WO2022188029A1 - Compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate, preparation method, use, and pharmaceutical composition thereof - Google Patents
Compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate, preparation method, use, and pharmaceutical composition thereof Download PDFInfo
- 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
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- BHTRKEVKTKCXOH-UHFFFAOYSA-N Taurochenodesoxycholsaeure Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)CC2 BHTRKEVKTKCXOH-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 239000008187 granular material Substances 0.000 title claims abstract description 51
- BHTRKEVKTKCXOH-LBSADWJPSA-N tauroursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-LBSADWJPSA-N 0.000 title claims abstract description 51
- 229960002232 sodium phenylbutyrate Drugs 0.000 title claims abstract description 50
- VPZRWNZGLKXFOE-UHFFFAOYSA-M sodium phenylbutyrate Chemical compound [Na+].[O-]C(=O)CCCC1=CC=CC=C1 VPZRWNZGLKXFOE-UHFFFAOYSA-M 0.000 title claims abstract description 49
- 239000000843 powder Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 title claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 5
- 239000000314 lubricant Substances 0.000 claims abstract description 22
- 239000000796 flavoring agent Substances 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 14
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 14
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 claims abstract description 12
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229950009041 edaravone Drugs 0.000 claims abstract description 12
- 229960004181 riluzole Drugs 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 11
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 11
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 238000007908 dry granulation Methods 0.000 claims abstract description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- 239000000463 material Substances 0.000 claims description 10
- 238000003825 pressing Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052782 aluminium Inorganic materials 0.000 claims description 6
- 239000011888 foil Substances 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 238000012856 packing Methods 0.000 claims description 5
- 238000007873 sieving Methods 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- 238000012546 transfer Methods 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 108010011485 Aspartame Proteins 0.000 claims description 3
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 3
- 239000000605 aspartame Substances 0.000 claims description 3
- 235000010357 aspartame Nutrition 0.000 claims description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 3
- 229960003438 aspartame Drugs 0.000 claims description 3
- 235000019634 flavors Nutrition 0.000 claims description 3
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 3
- 229940013618 stevioside Drugs 0.000 claims description 3
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019202 steviosides Nutrition 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000003292 glue Substances 0.000 claims 1
- 239000003607 modifier Substances 0.000 claims 1
- -1 sodium phenylbutyrate compound Chemical class 0.000 claims 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 24
- 235000019359 magnesium stearate Nutrition 0.000 description 12
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000010534 mechanism of action Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 208000028547 Inborn Urea Cycle disease Diseases 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 4
- 201000010901 lateral sclerosis Diseases 0.000 description 4
- 230000002438 mitochondrial effect Effects 0.000 description 4
- 208000005264 motor neuron disease Diseases 0.000 description 4
- 230000016273 neuron death Effects 0.000 description 4
- 230000000324 neuroprotective effect Effects 0.000 description 4
- 208000030954 urea cycle disease Diseases 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010056292 Androgen-Insensitivity Syndrome Diseases 0.000 description 2
- 206010020575 Hyperammonaemia Diseases 0.000 description 2
- 208000032382 Ischaemic stroke Diseases 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229940121657 clinical drug Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000002161 motor neuron Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010056677 Nerve degeneration Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 201000008752 progressive muscular atrophy Diseases 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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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Abstract
A compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate, comprising raw materials of sodium phenylbutyrate, tauroursodeoxycholic acid, a lubricant, a glidant, a flavoring agent, etc. The present application further relates to a preparation method for the compound powder/granule, comprising a step of dry granulation. In addition, also disclosed is a use of the compound powder/granule, i.e., an application in preparation of a drug for treating neurodegenerative diseases, comprising an application in treatment of amyotrophic lateral sclerosis (ALS). Furthermore, further disclosed is a pharmaceutical composition comprising the compound powder/granule, consisting of the powder/granule, riluzole, and/or edaravone.
Description
本发明属于药物领域，具体涉及一种含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂及其制备方法与用途。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.
苯丁酸钠单方临床主要用于治疗尿素循环障碍(UCDs)引起的氮排泄障碍，即高氨血症；牛磺熊去氧胆酸单方临床主要用于治疗胆囊胆固醇结石、原发硬化性胆管炎、原发胆汁性肝硬化和慢性丙型病毒性肝炎等。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.
