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WO2022188029A1 - Poudre/granulé composite contenant de l'acide tauroursodésoxycholique et du phénylbutyrate de sodium, méthode de préparation, utilisation et composition pharmaceutique associées - Google Patents

Poudre/granulé composite contenant de l'acide tauroursodésoxycholique et du phénylbutyrate de sodium, méthode de préparation, utilisation et composition pharmaceutique associées Download PDF

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Publication number
WO2022188029A1
WO2022188029A1 PCT/CN2021/079747 CN2021079747W WO2022188029A1 WO 2022188029 A1 WO2022188029 A1 WO 2022188029A1 CN 2021079747 W CN2021079747 W CN 2021079747W WO 2022188029 A1 WO2022188029 A1 WO 2022188029A1
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WO
WIPO (PCT)
Prior art keywords
sodium phenylbutyrate
tauroursodeoxycholic acid
granule
compound powder
powder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2021/079747
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English (en)
Chinese (zh)
Inventor
张莹莹
李小羿
戴向荣
殷雷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhaoke Pharmaceutical Guangzhou Co Ltd
Original Assignee
Zhaoke Pharmaceutical Guangzhou Co Ltd
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Priority to PCT/CN2021/079747 priority Critical patent/WO2022188029A1/fr
Publication of WO2022188029A1 publication Critical patent/WO2022188029A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate and a preparation method and application thereof.
  • Sodium phenylbutyrate is mainly used to treat nitrogen excretion disorders caused by urea cycle disorders (UCDs), namely hyperammonemia; tauroursodeoxycholic acid is mainly used to treat gallbladder cholesterol stones and primary sclerosing bile ducts. inflammation, primary biliary cirrhosis and chronic viral hepatitis C.
  • UCDs urea cycle disorders
  • tauroursodeoxycholic acid is mainly used to treat gallbladder cholesterol stones and primary sclerosing bile ducts. inflammation, primary biliary cirrhosis and chronic viral hepatitis C.
  • Atrophic lateral sclerosis is a rapidly progressive and fatal neurodegenerative disorder characterized by loss of upper and lower motor neurons of the central nervous system. Degeneration of lower motor neurons in the anterior horn of the spinal cord and brain stem leads to progressive muscular atrophy and ultimately death within a few years due to respiratory failure. Some complex biochemical and regulatory pathways may be involved in the pathogenesis of ALS. These different pathways interact with each other, ultimately leading to controlled cell death or apoptosis, which is thought to be a common promoter of many neurodegenerative diseases, including ALS. Furthermore, recent evidence suggests a role for mitochondrial dysfunction in the pathogenesis of this inevitable and rapidly fatal disease.
  • Amyotrophic lateral sclerosis is a rare disease with unknown pathogenesis. It has various clinical manifestations in the early stage, lacks specific biological diagnosis indicators, and cannot be cured. Compound tauroursodeoxycholic acid sodium phenylbutyrate pharmaceutical preparation for lateral sclerosis.
  • the present invention provides a tauroursodeoxychol Compound powder/granule of acid and sodium phenylbutyrate and its preparation method and use and the pharmaceutical composition comprising said compound preparation/granule, the object of the present invention is to use tauroursodeoxycholic acid and phenylbutyric acid
  • the combination of sodium can reduce mitochondrial and endoplasmic reticulum-dependent neuronal degeneration pathway disorders, reduce neuronal death in ALS patients, and play a neuroprotective role. It can be used to treat amyotrophic lateral sclerosis (ALS) and prolong patient survival.
  • the technical scheme of the present invention is: a compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate provided by the present invention
  • the raw materials include sodium phenylbutyrate, tauroursodeoxy cholic acid, lubricant, glidant, and flavoring agent
  • the mass percentages of the components in the raw materials are: sodium phenylbutyrate 55%-75%, tauroursodeoxycholic acid 15%-35%
  • the lubricant is 0%-3%
  • the glidant is 0%-10%
  • the flavoring agent is 0%-6%.
  • the present invention adopts tauroursodeoxycholic acid and sodium phenylbutyrate as main drug components, and is compounded with other adjuvants.
  • the action targets of sodium phenylbutyrate and tauroursodeoxycholic acid are different from those of existing clinical drugs for treating ALS. It is speculated that the mechanism of action is to reduce mitochondrial and endoplasmic reticulum-dependent neuronal degeneration pathway disorders, reduce neuronal death in ALS patients, and play a neuroprotective role.
  • the combination of the two is particularly effective in the treatment of neurodegenerative diseases, such as muscle Use in Atrophic Lateral Sclerosis ALS.
  • the lubricant and/or glidant include any one or more of stearic acid, micropowder silica gel, and colloidal silica.
  • the flavoring agent includes any one or more of sucrose, sodium saccharin, stevioside, aspartame, and mannitol.
  • the present invention also provides a method for preparing the powder/granule, comprising the steps of:
  • Dry granulation transfer the mixed material to a dry granulator to prepare granules: control the pressure of the pressing roller to be 0.5-0.8Mpa, the speed of the pressing wheel to be 4-10rpm, and the aperture of the whole granule screen to be 0.5-2.0mm;
