WO2023051490A1 - Glp-1受体激动剂固体组合物 - Google Patents

Glp-1受体激动剂固体组合物 Download PDF

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WO2023051490A1
WO2023051490A1 PCT/CN2022/121554 CN2022121554W WO2023051490A1 WO 2023051490 A1 WO2023051490 A1 WO 2023051490A1 CN 2022121554 W CN2022121554 W CN 2022121554W WO 2023051490 A1 WO2023051490 A1 WO 2023051490A1
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Prior art keywords
pharmaceutically acceptable
less
oad2
composition
acceptable salt
Prior art date
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Ceased
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PCT/CN2022/121554
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English (en)
French (fr)
Chinese (zh)
Inventor
陈眉眉
方洁
吴晖
谭芳
李海燕
肖黎
边聪
陈丽娜
阿尔玛里戈·D
阿南莎·A
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
vTv Therapeutics LLC
Original Assignee
Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
vTv Therapeutics LLC
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Application filed by Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd, vTv Therapeutics LLC filed Critical Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
Priority to CA3233453A priority Critical patent/CA3233453A1/en
Priority to US18/691,835 priority patent/US20250332157A1/en
Priority to EP22874875.2A priority patent/EP4410793A4/en
Priority to JP2024542230A priority patent/JP2024535134A/ja
Publication of WO2023051490A1 publication Critical patent/WO2023051490A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to pharmaceutical compositions of small molecule GLP-1R receptor agonists suitable for oral administration, more particularly to pharmaceutical compositions comprising (S)-2-(3S,8S)-3-(4-(3,4-dichloro Benzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[ 2,3-g]isoquinoline-8-carboxamido)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propanoic acid (“OAD2”) or its pharmaceutical Pharmaceutical compositions of acceptable salts, and methods for their preparation.
  • the invention also relates to methods of using such pharmaceutical compositions for the treatment of type 2 diabetes and indications associated with poor glycemic control.
  • Type II diabetes can be characterized by one or more of the following metabolic disturbances and disease progression: peripheral tissue insulin resistance, hyperglycemia, islet b-cell compensation, hyperinsulinemia, dyslipidemia, increased hepatic gluconeogenesis , and eventual loss of b-cell mass and function.
  • a pathophysiological consequence of abnormal glucose and lipid metabolism is toxicity to organs such as the kidney, eye, peripheral neurons, vasculature and heart. Therefore, there is a need for agents that can delay the progression of type 2 diabetes-related diseases, thereby achieving improved glycemic control and improved b-cell population and function.
  • Glucagon-like peptide-1 is a kind of brain-gut peptide secreted by ileal endocrine cells, and it is mainly used as the target of type II diabetes drugs.
  • An important function of GLP-1 is to activate its receptors on pancreatic b-cells, and its positive metabolic benefits may include, but are not limited to, suppression of excessive glucagon production, delayed gastric emptying time, and improved b-cell population and Function.
  • GLP-1 can provide positive effects on b-cell population and function: GLP-1-like therapy can delay early disease progression.
  • GLP-1 agonists can also be used in combination therapy, for example in combination with insulin in patients with type II diabetes.
  • OAD2 bishydrochloride is a non-peptide, oral glucagon-like peptide-1 receptor (GLP-1r) agonist.
  • WO 2010/114824 discloses the structure of the free base of OAD2, but does not systematically study the composition of OAD2 or its pharmaceutically acceptable salt.
  • OAD2 is a small molecule, non-peptidic glucagon-like peptide 1 (GLP-1) receptor agonist that It is being developed for the treatment of diabetes and other related indications.
  • GLP-1 non-peptidic glucagon-like peptide 1
  • OAD2 dihydrochloride has the following chemical structure:
  • the present invention provides a pharmaceutical composition comprising OAD2 or a pharmaceutically acceptable salt thereof, a process for its preparation or its use in the treatment of a condition in which modulation of the human GLP-1 receptor is beneficial, such as diabetes.
  • the invention provides a pharmaceutical composition with low level of impurity B through the research on the compatibility of raw materials and auxiliary materials and the screening of auxiliary materials.
  • the present invention provides a pharmaceutical composition with a low level of active oxygen species (ROS) by reducing oxides, peroxides, superoxides and other oxides or active oxygen structural components contained in raw and auxiliary materials.
  • ROS active oxygen species
  • the present invention also provides pharmaceutical compositions having low levels of total impurities.
  • the invention provides an OAD2 dihydrochloride pharmaceutical composition with good dissolution and good formulation process reproducibility.
  • the present invention provides OAD2 dihydrochloride pharmaceutical composition with low content of related substances including oxidative degradation impurity B.
  • the pharmaceutical composition provided by the invention has the following advantages: stable production process, strong reproducibility, good dissolution of the prepared OAD2 bishydrochloride pharmaceutical composition, low content of oxidative degradation impurity B, and low content of related substances.
  • the pharmaceutical composition of the invention allows effective control of the growth of related substances, enables the composition to be stored at normal temperature, reduces the probability of adverse reactions of the preparation composition, and ensures the safety of the drug.
  • the present invention provides a pharmaceutical composition, which comprises OAD2 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable auxiliary materials.
  • compositions of the present invention comprise OAD2, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients or carrier materials suitable for oral administration.
  • the composition of the present invention may comprise a desired amount of OAD2 or a pharmaceutically acceptable salt thereof mixed with one or more of disintegrants, binders, fillers and surfactants.
  • the composition may also include one or more of lubricants, glidants, acidulants, and absorption enhancers.
  • the composition may also optionally contain one or more antioxidants.
  • compositions are tabletted or encapsulated for convenient administration in the form of immediate release capsules or tablets.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising OAD2 or a pharmaceutically acceptable salt thereof and at least one solubilizer.
  • the mass percent content of the active ingredient is 1-60%.
  • the mass percent content of the active ingredient is 5%-40%.
  • the mass percent content of the active ingredient is 10%-20%.
  • the mass percent content of the active ingredient is 1-5%, 2-6%, 3-7%, 4-8%, 5-9%, 6-10%, 11-15% %, 12 ⁇ 16%, 13 ⁇ 17%, 14 ⁇ 18%, 15 ⁇ 19%, 16 ⁇ 20%, 21 ⁇ 25%, 22 ⁇ 26%, 23 ⁇ 27%, 24 ⁇ 28%, 25 ⁇ 29% %, 26 ⁇ 30%, 31 ⁇ 35%, 32 ⁇ 36%, 33 ⁇ 37%, 34 ⁇ 38%, 35 ⁇ 39%, 36 ⁇ 40%, 41 ⁇ 45%, 42 ⁇ 46%, 43 ⁇ 47% %, 44-48%, 45-49%, 46-50%, 51-55%, 52-56%, 53-57%, 54-58%, 55-59%, 56-60%.
  • the mass percent content of the active ingredient is 4 ⁇ 2%, 6 ⁇ 2%, 8 ⁇ 2%, 10 ⁇ 2%, 12 ⁇ 2%, 14 ⁇ 2%, 16 ⁇ 2% %, 18 ⁇ 2%, 20 ⁇ 2%, 22 ⁇ 2%, 24 ⁇ 2%, 26 ⁇ 2%, 28 ⁇ 2%, 30 ⁇ 2%, 32 ⁇ 2%, 34 ⁇ 2%, 36 ⁇ 2% %, 40 ⁇ 2%, 42 ⁇ 2%, 44 ⁇ 2%, 46 ⁇ 2%, 48 ⁇ 2%, 50 ⁇ 2%.
  • the mass of the active ingredient in the pharmaceutical composition is 1-600 mg, 5-300 mg, 10-150 mg, 20-75 mg, or 15-25 mg, 30-40 mg, 45-55 mg, 60 ⁇ 70mg, 75 ⁇ 85mg, 90 ⁇ 100mg, 105 ⁇ 115mg, 120 ⁇ 130mg, 135 ⁇ 145mg, 150 ⁇ 160mg, 165 ⁇ 175mg, 180 ⁇ 190mg, 200 ⁇ 210mg, 220 ⁇ 230mg, 240 ⁇ 250mg, 260 ⁇ 270mg, 280 ⁇ 290mg, 300 ⁇ 310mg, 320 ⁇ 330mg, 340 ⁇ 350mg, 360 ⁇ 370mg, 380 ⁇ 390mg, 400 ⁇ 410mg, 420 ⁇ 430mg, 440 ⁇ 450mg.
  • the mass of the active ingredient in the pharmaceutical composition is 10 ⁇ 2.5mg, 15 ⁇ 2.5mg, 20 ⁇ 2.5mg, 25 ⁇ 2.5mg, 30 ⁇ 2.5mg, 35 ⁇ 2.5mg, 40 ⁇ 2.5mg, 45 ⁇ 2.5mg, 50 ⁇ 2.5mg, 55 ⁇ 2.5mg, 60 ⁇ 2.5mg, 65 ⁇ 2.5mg, 70 ⁇ 2.5mg, 75 ⁇ 2.5mg, 80 ⁇ 2.5mg, 85 ⁇ 2.5mg, 90 ⁇ 2.5mg, 95 ⁇ 2.5mg, 100 ⁇ 2.5mg, 105 ⁇ 2.5mg, 110 ⁇ 2.5mg, 115 ⁇ 2.5mg, 120 ⁇ 2.5mg, 125 ⁇ 2.5mg, 130 ⁇ 2.5mg, 135 ⁇ 2.5mg, 140 ⁇ 2.5mg, 145 ⁇ 2.5mg, 150 ⁇ 2.5mg, 155 ⁇ 2.5mg, 160 ⁇ 2.5mg, 165 ⁇ 2.5mg, 170 ⁇ 2.5mg, 175 ⁇ 2.5mg, 180 ⁇ 2.5mg, 185 ⁇ 2.5mg, 190 ⁇ 2.5mg, 195 ⁇ 2.5m
  • the mass percentage content of the solubilizer is selected from 0.1% to 10%.
  • the mass percentage content of the solubilizer is 0.2%-5%.