萎缩性侧索硬化症(ALS)是一种迅速进行性的和致命的神经退行性病症，其特征在于中枢神经系统的上和下运动神经元的损失。脊髓前角和脑干中的下运动神经元的退化导致进行性肌萎缩，并因呼吸衰竭最终导致在几年内死亡。一些复杂的生化和调控通路可能参与ALS的发病。这些不同的通路彼此相互作用，最终导致受控的细胞死亡或细胞凋亡，其被认为是许多神经退行性疾病(包括ALS)的共同促进因子。此外，最近的证据提示线粒体功能障碍在这种必然且迅速致命的疾病的发病中的作用。Atrophic lateral sclerosis (ALS) 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.
肌萎缩性侧索硬化症(ALS)属于罕见病，发病机制不明，其在早期临床表现多样，缺乏特异的生物学确诊指标，且无法治愈，本发明主要解决目前临床还未有用于治疗肌萎缩性侧索硬化症的复方牛磺熊去氧胆酸苯丁酸钠药物制剂。Amyotrophic lateral sclerosis (ALS) 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.
发明内容SUMMARY OF THE INVENTION
为了解决现有技术中，还未有用于治疗肌萎缩性侧索硬化症的复方牛磺熊去氧胆酸苯丁酸钠药物制剂的问题，本发明提供了一种含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂及其制备方法与用途以及包含所述复方制剂/颗粒剂的药物组合物，本发明的目的在于，采用牛磺熊去氧胆酸和苯丁酸钠联合用药可以减少线粒体和内质网依赖性神经元变性通路障碍，减少ALS患者神经元死亡，起到神经保护作用，可用于治疗肌萎缩性侧索硬化症 (ALS)，延长患者生存期。In order to solve the problem that in the prior art, there is no compound tauroursodeoxycholic acid sodium phenylbutyrate pharmaceutical preparation for the treatment of amyotrophic 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.
为了实现上述目的，本发明的技术方案为：本发明提供的一种含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂，原材料包括苯丁酸钠、牛磺熊去氧胆酸、润滑剂、助流剂、矫味剂，所述各成分在原材料中的质量百分比分别为：苯丁酸钠55％-75％，牛磺熊去氧胆酸15％-35％，润滑剂为0％-3％，助流剂为0％-10％，矫味剂为0％-6％。本发明采用牛磺熊去氧胆酸、苯丁酸钠作为主药成分，复配其他助剂，苯丁酸钠和牛磺熊去氧胆酸作用靶点不同于现有治疗ALS临床用药的靶点，其作用机制推测为，减少线粒体和内质网依赖性神经元变性通路障碍，减少ALS患者神经元死亡，起到神经保护作用，二者联用对于治疗神经退行性疾病特别有效，例如肌萎缩侧索硬化ALS中的用途。In order to achieve the above purpose, 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%, and 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.
进一步的，所述润滑剂和/或助流剂包括硬脂酸、微粉硅胶、胶态二氧化硅中任意一种或一种以上。Further, the lubricant and/or glidant include any one or more of stearic acid, micropowder silica gel, and colloidal silica.
进一步的，所述矫味剂包括蔗糖、糖精钠、甜菊苷、阿司帕坦、甘露醇中任意一种或一种以上。Further, the flavoring agent includes any one or more of sucrose, sodium saccharin, stevioside, aspartame, and mannitol.
本发明还提供了制备所述散剂/颗粒剂的方法，包括如下步骤：The present invention also provides a method for preparing the powder/granule, comprising the steps of:
1)过筛：取苯丁酸钠、牛磺熊去氧胆酸过60-100目筛；将矫味剂、润滑剂和助流剂分别过60-80目筛；备用；1) sieving: get sodium phenylbutyrate, tauroursodeoxycholic acid and cross 60-100 mesh sieves; correcting agent, lubricant and glidant are respectively passed through 60-80 mesh sieves; for subsequent use;
2)混合：将过筛后的苯丁酸钠、牛磺熊去氧胆酸、矫味剂、0.5％重量份的润滑剂及助流剂在总混机中混合均匀；2) Mixing: the sieved sodium phenylbutyrate, tauroursodeoxycholic acid, flavoring agent, lubricant and glidant of 0.5% by weight are uniformly mixed in a total mixer;
3)干法制粒：将混合好的物料转移至干法制粒机中制备颗粒：控制压辊压力为0.5-0.8Mpa，压轮速度为4-10rpm，整粒筛网孔径为0.5-2.0mm；3) 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;
4)总混：将干法制粒颗粒与余下润滑剂置总混桶中混合均匀；4) Mixing: mix the dry granulation granules and the remaining lubricant in a mixing tank evenly;
5)包装：将混匀后物料包装在铝箔袋中，即得。5) Packing: Pack the mixed material in an aluminum foil bag.