  • the single drug preparation of tauroursodeoxycholic acid and sodium phenylbutyrate has the problems of inconvenience in taking, inaccurate dosage and inconvenience in carrying.
  • the raw materials of tauroursodeoxycholic acid are not very stable to high humidity and high temperature, and the raw materials of tauroursodeoxycholic acid and sodium phenylbutyrate are seriously hygroscopic.
  • the present invention adopts single-dose packaging, and the dosage is more accurate. Compared with the single preparation, the present invention has better stability.
  • the present invention is a powder/granule. Although the powder and granules are solid preparations, they form a solution when ingested with water, so they have better absorption, faster onset and higher bioavailability than tablets and capsules. Compared with the single preparation, the present invention is applicable to a wider population. When the powder/granule is mixed with water, the taste is good, and the patient is willing to accept it. It is especially suitable for children, and it is also convenient for the elderly and patients with dysphagia. Compared with the single preparation, the present invention is more convenient to produce, transport, store, carry and use.
  • the present invention also provides the use of the powder/granule for preparing a drug for treating neurodegenerative diseases.
  • the neurodegenerative disease is amyotrophic lateral sclerosis ALS.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the powder/granule, the composition is composed of the powder/granule, riluzole and/or edaravone, and the powder/granule of claim 1
  • the mass ratio with riluzole and edaravone is 500:5:3.
  • the combined application of the present invention and the existing drugs for treating amyotrophic lateral sclerosis (ALS) can act together with multiple targets, exerting cocktail therapy, and being used for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) , enhance the curative effect, prolong the survival period, and improve the quality of life of patients.
  • ALS amyotrophic lateral sclerosis
  • the beneficial effect of the present invention is that the present invention designs and develops a compound preparation with sodium phenylbutyrate and tauroursodeoxycholic acid as active ingredients, and the compound preparation treats muscular atrophy from a new target Lateral sclerosis (ALS), the existing drug targets for the treatment of ALS are single (for example, riluzole inhibits the release of glutamate; edaravone scavenges free radicals), and the curative effect is not ideal.
  • ALS Lateral sclerosis
  • the target of action is different from the target of existing clinical drugs for the treatment of ALS, and its mechanism of action is speculated to reduce mitochondrial and endoplasmic reticulum-dependent neuronal degeneration pathway obstacles, reduce neuronal death in ALS patients, and play a neuroprotective role;
  • the dosage form powder/granule selected by the present invention is a solid preparation, it forms a solution when ingested with water, so it has better absorption, faster onset and higher bioavailability than tablets and capsules.
  • the composition can be kept stable at room temperature, and can significantly reduce the storage and circulation costs of medicines;
  • the compound preparation is in the form of granules/powder, which is easy to carry, accurate in dosage, convenient for patients to take medicine, and has a simple preparation process, suitable cost, and is suitable for in industrialized production.
  • Embodiment 1 A compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate provided by the present invention, the raw materials include sodium phenylbutyrate, tauroursodeoxycholic acid, lubricants, and flow aids.
  • the mass percentages of the ingredients in the raw materials are: sodium phenylbutyrate 55%, tauroursodeoxycholic acid 35%, lubricant 3%, glidant 1%, Flavor is 6%.
  • the lubricant is magnesium stearate, the glidant is colloidal silicon dioxide, and the flavoring agent is sucrose.
  • the preparation method is: 1) sieving: take sodium phenylbutyrate and tauroursodeoxycholic acid and pass through a 60-100 mesh sieve; sucrose, colloidal silicon dioxide and magnesium stearate are respectively passed through a 60-80 mesh sieve; spare.
  • Dry granulation transfer the mixed material to a dry granulator to prepare granules: control the pressure of the pressing roller to be 0.5-0.8 Mpa, the speed of the pressing wheel to be 4-10 rpm, and the aperture of the whole granulation screen to be 0.5-2.0 mm.
  • Embodiment 2 a compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate provided by the present invention, the raw materials include sodium phenylbutyrate, tauroursodeoxycholic acid, lubricant, flow aid The mass percentages of the ingredients in the raw materials are: sodium phenylbutyrate 75%, tauroursodeoxycholic acid 15%, lubricant 2%, glidant 5%, Flavor is 3%.
  • the lubricant is magnesium stearate, the glidant is micropowder silica gel, and the flavoring agent is mannitol.
  • the preparation method is as follows: 1) sieving: take sodium phenylbutyrate and tauroursodeoxycholic acid and pass through a 60-100 mesh sieve; pass mannitol, micropowder silica gel and magnesium stearate through a 60-80 mesh sieve respectively; for subsequent use.