  • the mass percentage content of the solubilizer is 0.1-0.6%, 0.2-0.7%, 0.3-0.8%, 0.4-0.9%, 0.5-1.0%, 1.1-1.6%, 1.2-1.7% %, 1.3 ⁇ 1.8%, 1.4 ⁇ 1.9%, 1.5 ⁇ 2.0%, 2.1 ⁇ 2.6%, 2.2 ⁇ 2.7%, 2.3 ⁇ 2.8%, 2.4 ⁇ 2.9%, 2.5 ⁇ 3.0%, 3.1 ⁇ 3.6%, 3.2 ⁇ 3.7% %, 3.3 ⁇ 3.8%, 3.4 ⁇ 3.9%, 4.5 ⁇ 5.0%, 5.1 ⁇ 5.6%, 5.2 ⁇ 5.7%, 5.3 ⁇ 5.8%, 5.4 ⁇ 5.9%, 5.5 ⁇ 6.0%, 6.1 ⁇ 6.6%, 6.2 ⁇ 6.7% %, 6.3 ⁇ 6.8%, 6.4 ⁇ 6.9%, 6.5 ⁇ 7.0%, 7.1 ⁇ 7.6%, 7.2 ⁇ 7.7%, 7.3 ⁇ 7.8%, 7.4 ⁇ 7.9%, 7.5 ⁇ 8.0%, 8.1 ⁇ 8.6%, 8.2 ⁇ 8.7% %, 8.3-8.8%, 8.
  • the mass of the solubilizer in the pharmaceutical composition is 0.5-50 mg, 1-30 mg, 2-20 mg, or 2-5 mg, 6-9 mg, 10-14 mg, 15-19 mg, 20 ⁇ 24mg, 25 ⁇ 29mg, 30 ⁇ 34mg, 35 ⁇ 39mg, 40 ⁇ 44mg, 45 ⁇ 49mg.
  • the mass of the solubilizer in the pharmaceutical composition is 3 ⁇ 1mg, 6 ⁇ 1mg, 9 ⁇ 1mg, 12 ⁇ 1mg, 15 ⁇ 1mg, 18 ⁇ 1mg, 21 ⁇ 1mg, 24 ⁇ 1mg 1mg, 27 ⁇ 1mg, 30 ⁇ 1mg, 33 ⁇ 1mg, 36 ⁇ 1mg, 39 ⁇ 1mg, 42 ⁇ 1mg, 45 ⁇ 1mg, 48 ⁇ 1mg.
  • the solubilizer is selected from one of HS15, RH40, hydroxypropyl beta cyclodextrin, Soluplus, castor oil polyoxylate 35, and polyethylene glycol cetostearyl ether 12 or two or more.
  • the solubilizer is HS15.
  • the solubilizer is RH40.
  • the solubilizer is hydroxypropyl beta cyclodextrin.
  • the solubilizer is Soluplus.
  • OAD2 or a pharmaceutically acceptable salt thereof is the only active ingredient.
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, p-toluenesulfonate, sulfate, hydrobromide, tartrate, citrate, glycolate , one of the mesylate salts.
  • the pharmaceutically acceptable salt is dihydrochloride.
  • the active ingredient is OAD2 hydrochloride, OAD2 dihydrochloride, OAD2 p-toluenesulfonate, OAD2 sulfate, OAD2 hydrobromide, OAD2 tartrate, OAD2 citrate, OAD2 Glycolate, one of OAD2 mesylate.
  • the active ingredient is OAD2 dihydrochloride.
  • the existing form of the active ingredient in the pharmaceutical composition is free OAD2.
  • the form of the active ingredient in the pharmaceutical composition is OAD2 dihydrochloride.
  • the pharmaceutically acceptable salt of OAD2 described in the present invention is formed from OAD2 and a pharmaceutically acceptable acid.
  • the pharmaceutically acceptable acid is selected from 1-hydroxy-2-naphthoic acid, 4-aminosalicylic acid, adipic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, trans Cinnamic acid, citric acid, fumaric acid, galactobionic acid, gentisic acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, caproic acid, hippuric acid, hydrobromic acid, hydrochloric acid, L-lactic acid, malic acid Acid, L-malic acid, malonic acid, R-mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, niacin, oxalic acid, palmitic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, stearic acid, succinic acid, Sulfuric acid, L-tartaric acid, p-toluenesulfonic acid,
  • the pharmaceutically acceptable acid is selected from hydrobromic acid, hydrochloric acid, p-toluenesulfonic acid, tartaric acid, citric acid, glycolic acid, methanesulfonic acid, and sulfonic acid.
  • the total amount of the active ingredient (OAD2 or a pharmaceutically acceptable salt thereof) in the pharmaceutical composition or dosage form of the present invention is not limited.
  • the content of the active ingredient is in the range of 0.01 to 80 wt%, or 0.1 to 50 wt%, or 10 to 40 wt%, based on the total weight of the dosage form. In one embodiment, the content of the active ingredient is in the following range: 1 to 4wt%, or 2 to 5wt%, or 3 to 6wt%, or 4 to 7wt%, or 5 to 8wt%, or 6 to 9wt%, Or 7 to 10wt%, or 8 to 11wt%, or 9 to 12wt%, or 10 to 13wt%, or 11 to 14wt%, or 12 to 15wt%, or 13 to 16wt%, or 14 to 17wt%, or 15 to 18wt%, or 16 to 19wt%, or 17 to 20wt%, or 18 to 21wt%, or 19 to 22wt%, or 20 to 23wt%, or 21 to 24wt%, or 22 to 25wt%, or 23 to 26wt% %,
  • the content of the active ingredient is 4 ⁇ 2.5 wt%, 6 ⁇ 2.5 wt%, 8 ⁇ 2.5 wt%, 10 ⁇ 2.5 wt%, or 12 ⁇ 2.5 wt%, or 14 ⁇ 2.5wt%, or 16 ⁇ 2.5wt%, or 18 ⁇ 2.5wt%, or 20 ⁇ 2.5wt%, or 22 ⁇ 2.5wt%, or 24 ⁇ 2.5wt%, or 26 ⁇ 2.5wt%, or 28 ⁇ 2.5wt%, or 30 ⁇ 2.5wt%, or 32 ⁇ 2.5wt%, or 34 ⁇ 2.5wt%, or 36 ⁇ 2.5wt%, or 38 ⁇ 2.5wt%, or 40 ⁇ 2.5wt%, or 42 ⁇ 2.5wt%, or 44 ⁇ 2.5wt%, or 46 ⁇ 2.5wt%, or 48 ⁇ 2.5wt%, or 50 ⁇ 2.5wt%.
  • the content of active ingredient is 30 ⁇ 2.5 wt % or 12 ⁇ 2.5 wt %.
  • the amount of active ingredient contained in the dosage form ranges from 1 to 500 mg, or from 10 to 250 mg, or from 25 to 200 mg, or from 20 to 60 mg, or from 40 to 80 mg, Or from 60 to 100mg, or from 80 to 140mg, or from 100 to 160mg, or from 120 to 180mg, or from 140 to 200mg, or from 160 to 220mg, or from 180 to 240mg, or from 200 to 260mg.
  • the active ingredient is contained in the dosage form in an amount of 25 mg ⁇ 5 mg, or 30 mg ⁇ 5 mg, or 40 mg ⁇ 5 mg, or 50 mg ⁇ 5 mg, or 60 mg ⁇ 5 mg, or 75 mg ⁇ 5 mg, or 80 mg ⁇ 5 mg , or 90mg ⁇ 5mg, or 100mg ⁇ 5mg, or 110mg ⁇ 5mg, or 120mg ⁇ 5mg, or 125mg ⁇ 5mg, or 130mg ⁇ 5mg, or 140mg ⁇ 5mg, or 150mg ⁇ 5mg, or 160mg ⁇ 5mg, or 170mg ⁇ 5mg , or 175mg ⁇ 5mg, or 180mg ⁇ 5mg, or 190mg ⁇ 5mg, or 200mg ⁇ 5mg, or 225mg ⁇ 5mg, or 250mg ⁇ 5mg.
  • the active ingredient is contained in the dosage form in an amount of 25 mg ⁇ 5 mg, or 50 mg ⁇ 5 mg, or 75 mg ⁇ 5 mg, or 100 mg ⁇ 5 mg, or 125 mg ⁇ 5 mg. In another embodiment, the active ingredient is contained in the dosage form in an amount of 25 mg ⁇ 2.5 mg, or 50 mg ⁇ 2.5 mg, or 75 mg ⁇ 2.5 mg, or 100 mg ⁇ 2.5 mg, or 125 mg ⁇ 2.5 mg.
  • the active ingredient in the composition or dosage form is OAD2 dihydrochloride
  • the dosage form is suitable for oral administration once daily or twice daily, and the OAD2 dihydrochloride contained in the dosage form The amount is 25 mg ⁇ 2.5 mg, 50 mg ⁇ 2.5 mg, 75 mg ⁇ 2.5 mg or 100 mg ⁇ 2.5 mg.
  • the content of the active ingredient (preferably OAD2 dihydrochloride) in the composition or dosage form is equal to at least 90% of its original content before storage, or at least 98.0%, or at least 98.5%, or at least 99.0%, or at least 99.2%, or at least 99.4%, or at least 99.6%, or at least 99.8%.
  • the content of active ingredient (preferably OAD2 dihydrochloride) in the composition or dosage form is equal to its original content before storage.
  • the content of active ingredient (preferably OAD2 dihydrochloride) in the composition or dosage form is equal to its original content before storage.
  • the active ingredient in the composition or dosage form is equal to at least 90%, or at least 98.0%, or at least 98.5%, or at least 99.0%, or at least 99.2%, or at least 99.4%, or at least 99.6% of its original content before storage , or at least 99.8%.
  • Suitable methods for measuring the amount of active ingredient in a dosage form are well known to those skilled in the art, some of which are described in the Examples section below.
  • the pharmaceutical composition provided by the present invention can also contain one or more pharmaceutically acceptable excipients; the excipients can be disintegrants, fillers, viscose Mixtures, lubricants, wetting agents, glidants, acidulants, surfactants, absorption enhancers.
  • the excipients can be disintegrants, fillers, viscose Mixtures, lubricants, wetting agents, glidants, acidulants, surfactants, absorption enhancers.
  • the pharmaceutical composition provided by the present invention may also contain disintegrants, fillers, binders, lubricants, wetting agents, glidants, acidulants, surface Active agent, absorption enhancer.
  • compositions of the present invention optionally, but preferably comprise, as carrier material, one or more pharmaceutically acceptable fillers.
  • the pharmaceutical composition provided by the present invention further comprises a filler in addition to OAD2 or a pharmaceutically acceptable salt thereof.
  • the filler is selected from microcrystalline cellulose, lactose, sucrose, mannitol, corn starch, pregelatinized starch, dextrin, sorbitol, inorganic calcium salt, cellulose acetate, glucose, ethyl At least one of base cellulose and glyceryl palmitate stearate.
  • the weight percentage of the filler is 10-75%.
  • the filler is preferably one or more selected from microcrystalline cellulose, lactose, mannitol, and pregelatinized starch.
  • the filler is selected from a combination of microcrystalline cellulose and lactose.