牛磺熊去氧胆酸和苯丁酸钠的单方药物制剂在联合用药存在服用不方便，服用剂量不精确，携带不方便的问题。牛磺熊去氧胆酸原料药对高湿、高温都不是很稳定，且牛磺熊去氧胆酸和苯丁酸钠原料吸湿严重。本发明相比于单方制剂本发明采用单剂量包装，服用剂量更准确。本发明相比于单方制剂本发明的稳定性更好。由于散剂/颗粒剂无论在制造还是在贮存过程中， 始终都处于干燥无水的状态，且单剂量包装，包装严密，避免与空气和湿气接触，因而较单方制剂稳定。相比于单方制剂本发明的生物利用度更高。本发明为散剂/颗粒剂，散剂颗粒剂虽为固体制剂，但其在加水冲服时亦即组成了溶液剂，因而较片剂和胶囊剂吸收好、起效快、生物利用度高。相比于单方制剂本发明适用人群更广。散剂/颗粒剂加水冲服时，口感好，病人乐意接受，特别适合儿童应用，而且还方便老年人和吞咽困难的病人应用。相比于单方制剂本发明生产、运输、贮藏、携带和使用更方便。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. Compared with the single-dose preparation, the present invention adopts single-dose packaging, and the dosage is more accurate. Compared with the single preparation, the present invention has better stability. Because the powder/granule is always in a dry and anhydrous state during manufacture and storage, and is packaged in a single dose, the packaging is tight and avoids contact with air and moisture, so it is more stable than the single-dose preparation. Compared with the single preparation, the bioavailability of the present invention is higher. 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.
本发明还提供了所述散剂/颗粒剂的用途，用于制备治疗神经退行性疾病药物的应用。所述神经退行性疾病为肌萎缩侧索硬化ALS。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.
本发明还提供了包含所述散剂/颗粒剂的药物组合物，该组合物由所述散剂/颗粒剂、利鲁唑和/或依达拉奉组成，权利要求1所述的散剂/颗粒剂与利鲁唑、依达拉奉的质量比为500:5:3。本发明和现有治疗肌萎缩性侧索硬化症(ALS)药物联合应用，可多靶点共同作用，发挥鸡尾酒疗法，用于治疗治疗肌萎缩性侧索硬化症(ALS)等神经退行性疾病，增强疗效，延长生存期，改善患者生存质量。采用上述技术方案，本发明的有益效果为，本发明设计开发了一种以苯丁酸钠和牛磺熊去氧胆酸为活性成分的复方制剂，该复方制剂从一个全新靶点去治疗肌萎缩性侧索硬化症(ALS)，现有的用于治疗ALS的药物靶点单一(例如利鲁唑抑制谷氨酸释放；依达拉奉清除自由基)，疗效不理想，本发明的这种配方，作用靶点不同于现有治疗ALS临床用药的靶点，其作用机制推测为，减少线粒体和内质网依赖性神经元变性通路障碍，减少ALS患者神经元死亡，起到神经保护作用；且本发明选择的剂型散剂/颗粒剂虽为固体制剂，但其在加水冲服时亦即组成了溶液剂，因而较片剂和胶囊剂吸收好、起效快、生物利用度高。该组合物可在常温下保持稳定，可显著降低药品的储存和流通成本；该复方制剂剂型为颗粒剂/散剂，便于携带，剂量准确，方便患者用药，且制剂制备工艺简单、成本适宜，适用于工业化大生产。The present invention also provides 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. Adopting the above technical scheme, 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. The formula, 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; And although 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.
