a biliary cirrhosis model. All rats oh this group were operated on. They were randomly separated in two groups : BDL or simple laparotomy (SHAM, control-group). The BDL procedure was conducted as described previously (Kountouras J, Prolonged bile duct obstruction : a new experimental model for cirrhosis in the rat ; Br J Exp Pathol 1984) and as controlled in our lab.
• CCI 4 carbon tetrachloride
• Wistar rats received CCI 4 1 ml/kg body weight twice weekly for 8 weeks in mineral oil.
• Controls received mineral oil without CCI 4 .
• Treatments were administred intragastrically by gavage using a polyethylene catheter, without sedation.
• CCI 4 used in this experiment is below the dose used in Nagamine, which is more a model of acute liver injury (type A HE).
• type A HE acute liver injury
• use of a lower dose over a longer time makes it possible to better mimic pregressive liver injury and thus type C HE.
• the aim of this regimen was to produce chronic hyperammonemia.
• Rifaximin is an oral non-absorbable antibiotic validated in human to prevent recurrence of HE in association with lactulose.
• the exact mechanism of action is not well known but it supposed to decrease hyperammonemia and bacterial translocation because of its role on gut microbiota.
• Rifaximin (Sigma Aldrich) was mixed with water at the dose of 50 mg/kg/d and began 3 days after the surgery.
• Sodium benzoate validated in genetic disorder of urea cycle, was also mixed with water at the dose of 200 mg/kg/d and began 3 days after the surgery.
• Biotin was given mixed in animal food at a dose of 50mg/kg or 300mg/kg of food, corresponding to an ingested dose of 5mg/kg of animal/day or 30mg/kg of animal/day and a daily dose of 50mg or 300 mg in human.
• biotin is provided to the animals prior to inducement of HE, as the animals only experience one HE episod and quickly die after the development of HE following Bile Duct Ligation. Therefore, in this animal model, biotin can't be provided after surgery to study the ability of biotin to prevent a second HE episod. Survival of the animals was not studied as the animals were sacrified to study the Blood-Brain Barrier permeability. Behavioral Test
• the data analyzed after 6 minutes of experiments were : total distance travelled (cm), time of mobility (s), speed (cm/s), number of zone changes, distance travelled in the center and periphery zone, time spent in the center and periphery zone, number of rearing, total duration of rearing.
• BBB The integrity of BBB was investigated by measuring the extravasation from intravascular compartment of dextran-Texas Red (Life Technologies) conjugated.
• the brain was rapidly removed and the olfactory bulbs and brain stem eliminated with the cerebellum.
• the amount of fluorescent dextran ⁇ g/g) in supernatants was measured by fluorimetry (Tecan Infinite M200) at 620 nm upon excitation at 588 nm.
• the content of dye was valued by interpolation in standard curve.
• Plasmatic cytokines (IL6, TNFa, IFNg) were determined by a multiplex commercial kit.
• livers were extracted and weighted ; then we did a biopsy of the organ to determine the fibrosis status, confirm cirrhosis by a Sirius red coloring after fixing in 10% formalin.
• BDL and CCI 4 rat models both have cirrhosis. Extensive fibrosis and a destroyed architecture of the liver parenchyma can be observed, classified F4 with the METAVIR score. Consistently, the plasma hepatic markers are changed in the two models and differences between the two models reflects the rare of the liver disease. In BDL, the preponderant alteration is hyperbilirubinemia, whereas in CCI 4 it is transaminase (ASAT and ALAT) elevation ( Figure 1 and 4). Both BDL and CCI 4 rat models develop hyperammonemia ( Figure 3).
• the OpenField test shows that BDL rats develop neurological impairements: a significant shorter total distance travelled, a shorter duration of activity, a slower velocity, and less and shorter rearings, were observed, compared to Sham rats. These abnormalities were not found in CCI 4 rats. This suggests that BDL rats displayed HE in the OpenField test but not CCI 4 rats ( Figures 2 and 5).
• BDL rats have a significant increase in the intra-cerebral quantity of dextran-TexasRed compared to Sham even when not fed with a NH3-enriched water; this result was not confirmed in CCI 4 rats compared to those who received only mineral oil (Figure 9 and 10). This suggests that BDL rats would have an increased blood-brain barrier permeability to solutes.
• the CCI 4 model herein disclosed is different from the CCI 4 model disclosed in Nagamine et al or JPH01226814A which is a model of acute hyperammonemia with a single high dose shot.
• small doses of CCI 4 are administered to the animals over a few days to more closely mimick a chronic disease.
• BDL rats have increased BBB permeability, but not CCI 4 rats.
• Biotin provided at 30 mg/kg of animal /day (corresponding to a daily dosage of 300 mg in humans), but not biotin provided at 5 mg/kg of animal /day (corresponding to a daily dosage of 50 mg in humans) improves the animal's condition in terms of comportmental improvement and normalization of BBB permeability and would thus prevent development of HE.
• biotin acts by decreasing ammonemia and modulating inflammatory profile.

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Plural Heterocyclic Compounds (AREA)
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• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2016
  • 2016-07-29 EP EP16305989.2A patent/EP3275439A1/en not_active Ceased
• 2017
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  • 2017-07-28 AU AU2017303346A patent/AU2017303346A1/en not_active Abandoned
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  • 2017-07-28 KR KR1020197002991A patent/KR20190034550A/ko not_active Withdrawn
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  • 2017-07-28 WO PCT/EP2017/069194 patent/WO2018020010A1/en not_active Ceased
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• 2018
  • 2018-03-26 US US15/935,695 patent/US10117854B2/en not_active Expired - Fee Related
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• 2019
  • 2019-01-24 IL IL264460A patent/IL264460B/en active IP Right Grant
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