  • the mass percent content of the filler is 20-60%.
  • the mass percentage of the filler in the pharmaceutical composition of the present invention is 15-19%, 16-20%, 21-25%, 22-26%, 23-27%, 24-28%, 25-29%, 26-30%, 31-35%, 32-36%, 33-37%, 34-38%, 35-39%, 36-40%, 41-45%, 42-46%, 43-47%, 44-48%, 45-49%, 46-50%, 51-55%, 52-56%, 53-57%, 54-58%, 55-59%, 56-60%.
  • the mass of the filler in the pharmaceutical composition of the present invention is 50 ⁇ 2.5mg, 55 ⁇ 2.5mg, 60 ⁇ 2.5mg, 65 ⁇ 2.5mg, 70 ⁇ 2.5mg, 75 ⁇ 2.5mg mg, 80 ⁇ 2.5mg, 85 ⁇ 2.5mg, 90 ⁇ 2.5mg, 95 ⁇ 2.5mg, 100 ⁇ 2.5mg, 105 ⁇ 2.5mg, 110 ⁇ 2.5mg, 115 ⁇ 2.5mg, 120 ⁇ 2.5mg, 125 ⁇ 2.5mg mg, 130 ⁇ 2.5mg, 135 ⁇ 2.5mg, 140 ⁇ 2.5mg, 145 ⁇ 2.5mg, 150 ⁇ 2.5mg, 155 ⁇ 2.5mg, 160 ⁇ 2.5mg, 165 ⁇ 2.5mg, 170 ⁇ 2.5mg, 175 ⁇ 2.5mg mg, 180 ⁇ 2.5mg, 185 ⁇ 2.5mg, 190 ⁇ 2.5mg, 195 ⁇ 2.5mg, 200 ⁇ 2.5mg, 205 ⁇ 2.5mg, or 210 ⁇ 5mg, 220 ⁇ 5mg, 230 ⁇ 5mg, 240 ⁇ 5
  • compositions provided herein may also optionally comprise disintegrants, and in some embodiments preferably comprise one or more pharmaceutically acceptable disintegrants as carrier material, especially for tablet formulations .
  • the disintegrant is selected from microcrystalline cellulose, crospovidone, sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, dry starch , at least one of carboxymethylcellulose calcium.
  • the mass percentage of the disintegrant is 5-40%.
  • the disintegrant is preferably selected from one or more of microcrystalline cellulose, crospovidone, low-substituted hydroxypropyl cellulose, and croscarmellose sodium .
  • the disintegrant is a combination of microcrystalline cellulose and any one selected from crospovidone, low-substituted hydroxypropyl cellulose, and croscarmellose sodium.
  • the mass percent content of the disintegrant is 10-30%.
  • the mass percentage of the disintegrant in the pharmaceutical composition of the present invention is 5-9%, 6-10%, 11-15%, 12-16%, 13-17% , 14 ⁇ 18%, 15 ⁇ 19%, 16 ⁇ 20%, 21 ⁇ 25%, 22 ⁇ 26%, 23 ⁇ 27%, 24 ⁇ 28%, 25 ⁇ 29%, 26 ⁇ 30%, 31 ⁇ 35% , 32-36%, 33-37%, 34-38%, 35-39%, 36-40%.
  • the mass of the disintegrant in the pharmaceutical composition of the present invention is 30 ⁇ 2.5mg, 35 ⁇ 2.5mg, 40 ⁇ 2.5mg, 45 ⁇ 2.5mg, 50 ⁇ 2.5mg, 55 ⁇ 2.5mg, 60 ⁇ 2.5mg, 65 ⁇ 2.5mg, 70 ⁇ 2.5mg, 75 ⁇ 2.5mg, 80 ⁇ 2.5mg, 85 ⁇ 2.5mg, 90 ⁇ 2.5mg, 95 ⁇ 2.5mg, 100 ⁇ 2.5mg, 105 ⁇ 2.5mg, 110 ⁇ 2.5mg, 115 ⁇ 2.5mg, 120 ⁇ 2.5mg, 125 ⁇ 2.5mg, 130 ⁇ 2.5mg, 135 ⁇ 2.5mg, 140 ⁇ 2.5mg, 145 ⁇ 2.5mg, 150 ⁇ 2.5mg, 155 ⁇ 2.5mg, 160 ⁇ 2.5mg, 165 ⁇ 2.5mg, 170 ⁇ 2.5mg, 175 ⁇ 2.5mg, 180 ⁇ 2.5mg, 185 ⁇ 2.5mg, 190 ⁇ 2.5mg, 195 ⁇ 2.5mg, 200 ⁇ 2.5mg, 205 ⁇ 2.5mg, or 210 ⁇
  • the disintegrant is low-substituted hydroxypropyl cellulose, wherein the hydroxypropoxyl content of the low-substituted hydroxypropyl cellulose is 5-12%.
  • compositions provided herein may also optionally comprise a binder, and in some embodiments preferably comprise one or more pharmaceutically acceptable binders as carrier material, especially for tablets preparation.
  • binders ideally impart sufficient cohesion to the tableted powder to allow normal processing operations such as sizing, lubrication, compression, and packaging, yet allow, upon ingestion, the tablet to disintegrate and the composition to absorbed.
  • the binder is selected from pregelatinized starch, starch, lactose, methylcellulose, ethylcellulose, povidone, copovidone, hydroxypropylcellulose, hypromellose Cellulose, sodium carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, gelatin, sucrose, sodium alginate, carob gum, chitosan, dextrin, glyceryl behenate.
  • the mass percentage of the binder is selected from 5% to 40%.
  • the binder is preferably selected from one or more of pregelatinized starch, lactose, and hypromellose.
  • the mass percent content of the binder is 10%-30%.
  • the mass percentage of the binder is 11-15%, 12-16%, 13-17%, 14-18%, 15-19%, 16-20%, 21-25% %, 22-26%, 23-27%, 24-28%, 25-29%, 26-30%.
  • the mass of the binder in the pharmaceutical composition of the present invention is 30 ⁇ 2.5mg, 35 ⁇ 2.5mg, 40 ⁇ 2.5mg, 45 ⁇ 2.5mg, 50 ⁇ 2.5mg, 55 ⁇ 2.5mg, 60 ⁇ 2.5mg, 65 ⁇ 2.5mg, 70 ⁇ 2.5mg, 75 ⁇ 2.5mg, 80 ⁇ 2.5mg, 85 ⁇ 2.5mg, 90 ⁇ 2.5mg, 95 ⁇ 2.5mg, 100 ⁇ 2.5mg, 105 ⁇ 2.5mg, 110 ⁇ 2.5mg, 115 ⁇ 2.5mg, 120 ⁇ 2.5mg, 125 ⁇ 2.5mg, 130 ⁇ 2.5mg, 135 ⁇ 2.5mg, 140 ⁇ 2.5mg, 145 ⁇ 2.5mg, 150 ⁇ 2.5mg, 155 ⁇ 2.5mg, 160 ⁇ 2.5mg, 165 ⁇ 2.5mg, 170 ⁇ 2.5mg, 175 ⁇ 2.5mg, 180 ⁇ 2.5mg, 185 ⁇ 2.5mg, 190 ⁇ 2.5mg, 195 ⁇ 2.5mg, 200 ⁇ 2.5mg, 205 ⁇ 2.5mg, or 210 ⁇ 5
  • compositions of the present invention optionally include as carrier material one or more pharmaceutically acceptable lubricants.
  • the lubricant is selected from stearic acid, magnesium stearate, sodium stearyl fumarate, glyceryl behenate, micronized silica gel, talcum powder, polyethylene glycol, hydrogenated vegetable oil, Sodium Dialkyl Sulfate, Glyceryl Monostearate.
  • the mass percentage of the lubricant is selected from 0.1% to 10%.
  • the lubricant is preferably selected from one or more of magnesium stearate, micronized silica gel, and talcum powder.
  • the mass percentage content of the lubricant is 0.2%-5%.
  • the mass percentage of the lubricant is 0.1-0.6%, 0.2-0.7%, 0.3-0.8%, 0.4-0.9%, 0.5-1.0%, 1.1-1.6%, 1.2- 1.7%, 1.3 ⁇ 1.8%, 1.4 ⁇ 1.9%, 1.5 ⁇ 2.0%, 2.1 ⁇ 2.6%, 2.2 ⁇ 2.7%, 2.3 ⁇ 2.8%, 2.4 ⁇ 2.9%, 2.5 ⁇ 3.0%, 3.1 ⁇ 3.6%, 3.2 ⁇ 3.7%, 3.3 ⁇ 3.8%, 3.4 ⁇ 3.9%, 4.5 ⁇ 5.0%, 5.1 ⁇ 5.6%, 5.2 ⁇ 5.7%, 5.3 ⁇ 5.8%, 5.4 ⁇ 5.9%, 5.5 ⁇ 6.0%, 6.1 ⁇ 6.6%, 6.2 ⁇ 6.7%, 6.3 ⁇ 6.8%, 6.4 ⁇ 6.9%, 6.5 ⁇ 7.0%, 7.1 ⁇ 7.6%, 7.2 ⁇ 7.7%, 7.3 ⁇ 7.8%, 7.4 ⁇ 7.9%, 7.5 ⁇ 8.0%, 8.1 ⁇ 8.6%, 8.2 ⁇ 8.7%, 8.3-8.8%, 8.4-8.9%, 8.5-9.
  • the mass of the lubricant in the pharmaceutical composition of the present invention is 0.1-40 mg, 0.2-30 mg, 0.3-20 mg, 0.4-15 mg, 0.5-10 mg, or 1-6 mg, 2-2 mg 7mg, 3 ⁇ 8mg, 4 ⁇ 9mg, 5 ⁇ 10mg, 11 ⁇ 16mg, 12 ⁇ 17mg, 13 ⁇ 18mg, 14 ⁇ 19mg, 15 ⁇ 20mg, 21 ⁇ 26mg, 22 ⁇ 27mg, 23 ⁇ 28mg, 24 ⁇ 29mg, 25 ⁇ 30mg.
  • the quality of the lubricant in the pharmaceutical composition of the present invention is 1 ⁇ 0.5mg, 2 ⁇ 0.5mg, 3 ⁇ 0.5mg, 4 ⁇ 0.5mg, 5 ⁇ 0.5mg, 6 ⁇ 0.5 mg, 7 ⁇ 0.5mg, 8 ⁇ 0.5mg, 9 ⁇ 0.5mg, 10 ⁇ 0.5mg, 11 ⁇ 0.5mg, 12 ⁇ 0.5mg, 13 ⁇ 0.5mg, 14 ⁇ 0.5mg, 15 ⁇ 0.5mg, 16 ⁇ 0.5 mg, 17 ⁇ 0.5mg, 18 ⁇ 0.5mg, 19 ⁇ 0.5mg, 20 ⁇ 0.5mg.