下面通过具体的实施例对本发明做进一步的详细描述。需要说明的是，实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的 限制。另外，如果没有明确说明，在下面的实施例中所采用的所有试剂均为市场上可以购得的，或者可以按照本文或已知的方法合成的，对于没有列出的反应条件，也均为本领域技术人员容易获得的。The present invention will be further described in detail below through specific embodiments. It should be noted that the embodiments are exemplary, are only used to explain the present invention, and should not be construed as limiting the present invention. In addition, if not clearly stated, all the reagents used in the following examples are commercially available, or can be synthesized according to the methods herein or known, and the reaction conditions not listed are also readily available to those skilled in the art.
通过下面的技术方案，对发明内容做进一步的说明。The content of the invention is further described through the following technical solutions.
实施例一：本发明提供的一种含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂，原材料包括苯丁酸钠、牛磺熊去氧胆酸、润滑剂、助流剂、矫味剂，所述各成分在原材料中的质量百分比分别为：苯丁酸钠55％，牛磺熊去氧胆酸35％，润滑剂为3％，助流剂为1％，矫味剂为6％。所述润滑剂为硬脂酸镁、助流剂为胶态二氧化硅，所述矫味剂为蔗糖。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.
制备方法为：1)过筛：取苯丁酸钠、牛磺熊去氧胆酸过60-100目筛；将蔗糖、胶态二氧化硅和硬脂酸镁分别过60-80目筛；备用。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.
2)混合：将苯丁酸钠、牛磺熊去氧胆酸、蔗糖、胶态二氧化硅以及0.5％硬脂酸镁在总混机中混合均匀；2) Mixing: mix sodium phenylbutyrate, tauroursodeoxycholic acid, sucrose, colloidal silicon dioxide and 0.5% magnesium stearate in a total mixer uniformly;
3)干法制粒：将混合好的物料转移至干法制粒机中制备颗粒：控制压辊压力为0.5-0.8Mpa，压轮速度为4-10rpm，整粒筛网孔径为0.5-2.0mm。3) 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.
4)总混：将干法制粒颗粒与剩余硬脂酸镁置总混桶中混合均匀。4) Mixing: Mix the dry granulated granules and the remaining magnesium stearate in a mixing tank evenly.
5)包装：将混匀后物料包装在铝箔袋中，即得，得到的是散剂。5) Packing: Pack the mixed material in an aluminum foil bag, that is, the powder is obtained.
实施例二：本发明提供的一种含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂，原材料包括苯丁酸钠、牛磺熊去氧胆酸、润滑剂、助流剂、矫味剂，所述各成分在原材料中的质量百分比分别为：苯丁酸钠75％，牛磺熊去氧胆酸15％，润滑剂为2％，助流剂为5％，矫味剂为3％。所述润滑剂为硬脂酸镁、助流剂为微粉硅胶，所述矫味剂为甘露醇。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.
制备方法为：1)过筛：取苯丁酸钠、牛磺熊去氧胆酸过60-100目筛；将甘露醇、微粉硅胶和硬脂酸镁分别过60-80目筛；备用。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.
2)混合：将苯丁酸钠、牛磺熊去氧胆酸、甘露醇、微粉二氧化硅以及0.5％硬脂酸镁在总混机中混合均匀；2) Mixing: Mix sodium phenylbutyrate, tauroursodeoxycholic acid, mannitol, micronized silicon dioxide and 0.5% magnesium stearate in a total mixer uniformly;
3)干法制粒：将混合好的物料转移至干法制粒机中制备颗粒：控制压辊压力为0.5-0.8Mpa，压轮速度为4-10rpm，整粒筛网孔径为0.5-2.0mm。3) 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.
4)总混：将干法制粒颗粒与剩余硬脂酸镁置总混桶中混合均匀。4) Mixing: Mix the dry granulated granules and the remaining magnesium stearate in a mixing tank evenly.
5)包装：将混匀后物料包装在铝箔袋中，即得。最终制得颗粒剂。5) Packing: Pack the mixed material in an aluminum foil bag. Finally, granules are obtained.