  • Dry granulation transfer the mixed material to a dry granulator to prepare granules: control the pressure of the pressing roller to be 0.5-0.8 Mpa, the speed of the pressing wheel to be 4-10 rpm, and the aperture of the whole granulation screen to be 0.5-2.0 mm.
  • Embodiment 3 a kind of compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate
  • the raw materials include sodium phenylbutyrate, tauroursodeoxycholic acid, lubricant, glidant , flavoring agent
  • the mass percentages of the components in the raw materials are: sodium phenylbutyrate 68%, tauroursodeoxycholic acid 20%, lubricant 1%, glidant 10%, flavoring
  • the dosage is 1%.
  • the lubricant is magnesium stearate
  • the glidant is colloidal silicon dioxide
  • the flavoring agent is a mixture of sodium saccharin, stevioside and aspartame.
  • the preparation method is: 1) sieving: take sodium phenylbutyrate and tauroursodeoxycholic acid and pass through a 60-100 mesh sieve; pass the flavoring agent, colloidal silicon dioxide and magnesium stearate through a 60-80 mesh respectively Sieve; spare.
  • Dry granulation transfer the mixed material to a dry granulator to prepare granules: control the pressure of the pressing roller to be 0.5-0.8 Mpa, the speed of the pressing wheel to be 4-10 rpm, and the aperture of the whole granulation screen to be 0.5-2.0 mm.
  • Example 1 was powder, Example 2 and Example 3 were granules, the drying loss of the three formulations was controlled within 2%, the content, content uniformity and solubility were all in line with the requirements, and the process was feasible.
  • the compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate prepared by the present invention is used for the treatment of neurodegenerative diseases. It can effectively reduce the death of neurons in ALS patients and prolong their survival.
  • tauroursodeoxycholic acid In addition to increasing the cholesterol-dissolving activity of bile, tauroursodeoxycholic acid also inhibits mitochondria-related apoptosis, as well as cytoprotective and anti-apoptotic effects.
  • NADs nitrogen excretion disorders caused by urea cycle disorders (UCDs), namely hyperammonemia
  • sodium phenylbutyrate In addition to being used to treat nitrogen excretion disorders caused by urea cycle disorders (UCDs), namely hyperammonemia, sodium phenylbutyrate also has neuroprotective effects and reduces neuronal death.
  • the compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate prepared by the invention can be used for the treatment of neurodegenerative diseases, can reduce mitochondrial and endoplasmic reticulum-dependent neuron degeneration pathway obstacles, and reduce the neurological deficit of ALS patients. Yuan died.
  • the mechanism of action of riluzole in the treatment of AIS is to inhibit the release of glutamate; the mechanism of action of edaravone in the treatment of AIS is to scavenge free radicals.
  • the mechanism of action of riluzole and edaravone is completely different from that of the present invention, and their combined use with the present invention can treat ALS patients from different mechanisms and exert a synergistic effect; the curative effect of the combined drug is better than that of the single drug.
  • the combined use method of the present invention and riluzole is as follows: the dosage of the present invention is twice a day, one pack each time, a pack of 5g, and the dosage of riluzole is twice a day, one tablet each time, the specification is 50mg/ piece.
  • the present invention is used in combination with edaravone, and the usage method is as follows: the dosage of the present invention is twice a day, each time one pack (one pack of 5g); edaravone is taken once 30mg, twice a day, adding an appropriate amount of physiological Intravenous infusion after dilution in saline, within 30 minutes.
  • the present invention is used in combination with riluzole and edaravone, and the usage method is as follows: the dosage of the present invention is twice a day, one pack each time (one pack of 5g), and the dosage of riluzole is twice a day, each time The next one (pharmaceutical active ingredient 50mg/tablet).
  • Edaravone is 30 mg once a day, diluted in an appropriate amount of normal saline and then intravenously infused, and the infusion is completed within 30 minutes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une poudre/un granulé composite contenant de l'acide tauroursodésoxycholique et du phénylbutyrate de sodium, comprenant des matières premières de phénylbutyrate de sodium, d'acide tauroursodésoxycholique, un lubrifiant, un agent glissant, un agent aromatisant, etc. La présente invention concerne en outre une méthode de préparation de la poudre/du granulé composite, comprenant une étape de granulation à sec. De plus, l'invention concerne également une utilisation de la poudre/du granulé composite, c'est-à-dire une application dans la préparation d'un médicament pour le traitement de maladies neurodégénératives, comprenant une application dans le traitement de la sclérose latérale amyotrophique (SLA). En outre, l'invention concerne encore une composition pharmaceutique comprenant la poudre/le granulé composite, constituée de la poudre/du granulé, de riluzole et/ou d'édaravone.
PCT/CN2021/079747 2021-03-09 2021-03-09 Poudre/granulé composite contenant de l'acide tauroursodésoxycholique et du phénylbutyrate de sodium, méthode de préparation, utilisation et composition pharmaceutique associées Ceased WO2022188029A1 (fr)