  • the pharmaceutical composition provided by the invention may also optionally contain a wetting agent.
  • the humectant is selected from ethanol, glycerin, Tween.
  • the mass percent content of the wetting agent is selected from 0.1% to 10%.
  • the wetting agent is preferably Tween 80.
  • the mass percentage content of the wetting agent is 1%-10%.
  • the mass percentage content of the wetting agent is 0.1-0.6%, 0.2-0.7%, 0.3-0.8%, 0.4-0.9%, 0.5-1.0%, 1.1-1.6%, 1.2- 1.7%, 1.3 ⁇ 1.8%, 1.4 ⁇ 1.9%, 1.5 ⁇ 2.0%, 2.1 ⁇ 2.6%, 2.2 ⁇ 2.7%, 2.3 ⁇ 2.8%, 2.4 ⁇ 2.9%, 2.5 ⁇ 3.0%, 3.1 ⁇ 3.6%, 3.2 ⁇ 3.7%, 3.3-3.8%, 3.4-3.9%, 4.5-5.0%, 5.1-5.6%, 5.2-5.7%, 5.3-5.8%, 5.4-5.9%, 5.5-6.0%.
  • the mass of the wetting agent in the pharmaceutical composition of the present invention is 0.5-50 mg, 1-30 mg, 2-20 mg, or 2-5 mg, 6-9 mg, 10-14 mg, 15 mg ⁇ 19mg, 20 ⁇ 24mg, 25 ⁇ 29mg, 30 ⁇ 34mg, 35 ⁇ 39mg, 40 ⁇ 44mg, 45 ⁇ 49mg.
  • the mass of the wetting agent in the pharmaceutical composition of the present invention is 3 ⁇ 1mg, 6 ⁇ 1mg, 9 ⁇ 1mg, 12 ⁇ 1mg, 15 ⁇ 1mg, 18 ⁇ 1mg, 21 ⁇ 1mg , 24 ⁇ 1mg, 27 ⁇ 1mg, 30 ⁇ 1mg, 33 ⁇ 1mg, 36 ⁇ 1mg, 39 ⁇ 1mg, 42 ⁇ 1mg, 45 ⁇ 1mg, 48 ⁇ 1mg.
  • compositions of the present invention optionally include as carrier material one or more pharmaceutically acceptable glidants.
  • the glidant is selected from micropowdered silica gel, talc powder, and colloidal silicon dioxide.
  • the mass percent content of the glidant is selected from 0.1% to 10%.
  • the glidant is preferably micronized silica gel or colloidal silicon dioxide.
  • the mass percent content of the glidant is 0.2%-5%.
  • the mass percentage of the glidant is 0.1-0.6%, 0.2-0.7%, 0.3-0.8%, 0.4-0.9%, 0.5-1.0%, 1.1-1.6%, 1.2% ⁇ 1.7%, 1.3 ⁇ 1.8%, 1.4 ⁇ 1.9%, 1.5 ⁇ 2.0%, 2.1 ⁇ 2.6%, 2.2 ⁇ 2.7%, 2.3 ⁇ 2.8%, 2.4 ⁇ 2.9%, 2.5 ⁇ 3.0%, 3.1 ⁇ 3.6%, 3.2 ⁇ 3.7%, 3.3 ⁇ 3.8%, 3.4 ⁇ 3.9%, 4.5 ⁇ 5.0%, 5.1 ⁇ 5.6%, 5.2 ⁇ 5.7%, 5.3 ⁇ 5.8%, 5.4 ⁇ 5.9%, 5.5 ⁇ 6.0%, 6.1 ⁇ 6.6%, 6.2 ⁇ 6.7%, 6.3 ⁇ 6.8%, 6.4 ⁇ 6.9%, 6.5 ⁇ 7.0%, 7.1 ⁇ 7.6%, 7.2 ⁇ 7.7%, 7.3 ⁇ 7.8%, 7.4 ⁇ 7.9%, 7.5 ⁇ 8.0%, 8.1 ⁇ 8.6%, 8.2 ⁇ 8.7%, 8.3 ⁇ 8.8%, 8.4 ⁇ 8 ⁇ 8
  • the mass of the glidant in the pharmaceutical composition of the present invention is 0.1-40 mg, 0.2-30 mg, 0.3-20 mg, 0.4-15 mg, 0.5-10 mg, or 1-6 mg, 2 ⁇ 7mg, 3 ⁇ 8mg, 4 ⁇ 9mg, 5 ⁇ 10mg, 11 ⁇ 16mg, 12 ⁇ 17mg, 13 ⁇ 18mg, 14 ⁇ 19mg, 15 ⁇ 20mg, 21 ⁇ 26mg, 22 ⁇ 27mg, 23 ⁇ 28mg, 24 ⁇ 29mg , 25-30 mg.
  • the mass of the glidant in the pharmaceutical composition of the present invention is 1 ⁇ 0.5mg, 2 ⁇ 0.5mg, 3 ⁇ 0.5mg, 4 ⁇ 0.5mg, 5 ⁇ 0.5mg, 6 ⁇ 0.5mg 0.5mg, 7 ⁇ 0.5mg, 8 ⁇ 0.5mg, 9 ⁇ 0.5mg, 10 ⁇ 0.5mg, 11 ⁇ 0.5mg, 12 ⁇ 0.5mg, 13 ⁇ 0.5mg, 14 ⁇ 0.5mg, 15 ⁇ 0.5mg, 16 ⁇ 0.5mg, 17 ⁇ 0.5mg, 18 ⁇ 0.5mg, 19 ⁇ 0.5mg, 20 ⁇ 0.5mg.
  • compositions of the present invention optionally comprise one or more pharmaceutically acceptable acidulants as carrier material.
  • the acidulant is selected from tartaric acid, citric acid, propionic acid, phosphoric acid, malic acid, lactic acid, hydrochloric acid.
  • the mass percent content of the acidulant is selected from 1% to 40%.
  • the acidulant is preferably selected from citric acid or anhydrous citric acid.
  • the mass percent content of the acidulant is 5%-20%.
  • compositions of the present invention optionally contain one or more absorption enhancers.
  • the absorption enhancer is selected from the group consisting of oleic acid, cinnazone, menthol, vitamin E, vitamin E-TPGS, propylene glycol, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin , sodium lauryl sulfate, N-methyl-2-pyrrolone, dimethyl sulfoxide, ethanol, ethylene glycol, ethoxydiethylene glycol, bisabolol, liposome, azone, piperine , Sodium Caprylate, Sodium Caprate, Sodium Caproate, Capryl Carnitine, Sucrose Ester, Chitosan.
  • the mass percent content of the absorption enhancer is selected from 0.1% to 10%.
  • the absorption enhancer is preferably selected from one or more of vitamin E, oleic acid, propylene glycol, and hydroxypropyl- ⁇ -cyclodextrin.
  • the mass percent content of the absorption enhancer is 0.5%-5%.
  • compositions of the present invention optionally, but preferably comprise as carrier material one or more pharmaceutically acceptable surfactants.
  • Such surfactants are preferably selected to keep OAD2, or a pharmaceutically acceptable salt thereof, tightly bound to water.
  • the surfactant is selected from the group consisting of lecithin, fatty acid glycerides, sucrose fatty acid esters, Span, Tween, Maize, Bianze, poloxamer, sodium lauryl sulfate, Sodium Cetyl Sulfate, Sodium Octadecyl Sulfate, Sodium Dioctyl Sulfuccinate, Sodium Sulfuccinate Dicaproate, Sodium Dodecylbenzene Sulfonate, Bianyl Benzoate, Docusate Sodium .
  • the mass percent content of the surfactant is selected from 0.2% to 20%.
  • compositions of the present invention optionally comprise one or more antioxidants.
  • antioxidant refers to a component of a composition which prevents and/or inhibits the formation of unacceptable amounts of oxidative degradation products in the composition after a certain shelf life.
  • antioxidants can react with oxygen that might otherwise damage the composition by producing impurities in the composition.
  • Oxygen can originate from the environment of the composition or from the composition itself.
  • the oxygen can be derived from residual oxygen present in the headspace of the vial containing the composition.
  • the oxidative degradants include Impurity B
  • the antioxidant can limit the formation of oxidative degradants (e.g., Impurity B) in the composition to less than about 5%, or less than At about 4%, or less than about 3%, or less than about 2.5%, or less than about 2%, or less than about 1.5%, or less than about 1%, or less than about 0.9%, or less than About 0.8%, or less than about 0.7%, or less than about 0.6%, or less than about 0.5%, or less than about 0.4%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1%, or less than about 0.05%, or less than about 0.04%, or less than about 0.03%, or less than about 0.02%, or less than about 0.01%.
  • Impurity B oxidative degradants
  • an antioxidant may be present at a minimum concentration that inhibits and/or prevents the composition from undergoing unacceptable physical changes. In some embodiments, the antioxidant may be present at a minimum concentration that inhibits and/or prevents unacceptable oxidation of the components of the composition.
  • the antioxidant is selected from the group consisting of sulfites, ascorbic acid, thiourea, cysteine, ascorbyl palmitate, alpha-tocopherol, dibutyl cresol, dibutyl thiodiacetate, tartaric acid , citric acid, disodium edetate, tocopheryl polyethylene glycol succinate, vitamin E and its derivatives, etc.
  • the mass percent content of the antioxidant is selected from 0.5% to 10%.
  • the mass percent content refers to the percentage of the total weight of the drug, and the total weight of the drug does not include the weight of the coating, for a specific dosage form, such as the weight of the tablet core or granules .
  • active ingredient 1 ⁇ 60% Solubilizers 0.1 ⁇ 10% filler 10 ⁇ 75% disintegrant 5 ⁇ 40% optional, adhesive 5 ⁇ 40% optional, lubricant 0.2 ⁇ 5% optional, wetting agent 0.1 ⁇ 10% optional, glidant 0.1 ⁇ 10% optional acidulant 1 ⁇ 40% Optional, absorption enhancer 0.1 ⁇ 10% Optional, surfactant 0.1 ⁇ 5% optional, antioxidant 0.2 ⁇ 20%
  • surfactant 0.1 ⁇ 2.5% optional, antioxidant 0.5 ⁇ 10%
  • Suitable fillers also include: lactose USP; lactose USP, anhydrous; lactose USP, spray dried; starch USP; pregelatinized starches (eg National 1511 and Starch 1500); direct compressible starches ; mannitol USP; sorbitol; dextrose monohydrate; microcrystalline cellulose NF; calcium hydrogen phosphate dihydrate NF; sucrose-based bulking agent; powdered sugar (confectioner's sugar); monobasic calcium sulfate monohydrate); calcium sulfate dihydrate NF; calcium lactate trihydrate granular NF; dextrates, inositol; hydrolyzed grain solids such as Maltrons and Mor-Rex; amylase; Rexcel; powder Cellulose (eg, Elcema); Calcium Carbonate; Glycine; Bentonite Clay; Such fillers, if present, comprise in total from about 5% to about 99%, or from about 10% to about 85%
  • lactose, pregelatinized starch and microcrystalline cellulose are preferred fillers.