实施例三：发明提供的一种含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂，原材料包括苯丁酸钠、牛磺熊去氧胆酸、润滑剂、助流剂、矫味剂，所述各成分在原材料中的质量百分比分别为：苯丁酸钠68％，牛磺熊去氧胆酸20％，润滑剂为1％，助流剂为10％，矫味剂为1％。所述润滑剂为硬脂酸镁、助流剂为胶态二氧化硅，所述矫味剂为糖精钠、甜菊苷、阿司帕坦的混合物。Embodiment 3: a kind of compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate provided by the invention, 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, and the flavoring agent is a mixture of sodium saccharin, stevioside and aspartame.
制备方法为：1)过筛：取苯丁酸钠、牛磺熊去氧胆酸过60-100目筛；将矫味剂、胶态二氧化硅和硬脂酸镁分别过60-80目筛；备用。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.
2)混合：将苯丁酸钠、牛磺熊去氧胆酸、矫味剂、胶态二氧化硅以及0.5％硬脂酸镁在总混机中混合均匀；2) Mixing: mix sodium phenylbutyrate, tauroursodeoxycholic acid, flavoring agent, colloidal silicon dioxide and 0.5% magnesium stearate in a total mixer uniformly;
3)干法制粒：将混合好的物料转移至干法制粒机中制备颗粒：控制压辊压力为0.5-0.8Mpa，压轮速度为4-10rpm，整粒筛网孔径为0.5-2.0mm。3) 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.
4)总混：将干法制粒颗粒与剩余硬脂酸镁置总混桶中混合均匀。4) Mixing: Mix the dry granulated granules and the remaining magnesium stearate in a mixing tank evenly.
5)包装：将混匀后物料包装在铝箔袋中，即得。制得颗粒剂。5) Packing: Pack the mixed material in an aluminum foil bag. Granules were prepared.
需要说明的是，在本发明技术方案中各个原材料的质量百分比范围内、采用的可替换原材料以及制备方法，制得的含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂其稳定性、活性成分回收率、溶化性能等尽管条件参数略有不同，但是总体性能都是一致的，故为了减少不必要的重复，不再逐一列举实施例，以及实施例的性能参数，仅以上述三个实施例为举例说明。最终得到的含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂性能如下表所示：It should be noted that, within the mass percentage range of each raw material in the technical solution of the present invention, the alternative raw materials used and the preparation method, the obtained compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate Although its stability, active ingredient recovery rate, melting performance, etc. are slightly different, the overall performance is the same, so in order to reduce unnecessary repetition, the examples and performance parameters of the examples are not listed one by one. The above three embodiments are taken as examples for illustration. The properties of the finally obtained compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate are shown in the following table:
表格1：实施案例检测结果对比Table 1: Comparison of test results of implementation cases
| 检测项目Test items | 实施例一Example 1 | 实施例二Embodiment 2 | 实施例三Embodiment 3 |
| 外观Exterior | 类白色粉末off-white powder | 类白色粉末off-white powder | 类白色粉末off-white powder |
| 干燥失重(％)Loss on drying (%) | 1.0％1.0% | 0.9％0.9% | 1.1％1.1% |
| 含量均匀度(％)Content uniformity (%) | 3％3% | 2％2% | 2％2% |
| 溶化性Solubility | 符合要求meet the requirements | 符合要求meet the requirements | 符合要求meet the requirements |
| 牛磺熊去氧胆酸(％)Tauroursodeoxycholic acid (%) | 99.7％99.7% | 99.5％99.5% | 100.1％100.1% |
| 苯丁酸钠(％)Sodium phenylbutyrate (%) | 99.6％99.6% | 99.9％99.9% | 99.4％99.4% |
结果：实施例一为散剂，实施例二、实施例三为颗粒剂，三个处方制剂的干燥失重控制在2％以内，含量、含量均匀度、溶化性均符合要求，工艺可行性良好。Results: 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.