Priority Applications (1)

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PCT/CN2021/079747 WO2022188029A1 (fr) 2021-03-09 2021-03-09 Poudre/granulé composite contenant de l'acide tauroursodésoxycholique et du phénylbutyrate de sodium, méthode de préparation, utilisation et composition pharmaceutique associées

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/079747 WO2022188029A1 (fr) 2021-03-09 2021-03-09 Poudre/granulé composite contenant de l'acide tauroursodésoxycholique et du phénylbutyrate de sodium, méthode de préparation, utilisation et composition pharmaceutique associées

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105050593A (zh) * 2013-03-24 2015-11-11 艾米利克斯制药公司 用于提高细胞存活力的组合物和使用该组合物的方法
US20200179355A1 (en) * 2017-08-14 2020-06-11 Prilenia Neurotherapeutics Ltd. Method of treating amyotrophic lateral sclerosis with pridopidine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105050593A (zh) * 2013-03-24 2015-11-11 艾米利克斯制药公司 用于提高细胞存活力的组合物和使用该组合物的方法
CN109999043A (zh) * 2013-03-24 2019-07-12 艾米利克斯制药公司 用于提高细胞存活力的组合物和使用该组合物的方法
CN110787169A (zh) * 2013-03-24 2020-02-14 艾米利克斯制药公司 用于提高细胞存活力的组合物和使用该组合物的方法
US20200179355A1 (en) * 2017-08-14 2020-06-11 Prilenia Neurotherapeutics Ltd. Method of treating amyotrophic lateral sclerosis with pridopidine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PAGANONI SABRINA, HENDRIX SUZANNE, DICKSON SAMUEL P., KNOWLTON NEWMAN, MACKLIN ERIC A., BERRY JAMES D., ELLIOTT MICHAEL A., MAISER: "Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis", MUSCLE AND NERVEMUSCLE, JOHN WILEY & SONS, INC., HOBOKEN, USA, vol. 63, no. 1, 1 January 2021 (2021-01-01), Hoboken, USA, pages 31 - 39, XP055965835, ISSN: 0148-639X, DOI: 10.1002/mus.27091 *
SABRINA PAGANONI, ERIC A. MACKLIN, SUZANNE HENDRIX, JAMES D. BERRY, MICHAEL A. ELLIOTT, SAMUEL MAISER, CHAFIC KARAM, JAMES B. CARE: "Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis", THE NEW ENGLAND JOURNAL OF MEDICINE, MASSACHUSETTS MEDICAL SOCIETY, US, vol. 383, no. 10, 3 September 2020 (2020-09-03), US , pages 919 - 930, XP055754071, ISSN: 0028-4793, DOI: 10.1056/NEJMoa1916945 *

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