  • the filler comprises microcrystalline cellulose and/or pregelatinized starch in an amount ranging from 20% to 60% by weight of the total composition.
  • the filler comprises microcrystalline cellulose in an amount of 20% to 40% by weight of the total composition.
  • the fillers comprise a total of about 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, or 30 wt% ⁇ 2.5 wt% of the total weight of the composition.
  • Suitable disintegrants also include: starches; sodium starch glycolate; clays (such as Veegum HV); celluloses (such as purified cellulose, methylcellulose, sodium carboxymethylcellulose and carboxymethylcellulose alginate; pregelatinized corn starch (e.g. National 1551 and National 1550); crospovidone USP NF; and gums (e.g. agar, guar, carob, carrageenan, pectin and tragacanth).
  • the disintegrant may be added at any suitable step during the preparation of the composition, in particular as an extragranular excipient prior to granulation or prior to compression.
  • Such disintegrants constitute in total from about 0.2 wt% to about 30 wt%, or from about 0.2 wt% to about 10 wt%, or from about 0.2 wt% to about 5 wt%, of the total weight of the composition.
  • the disintegrants comprise a total of about 5%, 10%, 15%, 20%, 25%, or 30% ⁇ 2.5% by weight of the total weight of the composition.
  • Crospovidone cross-linked polyvinylpyrrolidone is the preferred disintegrant for tablet or capsule disintegration and, if present, may comprise from about 0.1 wt% to about 20 wt%, or about 0.2 wt% of the total weight of the composition. wt% to about 10 wt%, or about 0.2 wt% to about 6 wt%, or about 0.2 wt% to about 5 wt%, or about 1 wt% to about 5 wt%.
  • the crospovidone comprises a total of about 2%, 5%, 10%, 15%, 20%, 25%, or 30% ⁇ 1.5% by weight of the total composition.
  • the crospovidone used in the pharmaceutical composition can be European Pharmacopoeia Crospovidone Monograph Class A or Class B quality.
  • the amount of peroxide in crospovidone as measured by the European Pharmacopoeia Crospovidone Monograph Class A method does not exceed 50 ppm, or 45 ppm, or 40 ppm, or 35 ppm, or 30 ppm, or 25 ppm, or 20ppm, or 15ppm, or 10ppm.
  • the amount of peroxide in the crospovidone as measured by the European Pharmacopoeia Crospovidone Monograph Type B method does not exceed 125 ppm, or 100 ppm, or 75 ppm, or 50 ppm, or 25 ppm.
  • the quality of crospovidone is equivalent to the quality of grade "Ultra” or "Ultra-10" available from Ashland under the tradename PolyplasdoneTM Ultra.
  • the typical average particle size of crospovidone is 110-140 microns or 25-40 microns.
  • Binders may also include (alone or in combination): gum arabic; tragacanth; sucrose; gelatin; glucose; starch; cellulosic materials such as, but not limited to, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose); alginic acid and alginate; magnesium aluminum silicate; polyethylene glycol; guar gum; polysaccharide acid; bentonite; polyvinylpyrrolidone; copovidone (copolymer of vinylpyrrolidone and vinyl acetate); Methacrylates; Hydroxypropylmethylcellulose (HPMC); Hydroxypropylcellulose (Klucel); Ethylcellulose (Ethocel); Pregelatinized starches (such as National 1511 and Starch 1500).
  • Such binders if present, total from about 0.1 wt% to about 20 wt%, or from about 0.75 wt% to about 15 wt%, or from about 1 wt% to about 10 wt%, or from about 1 wt% to about 5wt%.
  • Crospovidone is the preferred binder for tablet or capsule disintegration and, if present, comprises from about 0.1 wt% to about 10 wt%, or from about 0.2 wt% to about 5 wt% of the total weight of the composition , or about 0.3 wt% to about 4 wt%, or about 0.4 wt% to about 3 wt%, or about 0.5 wt% to about 1 wt%.
  • the amount of crospovidone present in the composition is about 0.5 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, based on the total weight of the composition.
  • Suitable lubricants also include: glyceryl behapate (Compritol 888); stearates (magnesium, calcium and sodium); stearic acid; hydrogenated vegetable oils (eg, Sterotex) ; Talc; Wax; Stearowet; Boric Acid; Sodium Benzoate; Sodium Acetate; Sodium Fumarate; Sodium Chloride; DL-Leucine; Polyethylene Glycols (eg Carbowax 4000 and Carbowax 6000); sodium sulfate; and magnesium lauryl sulfate.
  • Such lubricants if present, constitute in total from about 0.1 wt% to about 10 wt%, from about 0.2 wt% to about 8 wt%, or from about 0.25 wt% to about 5 wt%, of the total weight of the composition.
  • magnesium stearate is a preferred lubricant and is present in an amount of 0.25% to about 1.5% by weight of the total composition.
  • Suitable glidants also include magnesium trisilicate, powdered cellulose, starch, talc, tricalcium phosphate, stearates and colloidal silicon dioxide, and preferred glidants are colloidal silica.
  • Such glidants if present, constitute in total from about 0.1 wt% to about 10 wt%, or from about 0.2 wt% to about 8 wt%, or preferably from about 0.25 wt% to about 5 wt%, of the total weight of the composition.
  • the glidant comprises colloidal silicon dioxide and is present in an amount of 0.25% to about 1.5% by weight of the total composition.
  • Suitable acidulants also include acetic acid, amino acids, citric acid, nitric acid, fumaric acid and other alpha-hydroxy acids, hydrochloric acid, ascorbic acid and nitric acid and others known to those of ordinary skill in the art .
  • the acidulant is citric acid.
  • Such acidulants comprise in total about 0.1 wt% to about 50 wt%, about 1 wt% to about 50 wt%, about 1 wt% to about 10 wt%, about 5 wt% to about 15 wt%, about 10 wt% of the total weight of the composition % to about 20 wt%, about 15 wt% to about 25 wt%, about 20 wt% to about 30 wt%, about 25 wt% to about 35 wt%.
  • the acidulant includes citric acid. In another embodiment, the acidulant is citric acid and is present in an amount ranging from 5% to 15% or from 25% to 35% by weight of the total composition.
  • Absorption enhancers can also be surface active agents, which act both as dissolution enhancers and uptake enhancers. Solubility enhancers can improve the ability of active ingredients to dissolve in the aqueous environment in which they are initially released, or in the lipophilic environment of the intestinal wall lining the mucus layer, or both. Transit (uptake) enhancers (which are usually the same surfactants used as dissolution enhancers) are those that facilitate the easy passage of the active ingredient through the intestinal wall.
  • the one or more absorption enhancers may only perform one function (eg, dissolution), or the one or more absorption enhancers may only perform another function (eg, uptake). It is also possible to have a mixture of several compounds, some of which provide improved solubility, some of which provide improved uptake and/or some of which perform both functions.
  • Surfactants can be used as dissolution enhancers and uptake enhancers.
  • absorption enhancers include: salicylates such as sodium salicylate, 3-methoxysalicylate, 5-methoxysalicylate, and homovanilate; cholic acids such as taurochol acid, tauorodeoxycholic, and deoxycholic acid; nonionic surfactants such as polyoxyethylene ethers, p-t-octylphenoxyethoxylates, nonylphenoxyethoxylates Ethers, polyoxyethylene sorbitan esters (such as Tween-20, Tween-80, etc.), d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS); anionic surfactants, such as sulphonic acid dioctyl sodium succinate; lysophospholipids such as lysophosphatidylcholine and lysophosphatidylethanolamine; acylcarnitines, acyl
  • Such absorption enhancers constitute in total from about 0.1 wt% to about 5 wt%, or from about 0.25 wt% to about 5 wt%, or from about 0.5 wt% to about 4 wt%, of the total weight of the composition.
  • the absorption enhancer comprises Vitamin E TPGS in an amount of 0.5% to 5% or 0.5% to 2.5% by weight of the total composition.
  • Suitable surfactants also include oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbate, Sorbitan Monooleate (Tween 80), d-alpha Tocopheryl Macrogol 1000 Succinate (Vitamin E TPGS), Polyoxyethylene Sorbitan Monolaurate, Sodium Oleate, Lauryl Sodium Alkyl Sulfate, Poloxamer and Poloxamer 188.
  • Such surfactants if present, constitute in total from about 0.25% to about 15%, or from about 0.4% to about 10%, or from about 3% to about 9% by weight of the total composition.
  • the surfactant comprises one or two surfactants selected from polyoxyethylene sorbitan monooleate and poloxamer 188, wherein the surfactant is present in an amount of It is present in an amount of 0.5 wt% to 5 wt%. In another embodiment, the surfactant is present in the composition in an amount of about 0.5 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt% of the total weight of the composition %, 4.0wt%, 4.5wt% or 5.0wt% ⁇ 0.5wt%.
  • Suitable antioxidants also include amino acid sulfites (such as L-lysine sulfite), ascorbic acid, ascorbyl palmitate, benzotriazoles, butylhydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), Citric Acid, Cysteine, Cysteine Hydrochloride, Calcium Disodium EDTA, Disodium EDTA, Dithiothreitol, DL- ⁇ -Tocopherol, Erythorbic Acid, Ethoxyquinoline, EDTA, Fumaric Acid, Glutathione, Guaiac, Homocysteine, Isopropyl Citrate, L-Ascorbic Acid Stearate, Thioglycerin, Nordihydroguaiaretic Acid (NDGA), Palmitic Acid, Ascorbic Acid, Sodium Ascorbate, Sodium Bisulfite, Tetrasodium EDTA, Sodium Erythorbate, Sodium Bis
  • the antioxidant may be present at a concentration ranging from about 0.1 to 9.0 wt%, or at a concentration ranging from about 0.5 and 5.0 wt%, or at a concentration ranging from about 0.3 and 1.5 wt%, or present at a concentration in the range of about 0.4 and 1.6 wt%, or in the range of 0.5 and 1.7 wt%, or in the range of 0.6 and 1.8 wt%, or in the range of 0.7 and 1.9 wt% Concentrations exist, or exist in concentrations ranging from 0.8 and 2.0 wt%, or exist in concentrations ranging from 1.0 to 2.5 wt%, or exist in concentrations ranging from 1.5 to 3.0 wt%, or exist in concentrations ranging from 2.0 and 3.5 wt% A range of concentrations is present, or present in a concentration ranging from 2.5 and 4.0 wt%, or present in a concentration ranging from 3.0 and 5.0 wt%.