表格2：高湿影响性因素水分检测结果Table 2: Moisture test results of high humidity influencing factors
| 时间time | 0天0 days | 5天5 days | 10天10 days | 30天30 days |
| 实施例一Example 1 | 1.0％1.0% | 1.1％1.1% | 1.0％1.0% | 1.0％1.0% |
| 实施例二Embodiment 2 | 0.9％0.9% | 1.0％1.0% | 0.9％0.9% | 1.0％1.0% |
| 实施例三Embodiment 3 | 1.1％1.1% | 1.1％1.1% | 1.1％1.1% | 1.1％1.1% |
结论：采用药用铝箔包装，包装严密，避免与空气和湿气接触，制剂始终处于干燥状态，制剂稳定性良好。Conclusion: It is packed in medicinal aluminum foil, which is tightly packed and avoids contact with air and moisture. The preparation is always in a dry state, and the stability of the preparation is good.
本发明制得的含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂用于治疗神经退行性疾病，其服用剂量为每日两次，每次一包，一包5g，可以有效减少ALS患者神经元的死亡，延长其存活期。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.
牛磺熊去氧胆酸除了可以增加胆汁的胆固醇溶解活性，还具有抑制线粒体相关的细胞凋亡以及细胞保护和抗细胞凋亡作用。苯丁酸钠除了可以用于治疗尿素循环障碍(UCDs)引起的氮排泄障碍，即高氨血症外，还具有神经保护作用，减少神经元死亡。本发明制得的含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂用于治疗神经退行性疾病可以减少线粒体和内质网依赖性神经元变性通路障碍，减少ALS患者神经元死亡。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. 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.
利鲁唑治疗AIS的作用机制是抑制谷氨酸释放；依达拉奉治疗AIS的作用机制是清除自由基。利鲁唑，依达拉奉的作用机制和本发明完全不同，其和本发明联合使用可以从不同机制去治疗ALS患者，发挥协同作用；联合用药疗效优于单独用药。本发明和利鲁唑联用使用方法为：本发明服用剂量为每日两次，每次一包，一包5g，利鲁唑服用剂量为每日两次，每次一片，规格为50mg/片。本发明和依达拉奉联用，使用方法为：本发明服用剂量为每日两次，每次一包(一包5g)；依达拉奉服一次30mg，每日两次，加入适量生理盐水中稀释后静脉滴注，30分钟内滴完。本发明和利鲁唑、依达拉奉联用，使用方法为：本发明服用剂量为每日两次，每次一包(一包5g)，利鲁唑服用剂量为每日两次，每次一片(药物活性成分50mg/片)。依达拉奉服一次30mg，每日一次，加入适量生理盐水中稀释后静脉滴注，30分钟内滴完。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.
上述技术方案仅体现了本发明技术方案的优选技术，本领域的技术人员对其中某些部分所可能做出的一些变动均体现了本发明原理，属于本发明的保护范围之内。The above technical solutions only reflect the preferred technologies of the technical solutions of the present invention, and some changes that those skilled in the art may make to some parts of them all reflect the principles of the present invention and fall within the protection scope of the present invention.
Claims (7)
- 一种含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂，其特征在于，原材料包括苯丁酸钠、牛磺熊去氧胆酸、润滑剂、助流剂、矫味剂，所述各成分在原材料中的质量百分比分别为：苯丁酸钠55％-75％，牛磺熊去氧胆酸15％-35％，润滑剂为0％-3％助流剂为0％-10％，矫味剂为0％-6％。A compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate, characterized in that the raw materials include sodium phenylbutyrate, tauroursodeoxycholic acid, lubricants, glidants, flavor modifiers The mass percentages of the components in the raw materials are: sodium phenylbutyrate 55%-75%, tauroursodeoxycholic acid 15%-35%, lubricant 0%-3% 0%-10%, the flavoring agent is 0%-6%.
- 根据权利要求1所述的含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂，其特征在于，所述润滑剂和/或助流剂包括硬脂酸、微粉硅胶、胶态二氧化硅中任意一种或一种以上。The compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate according to claim 1, is characterized in that, described lubricant and/or glidant comprise stearic acid, micropowder silica gel, glue Any one or more than one type of silica.
- 根据权利要求1所述的含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂，其特征在于，所述矫味剂包括蔗糖、糖精钠、甜菊苷、阿司帕坦、甘露醇中任意一种或一种以上。The compound powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate according to claim 1, wherein the flavoring agent comprises sucrose, sodium saccharin, stevioside, aspartame, Any one or more of mannitol.