  • the pharmaceutical composition of OAD2 or a pharmaceutically acceptable salt thereof provided by the present invention is an oral pharmaceutical composition.
  • the liquid preparation for example, suspension, tincture etc.
  • the liquid preparation can be prepared according to the technique known in the art, can use any common medium simultaneously, for example, water, ethylene glycol , oil, alcohol and so on.
  • Solid preparations suitable for oral administration for example, tablets, capsules, granules and pills
  • some solid excipients can be used, for example, fillers, binders, disintegrants, etc. solution, etc.
  • the pharmaceutical composition of OAD2 or a pharmaceutically acceptable salt thereof provided by the present invention is a solid pharmaceutical composition.
  • the pharmaceutical composition of OAD2 or a pharmaceutically acceptable salt thereof provided by the present invention is selected from the dosage forms of tablets, pills, capsules, mini-tablets or granules, wherein the tablet, Pills, granules may or may not be coated.
  • the pharmaceutical composition of the present invention can also be further coated, including using one or more selected from water-soluble polymers, water-insoluble polymers, gastric-soluble polymers, and enteric-soluble polymers. A variety of coating layers.
  • the pharmaceutical composition of OAD2 or a pharmaceutically acceptable salt thereof provided by the present invention is a tablet.
  • the present invention further provides a preparation method of a pharmaceutical composition, which mainly includes the following steps:
  • Granulation mixing the prescription amount of OAD2 or its pharmaceutically acceptable salt, filler, solubilizer, disintegrant, and optional binder, acidulant, lubricant, wetting agent, acidulant , glidants, absorption accelerators and surfactants for granulation and mixing;
  • composition of the present invention comprises OAD2 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients suitable for oral administration.
  • compositions of the present invention can be adapted for administration by any suitable oral route by selection of suitable excipient materials and dosage of the active ingredients which are intended to be therapeutically effective.
  • any carrier material used may be solid or liquid, or both, and the composition contains from about 1% to about 95%, or from about 10% to about 90%, or from about 25% to about 85%, by weight, Or about 10% to about 40% OAD2 or a pharmaceutically acceptable salt thereof.
  • Such pharmaceutical compositions may be prepared by any of the well-known techniques of pharmacy which involve admixing the components.
  • composition of the present invention contains the required amount of OAD2 or a pharmaceutically acceptable salt thereof per dosage unit, and can be in the form of, for example, tablets, pills, hard or soft capsules, lozenges, cachets, dispersible Powder (a dispensable powder), granules, suspension, elixir, liquid or any other form reasonably suitable for oral administration.
  • Such compositions may be presented in the form of discrete dosage units such as tablets, pills or capsules, each unit containing a predetermined amount of OAD2 or a pharmaceutically acceptable salt thereof.
  • tablets, pills, etc. may be prepared with or without coatings.
  • compositions of the present invention may be prepared by any suitable pharmaceutical method comprising the step of combining OAD2 or a pharmaceutically acceptable salt thereof with a carrier material.
  • the compositions are prepared by uniformly and intimately mixing OAD2 or a pharmaceutically acceptable salt thereof with liquid or finely divided solid carriers or both, and then, if necessary, encapsulating or shaping the product.
  • a tablet may be prepared by compressing or molding a powder or granules of the compound with one or more excipients.
  • Compressed tablets can be prepared by compressing in a suitable machine a free-flowing composition, such as a powder or granules, comprising OAD2 or a pharmaceutically acceptable salt thereof, in admixture with one or more excipients.
  • Molded tablets may be made by molding in a suitable machine the powdered compound moistened with an inert liquid filler.
  • compositions may be appropriately added alone, or two or more pharmaceutical excipients may be added in combination in appropriate amounts.
  • each excipient can be used in an amount that can achieve the desired effect of the present invention.
  • composition for oral administration of the present invention can be prepared by known methods including, for example, steps of mixing, granulating, drying, molding (tabletting), film coating and the like.
  • steps of mixing, granulating, drying, molding (tabletting), film coating and the like The production method of the composition for oral administration of the present invention will be explained below.
  • the active ingredient and any solid excipients may be comminuted and/or sieved in ordinary pharmaceutical manner prior to mixing.
  • pulverizers include hammer mills, ball mills, jet mills, colloid mills, and the like.
  • the pulverization conditions can be appropriately selected and are not particularly limited.
  • neither the device nor the means are particularly limited as long as it is a method that can uniformly mix the components in an ordinary pharmaceutical manner.
  • neither the device nor the means are particularly limited as long as it is a method that can granulate the active ingredient and appropriate excipients in an ordinary pharmaceutical manner.
  • Examples of granulation methods and granulation equipment used in wet granulation using a solvent such as water include high shear granulation, grinding (crushing) granulation, fluidized bed granulation, extrusion granulation Granulation method, drum granulation method, spray granulation method and equipment, etc.
  • a spray granulation method and a spray granulator are preferred, and there is no particular limitation on the drying method as long as it can be dried in an ordinary pharmaceutical manner.
  • neither the device nor the means are particularly limited as long as it is a method capable of drying a granular product in an ordinary pharmaceutical manner.
  • devices include forced air dryers, reduced pressure dryers, vacuum dryers, fluidized bed granulation dryers, and the like.
  • the dried product may be sieved and classified using a sieve, comil, or the like, if necessary.
  • neither the device nor the means are particularly limited as long as it is a method of molding the pharmaceutical composition for oral administration of the present invention.
  • the method include a method in which the active ingredient and a suitable excipient are granulated and dried, and compression molded to prepare a pharmaceutical composition for oral administration, or a method in which the active ingredient and a suitable excipient are granulated and Further mixed with one or more extragranular excipients (such as binders, fillers, glidants, lubricants and/or acidifiers), and the mixture is compression molded to prepare a medicament for oral administration method of composition; etc.
  • extragranular excipients such as binders, fillers, glidants, lubricants and/or acidifiers
  • the surface of the pharmaceutical composition for oral administration may be film-coated.
  • the method of film coating is not particularly limited as long as it can be coated in an ordinary pharmaceutical manner. Examples of coatings include pan coatings, dip coatings, and the like.
  • the film coating agents may be added singly as appropriate, or in combination of two or more in appropriate amounts.
  • the coating rate is, for example, 0.5 wt% to 10 wt% relative to the total weight of the pharmaceutical composition for oral administration. In another embodiment, the coating results in a weight gain of between 0.5 wt% and 5 wt%, or between 2 wt% and 4 wt%.
  • the coated product can be dried.
  • the drying method There is no particular limitation on the drying method as long as it can be dried in an ordinary pharmaceutical manner.
  • Conditions for drying are not particularly limited as long as they can be appropriately selected in view of, for example, the stability of the pharmaceutical composition for oral administration.
  • the present invention further provides the application of the pharmaceutical composition of OAD2 and its pharmaceutically acceptable salt in the field of medicine.
  • the present invention provides the use of a pharmaceutical composition of OAD2 and a pharmaceutically acceptable salt thereof in the preparation of a medicament for mediating GLP-1 receptor.
  • the present invention provides the use of a pharmaceutical composition of OAD2 and a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing GLP-1 receptor-mediated diseases.
  • the present invention provides the use of a pharmaceutical composition of OAD2 and a pharmaceutically acceptable salt thereof in the preparation of a drug for treating or preventing metabolic diseases and/or disorders; wherein said metabolic diseases And/or conditions include but are not limited to those selected from the group consisting of metabolic syndrome, glucose intolerance, hyperglycemia, dyslipidemia, type 1 diabetes, type 2 diabetes, syndrome X, insulin resistance, impaired glucose tolerance (IGT), obesity, Diabetic dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, other cardiovascular diseases that benefit from activation of GLP-1 receptors, hypertension, metabolic disorders that benefit from activation of GLP-1 receptors, etc., and those caused by diabetes Complications caused by or associated with it, including but not limited to neurological disease, retinopathy, nephropathy, and poor wound healing.
  • metabolic diseases And/or conditions include but are not limited to those selected from the group consisting of metabolic syndrome, glucose intolerance, hyperglycemia, dyslipidemia, type 1 diabetes, type 2 diabetes, syndrome X,
  • the present invention provides the use of a pharmaceutical composition of OAD2 and a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing type II diabetes.
  • the present invention also relates to a method for mediating GLP-1 receptors, comprising administering a therapeutically effective dose of OAD2 and a pharmaceutical composition of a pharmaceutically acceptable salt thereof to a patient in need.
  • the present invention also relates to a method for treating or preventing diseases mediated by GLP-1 receptor agonists, which comprises administering a therapeutically effective amount of OAD2 and a pharmaceutical composition of pharmaceutically acceptable salts thereof to patients in need.
  • the present invention also relates to a method for treating or preventing metabolic diseases and/or disorders, which comprises administering a therapeutically effective amount of OAD2 and a pharmaceutical composition of a pharmaceutically acceptable salt thereof to a patient in need; wherein said metabolic Disease and/or condition selected from but not limited to metabolic syndrome, glucose intolerance, hyperglycemia, dyslipidemia, type 1 diabetes, type 2 diabetes, syndrome X, insulin resistance, impaired glucose tolerance (IGT), obesity, Diabetic dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, other cardiovascular diseases, hypertension, metabolic disorders benefiting from the activation of GLP-1 receptors, etc., and complications caused by or associated with diabetes, Including but not limited to neurological disease, retinopathy, kidney disease and poor wound healing.
  • metabolic Disease and/or condition selected from but not limited to metabolic syndrome, glucose intolerance, hyperglycemia, dyslipidemia, type 1 diabetes, type 2 diabetes, syndrome X, insulin resistance, impaired glucose tolerance (IGT), obesity, Diabetic dyslipidemia, hyperlipid
  • the present invention also relates to a method for treating or preventing type II diabetes, which comprises administering a therapeutically effective amount of OAD2 and a pharmaceutical composition of a pharmaceutically acceptable salt thereof to a patient in need.
  • the present invention also relates to pharmaceutical compositions of OAD2 and pharmaceutically acceptable salts thereof, which are used as GLP-1 receptor agonists.
  • the present invention also relates to a pharmaceutical composition of OAD2 and a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diseases and/or disorders mediated by GLP-1 receptors.
  • the present invention also relates to a pharmaceutical composition of OAD2 and a pharmaceutically acceptable salt thereof, which are used for treating or preventing metabolic diseases and/or disorders, but not limited to being selected from metabolic syndrome , Glucose intolerance, Hyperglycemia, Dyslipidemia, Type I diabetes, Type II diabetes, Syndrome X, Insulin resistance, Impaired glucose tolerance (IGT), Obesity, Diabetic dyslipidemia, Hyperlipidemia, Arteriosclerosis, Arteriosclerosis Atherosclerosis, other cardiovascular diseases, hypertension, metabolic disorders benefiting from the activation of GLP-1 receptors, etc., and complications caused by or related to diabetes, including but not limited to neurological diseases, retinopathy, nephropathy and wounds Poor healing.
  • metabolic syndrome Glucose intolerance
  • Hyperglycemia Dyslipidemia
  • Type I diabetes Type II diabetes
  • Syndrome X Insulin resistance
  • ITT Impaired glucose tolerance
  • Obesity Diabetic dyslipidemia
  • Hyperlipidemia Arteriosclerosis
  • the present invention also relates to a pharmaceutical composition of OAD2 and a pharmaceutically acceptable salt thereof, which is used for treating or preventing type II diabetes.
  • the present invention provides a method of treating type 1 diabetes by administering to a human subject a therapeutically effective amount of OAD2, or a pharmaceutically acceptable salt thereof, as part of a pharmaceutical composition described herein.
  • the present invention provides a method of treating obesity by administering to a human subject a therapeutically effective amount of OAD2, or a pharmaceutically acceptable salt thereof, as part of a pharmaceutical composition described herein.
  • the present invention provides a method of slowing gastric emptying by administering to a human subject a therapeutically effective amount of OAD2, or a pharmaceutically acceptable salt thereof, as part of a pharmaceutical composition described herein.
  • the present invention provides a method of reducing HbA1c levels by administering to a human subject a therapeutically effective amount of OAD2, or a pharmaceutically acceptable salt thereof, as part of a pharmaceutical composition described herein.
  • the method reduces the amount of HbA1c in a subject in need thereof by at least 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5%, or 0.6%, or 0.7%, or 0.8%, or 0.9%, or 1.0%.
  • the method of treatment reduces the HbA1c level to less than 7% in a subject in need thereof.
  • the level of HbA1c may be reduced to a level between 5% and 6.5%.
  • the dose of OAD2 or the pharmaceutical composition of the pharmaceutically acceptable salt thereof used in the treatment method provided by the present invention can be changed with factors such as the progress of the disease, the severity of the disease, the basic condition of the subject, and usually,
  • the appropriate dose of the pharmaceutical composition of the present invention may be 0.5-1000 mg.
  • OAD2 or a pharmaceutically acceptable salt thereof may be administered in a dose such that OAD2 or a pharmaceutically acceptable salt thereof is administered in an amount of between 1 mg and 1000 mg per day, or 25 to 200 mg per day, or 25 mg per day. to 75 mg, or 50 to 100 mg per day, or 75 to 125 mg per day, or 100 to 150 mg per day, or 125 to 175 mg per day, or 150 mg to 200 mg per day, or 75 mg to 150 mg per day, or 25 mg ⁇ 5 mg per day, or 30 mg ⁇ 5mg, or 40 ⁇ 5mg per day, 50mg ⁇ 5mg per day, or 60mg ⁇ 5mg per day, or 75mg ⁇ 5mg per day, or 80mg ⁇ 5mg per day, or 90mg ⁇ 5mg per day, or 100mg ⁇ 5mg per day, or 110mg ⁇ 5mg per day, Or 125mg ⁇ 5mg per day, or 150mg ⁇ 5mg per day, or 175mg ⁇ 5mg per
  • OAD2 or a pharmaceutically acceptable salt thereof may be administered at a dose such that OAD2 or a pharmaceutically acceptable salt thereof is administered in an amount of: 25 mg ⁇ 2.5 mg per day, or 50 mg ⁇ 2.5 mg per day 2.5mg, or 75mg ⁇ 2.5mg per day, or 100mg ⁇ 2.5mg per day, or 125mg ⁇ 2.5mg per day, or 150mg ⁇ 2.5mg per day.
  • Dosage can be individualized by the clinician based on the particular clinical condition of the subject being treated.
  • any particular dosage level for any particular subject will depend upon a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and The severity of the specific condition being treated.
  • the dosage of the pharmaceutical composition of OAD2 and its pharmaceutically acceptable salts of the present invention is 0.5-1000 mg per day, or 1-500 mg per day, 2-300 mg per day, 5-200 mg per day, and 10-100 mg per day , 20 ⁇ 50mg per day, or 5 ⁇ 20mg per day, 25 ⁇ 40mg per day, 45 ⁇ 60mg per day, 65 ⁇ 80mg per day, 85 ⁇ 100mg per day, 105 ⁇ 120mg per day, 125 ⁇ 140mg per day, 145 ⁇ 160mg per day, 165 ⁇ 180mg per day, 185 ⁇ 200mg per day, or 10 ⁇ 2.5mg per day, 15 ⁇ 2.5mg per day, 20 ⁇ 2.5mg per day, 25 ⁇ 2.5mg per day, 30 ⁇ 2.5mg per day, 35 ⁇ 2.5mg per day, 40 ⁇ 2.5mg per day, 45 ⁇ 2.5mg per day, 50 ⁇ 2.5mg per day, 55 ⁇ 2.5mg per day, 60 ⁇ 2.5mg per day, 65 ⁇ 2.5mg per day, 70 ⁇
  • the present invention also relates to the combined medicine or combined medicine of the pharmaceutical composition of OAD2 and its pharmaceutically acceptable salt and one or more other pharmaceutical active ingredients.
  • the invention provides for administering OAD2, or a pharmaceutically acceptable salt thereof, in combination with one or more other pharmaceutically active compounds (eg, other antidiabetic drugs).
  • Combination therapy may involve the administration of the active ingredients and other pharmaceutically active compounds in a single pharmaceutical composition as well as in two separate pharmaceutical compositions to the same subject simultaneously or at intervals determined by those skilled in the art.
  • the present invention provides compositions that may have low or minor levels of impurities.
  • impurity refers to an undesired substance in a composition.
  • the amount of impurities may be present in the initial composition and/or may form after a certain shelf-life of the composition.
  • impurities may form through the degradation of one or more components of the composition (eg, active ingredients).
  • Sources of degrading impurities include, but are not limited to, oxidation, racemization, visible light, ultraviolet light, moisture, heat, pH changes, and interaction of components of the composition.
  • the total content of impurities in the pharmaceutical composition provided by the invention is not higher than 5% by mass from the preparation of the composition to the shelf life, or the total impurity by mass of the pharmaceutical composition provided by the invention below 4.8%, or below 4.7%, or below 4.6%, or below 4.5%, or below 4.4%, or below 4.3%, or below 4.2%, or below 4.1%, or below 4.0%, or less than 3.9%, or less than 3.8%, or less than 3.7%, or less than 3.6%, or less than 3.5%, or less than 3.4%, or less than 3.3%, or less than 3.2% , or less than 3.1%, or less than 3.0%, or less than 2.9%, or less than 2.8%, or less than 2.7%, or less than 2.6%, or less than 2.5%, or less than 2.4%, or Below 2.3%, or below 2.2%, or below 2.2%, or below 2.1%, or below 2.0%, or below 1.9%, or below 1.8%, or below 1.7%, or below 1.6%, or less than 1.5%, or less than 1.4%, or less
  • the composition may have no more than about 10 wt% total impurities after a certain period of shelf life. In another embodiment, the composition may have no more than about 9.9 wt%, or no more than about 9.8 wt%, or no more than about 9.6 wt%, or no more than about 9.4 wt%, or no more than about 9.2 wt%, or Not more than about 9 wt%, or not more than about 8.8 wt%, or not more than about 8.6 wt%, or not more than about 8.4 wt%, or not more than about 8.2 wt%, or not more than about 8 wt%, or not more than about 7.8 wt% wt%, or not more than about 7.6wt%, or not more than about 7.4wt%, or not more than about 7.2wt%, or not more than about 7wt%, or not more than about 6.8wt%, or not more than about 6.6wt%, Or not more than about about 9.9 w
  • the invention provides a technical scheme and technical means for reducing the impurity content of the composition, especially for degrading the impurity B content, through the research on the compatibility of raw materials and auxiliary materials.
  • the present invention predicts the potential incompatibility of the drug in the final dosage form by studying the compatibility of raw materials and auxiliary materials in the pharmaceutical composition, and screens the selection and dosage of each auxiliary material.
  • the research on the compatibility of raw materials and excipients includes, but is not limited to: selection of excipients/excipients, evaluation of composition stability, identification of degradation products and research on interaction mechanisms, etc.
  • the researchers of the present invention have studied the chemical interactions between drug raw materials and excipients/excipients in pharmaceutical compositions, such as hydrolysis, dehydration, isomerization, elimination, cyclization, oxidation, photodegradation effects, and special reactions between excipients/excipients; the main factors affecting the above reactions include but are not limited to temperature, pH, moisture content, relative temperature, light, oxygen, physical form, and particle size of excipients; research focuses on moisture and excipients. The influence of the pH value of the microenvironment, the reaction of excipients/excipients and their impurities, the investigation of stabilizers, etc.
  • impurities are formed during standing of the composition, eg, affected by temperature, humidity, oxygen content, pH, light exposure, and the like.
  • impurity B is an impurity formed after oxidation or degradation of OAD2 and its pharmaceutically acceptable salts.
  • Oxides such as oxides or active oxygen structural components can help reduce the formation or growth of degraded impurity B.
  • the present invention further provides pharmaceutical compositions having low levels of impurity B.
  • the present invention provides a composition of excipients/excipients containing low active oxygen species by studying the influence of active oxygen species in the excipients/excipients, which can effectively control the impurities in the composition content.
  • the concentration or amount of impurities present in the composition may be attributable, at least in part, to degradation of components of the composition other than the active ingredient after a certain period of shelf life.
  • the concentration or amount of impurities present in the composition at the end of shelf life can be attributable, at least in part, to degradation of the active ingredient.
  • degradation of OAD2 or a pharmaceutically acceptable salt thereof may be the result of physical or chemical stress. Examples of stress include, but are not limited to, exposure to oxygen, ROS, HPO, pH, light, processed surfaces, and soluble trace metals.