- 一种制备权利要求1-3任意一项含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂的方法，其特征在于，该方法包括如下步骤：A method for preparing the compound powder/granule of any one of claims 1-3 containing tauroursodeoxycholic acid and sodium phenylbutyrate, wherein the method comprises the steps:1)过筛：取苯丁酸钠、牛磺熊去氧胆酸过60-100目筛；将矫味剂、润滑剂和助流剂分别过60-80目筛；备用；1) sieving: get sodium phenylbutyrate, tauroursodeoxycholic acid and cross 60-100 mesh sieves; correcting agent, lubricant and glidant are respectively passed through 60-80 mesh sieves; for subsequent use;2)混合：将过筛后的苯丁酸钠、牛磺熊去氧胆酸、矫味剂、0.5％重量份的润滑剂及助流剂在总混机中混合均匀；2) Mixing: the sieved sodium phenylbutyrate, tauroursodeoxycholic acid, flavoring agent, lubricant and glidant of 0.5% by weight are uniformly mixed in a total mixer;3)干法制粒：将混合好的物料转移至干法制粒机中制备颗粒：控制压辊压力为0.5-0.8Mpa，压轮速度为4-10rpm，整粒筛网孔径为0.5-2.0mm；3) 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;4)总混：将干法制粒颗粒与余下润滑剂置总混桶中混合均匀；4) Mixing: mix the dry granulation granules and the remaining lubricant in a mixing tank evenly;5)包装：将混匀后物料包装在铝箔袋中，即得。5) Packing: Pack the mixed material in an aluminum foil bag.
- 一种权利要求1-3任意一项含牛磺熊去氧胆酸、苯丁酸钠的复方散剂/颗粒剂的用途，其特征在于，用于制备治疗神经退行性疾病药物的应用。A use of any one of claims 1-3 containing tauroursodeoxycholic acid and sodium phenylbutyrate compound powder/granule, characterized in that it is used for the preparation of a drug for the treatment of neurodegenerative diseases.
- 根据权利要求5所述的含牛磺熊去氧胆酸、苯丁酸钠的用途，其特征在于，所述神经退行性疾病包括肌萎缩侧索硬化ALS。The use containing tauroursodeoxycholic acid and sodium phenylbutyrate according to claim 5, wherein the neurodegenerative disease comprises amyotrophic lateral sclerosis (ALS).
- 一种包含有权利要求1所述含牛磺熊去氧胆酸、苯丁酸钠的散剂/颗粒剂的药物组合物，其特征在于，该组合物由权利要求1所述的散剂/颗粒剂、利鲁唑和/或依达拉奉组成,权利要求1所述的散剂/颗粒剂与利鲁唑、依达拉奉的质量比为500:5:3。A pharmaceutical composition comprising the powder/granule containing tauroursodeoxycholic acid and sodium phenylbutyrate according to claim 1, wherein the composition is composed of the powder/granule according to claim 1 , riluzole and/or edaravone, and the mass ratio of the powder/granule of claim 1 to riluzole and edaravone is 500:5:3.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105050593A (en) * | 2013-03-24 | 2015-11-11 | 艾米利克斯制药公司 | Compositions for improving cell viability and methods of use thereof |
| US20200179355A1 (en) * | 2017-08-14 | 2020-06-11 | Prilenia Neurotherapeutics Ltd. | Method of treating amyotrophic lateral sclerosis with pridopidine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105050593A (en) * | 2013-03-24 | 2015-11-11 | 艾米利克斯制药公司 | Compositions for improving cell viability and methods of use thereof |
| CN109999043A (en) * | 2013-03-24 | 2019-07-12 | 艾米利克斯制药公司 | For improving the composition of cell viability and using the method for the composition |
| CN110787169A (en) * | 2013-03-24 | 2020-02-14 | 艾米利克斯制药公司 | Compositions for improving cell viability and methods of using the same |
| US20200179355A1 (en) * | 2017-08-14 | 2020-06-11 | Prilenia Neurotherapeutics Ltd. | Method of treating amyotrophic lateral sclerosis with pridopidine |
Non-Patent Citations (2)
| Title |
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| 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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