  • the impurities will be affected by the components of the excipients in the composition.
  • the formation of impurities or the growth rate of impurities can be suppressed to a certain extent.
  • the components of the composition may be present in concentrations or amounts that at least partially inhibit the formation of impurities in the composition.
  • the composition may comprise excipients with low levels of reactive oxygen species (ROS) such as HPO.
  • ROS reactive oxygen species
  • the amount of Impurity B in the composition may be greater than zero and not more than about 5% by weight after a certain period of shelf life. In another embodiment, the amount of impurity B in the composition may be greater than zero and have no more than about 4.9 wt%, or no more than about 4.8 wt%, or no more than about 4.7 wt%, or no more than about 4.6 wt%, Or not more than about 4.5wt%, or not more than about 4.4wt%, or not more than about 4.3wt%, or not more than about 4.2wt%, or not more than about 4.1wt%, or not more than about 4wt%, or not more than About 3.9wt%, or not more than about 3.8wt%, or not more than about 3.7wt%, or not more than about 3.6wt%, or not more than about 3.5wt%, or not more than about 3.4wt%, or not more than about 3.3 wt%, or not more than about 3.3 wt
  • the content of degraded impurity B in the pharmaceutical composition provided by the present invention is not higher than 4% by mass from the preparation of the composition to the shelf life, or the total impurity mass of the pharmaceutical composition provided by the present invention is 100%.
  • the mass percentage of the degraded impurity B in the composition from preparation to shelf life is maintained at 0-1%.
  • the amount of Impurity B is greater than zero and not more than about 1.0 wt%, based on the total weight of the pharmaceutical dosage form, after a certain shelf-life. In another preferred embodiment, the amount of impurity B is greater than zero and after 12 months at 25°C ⁇ 2°C/60%RH ⁇ 5%RH or at 30°C ⁇ 2°C/65%RH ⁇ 5%RH , not more than about 1.0 wt%, or after 6 months at 30°C ⁇ 2°C/65%RH ⁇ 5%RH, not more than about 1.0wt%, or at 40°C ⁇ 2°C/75%RH ⁇ 5% After 6 months under RH, not more than about 1.0 wt%.
  • the initial amount of impurity B in the composition or after a certain storage period may be greater than zero and not more than about 2.5 wt%, or not more than about 2 wt%, or not more than about 1.5 wt%, or not more than about 1 wt%, or not more than about 0.5 wt%, or not more than about 0.4 wt%, or not more than about 0.3 wt%, or not more than about 0.2 wt%, or not more than about 0.1 wt%, or not more than about 0.09 wt% , or not more than about 0.08 wt%, or not more than about 0.07 wt%, or not more than about 0.06 wt%, or not more than about 0.05 wt%, or not more than about 0.04 wt%, or not more than about 0.03 wt%, or Not more than about 0.02 wt%, or not more than about 0.01 wt%.
  • impurity B formation may be affected by an oxygen-dependent mechanism, such that reducing the oxygen accessible to the composition can reduce the rate of impurity B formation.
  • the content of active oxygen will affect the growth rate of impurity B.
  • the concentration of oxidative degradation products present in the composition is such that the composition does not undergo physical changes after a certain period of shelf life.
  • physical changes include, but are not limited to, color changes and insoluble particle formation.
  • the rate of formation and/or concentration of oxidative degradation products in the composition may be reduced by other components of the composition after a certain shelf life. In some embodiments, the rate of formation and/or concentration of oxidative degradation products in the composition can be reduced by the presence of an antioxidant.
  • impurity B can be used as a reference substance for OAD2 or a pharmaceutically acceptable salt thereof.
  • the invention also provides compositions comprising low levels of ROS, such as HPO.
  • any excipients or carrier materials formulated with the active ingredient may contain low levels of ROS, such as one or more HPOs.
  • the HPO value may simply be a measure of the amount of H2O2 .
  • the combined or total HPO value of all materials in the composition or the composition as a whole has an HPO value of less than 200 ppm, or less than 190 ppm, or less than 180 ppm, or less than 170 ppm, or Less than 160ppm, or less than 150ppm, or less than 140ppm, or less than 130ppm, or less than 120ppm, or less than 110ppm, or less than 100ppm, or less than 90ppm, or less than 80ppm, or less than 70ppm, or Less than 60ppm, or less than 50ppm, or less than 40ppm, or less than 30ppm, or less than 20ppm, or less than 10ppm, or less than 5ppm.
  • the combined HPO value of all materials in the composition or the composition as a whole has an HPO value of less than 20,000 nmole/g, or less than 19,000 nmole/g, or less than 18,000 nmole/g , or less than 17,000 nmole/g, or less than 16,000 nmole/g, or less than 15,000 nmole/g, or less than 12,000 nmole/g, or less than 11,000 nmole/g, or less than 10,000 nmole/g, or Less than 9000nmol/g, or less than 8000nmol/g, or less than 7000nmol/g, or less than 6000nmol/g, or less than 5000nmol/g, or less than 4000nmol/g, or less than 3000nmol/g, or less At 2000nmole/g, or less than 1000nmole/g, or less than 500nmole/g.
  • the combined HPO value of all materials in the composition or the composition as a whole has the following HPO value: less than 10.0 mEqO2/kg, or less than 9.5 mEqO2/kg, or less than 9.0mEq ⁇ O2/kg, or less than 8.5mEq ⁇ O2/kg, or less than 8.0mEq ⁇ O2/kg, or less than 7.5mEq ⁇ O2/kg, or less than 7.0mEq ⁇ O2/kg, or less than 6.5mEq ⁇ O2/kg, or less than 6.0mEq ⁇ O2/kg, or less than 5.5mEq ⁇ O2/kg, or less than 5.0mEq ⁇ O2/kg, or less than 4.5mEq ⁇ O2/kg, or less than 4.0mEq ⁇ O2/kg, or less than 3.5mEq ⁇ O2/kg, or less than 3.0mEq ⁇ O2/kg, or less than 2.5mEq ⁇ O2/kg, or less than 2.0mEq ⁇ O2/kg, or less than 1.5mEq ⁇
  • the composition comprises a disintegrant, wherein the disintegrant has a HPO value of less than 50 ppm, or less than 49 ppm, or less than 48 ppm, or less than 47 ppm, or less than 46 ppm, or Less than 45ppm, or less than 44ppm, or less than 43ppm, or less than 42ppm, or less than 41ppm, or less than 40ppm, or less than 39ppm, or less than 38ppm, or less than 37ppm, or less than 36ppm, or Less than 35ppm, or less than 34ppm, or less than 33ppm, or less than 32ppm, or less than 31ppm, or less than 30ppm, or less than 29ppm, or less than 28ppm, or less than 27ppm, or less than 26ppm, or Less than 25ppm, or less than 24ppm, or less than 23ppm, or less than 22ppm, or less than 21ppm, or less than 20ppm, or less than 19pp
  • the composition comprises a disintegrant, wherein the disintegrant has a HPO value of less than 50 ppm, or less than 40 ppm, or less than 30 ppm, or less than 25 ppm, or less than 10 ppm.
  • the composition comprises a disintegrant, wherein the disintegrant is crospovidone, and the disintegrant has the following HPO value or H2 determined according to the European Pharmacopoeia Class A method O 2 value: less than 50ppm, or less than 40ppm, or less than 30ppm, or less than 25ppm, or less than 10ppm.
  • the European Pharmacopoeia Class A method may be a method in 2012, 2013, 2014 or 2015.
  • the composition comprises a disintegrant, wherein the disintegrant is crospovidone, and the disintegrant has the following HPO value or H2 determined according to the European Pharmacopoeia Class B method O 2 value: less than 125ppm, or less than 100ppm, or less than 75ppm, or less than 50ppm.
  • the European Pharmacopoeia Class B method may be a method in 2012, 2013, 2014 or 2015.
  • the composition comprises a disintegrant, wherein the disintegrant has a HPO value of less than 6000 nmole/g, or less than 5000 nmole/g, or less than 4900 nmole/g, or less than 4800 nmole/g g, or less than 4700nmol/g, or less than 4600nmol/g, or less than 4500nmol/g, or less than 4400nmol/g, or less than 4300nmol/g, or less than 4200nmol/g, or less than 4100nmol/g , or less than 4000 nmole/g, or less than 3900 nmole/g, or less than 3800 nmole/g, or less than 3700 nmole/g, or less than 3600 nmole/g, or less than 3500 nmole/g, or less than 3400 nmole/g, Or less than 3300nmol/g, or less than 3200nmol/g, or less than 3100
  • the composition comprises a disintegrant, wherein the disintegrant has a HPO value of less than 5000 nmole/g or less than 4000 nmole/g.
  • the composition comprises a disintegrant, wherein the disintegrant is crospovidone, and the disintegrant has a HPO value of less than 5000 nmole/g or less than 4000 nmole/g.
  • the composition comprises a disintegrant, wherein the disintegrant has an HPO value of less than 2.00 mEq O2/kg, or less than 1.90 mEq O2/kg, or less than 1.80 mEq ⁇ O2/kg, or less than 1.70mEq ⁇ O2/kg, or less than 1.60mEq ⁇ O2/kg, or less than 1.50mEq ⁇ O2/kg, or less than 1.40mEq ⁇ O2/kg, or less than 1.30mEq ⁇ O2/kg, or less than 1.20mEq ⁇ O2/kg, or less than 1.10mEq ⁇ O2/kg, or less than 1.00mEq ⁇ O2/kg, or less than 0.90mEq ⁇ O2/kg, or less than 0.80mEq ⁇ O2/kg, or less than 0.70mEq ⁇ O2/kg, or less than 0.60mEq ⁇ O2/kg, or less than 0.50mEq ⁇ O2/kg, or less than 0.40mEq ⁇ O2/kg, or less than 0.30m
  • the composition comprises a disintegrant, wherein the disintegrant has a HPO value of less than 1.00 mEq ⁇ O2/kg.
  • the composition comprises a disintegrant, wherein the disintegrant is crospovidone, and the disintegrant has a HPO value of less than 1.00 mEq ⁇ O2/kg.
  • the measured HPO can be a measure of total HPO or H2O2 .
  • quantification of HPO levels can be accomplished using methods known to those skilled in the art.
  • HPO levels can be determined by measuring the reduction of HPO by Fe(II) under acidic conditions, such as described in Gay (Gay et al., 1999. "Hydroperoxide assay with the ferric-xylenol orange complex” Methods in Anal. Biochem 273:149-155).
  • HPO levels can be determined according to a method for measuring the formation of triphenylphosphine oxide from triphenylphosphine, such as described in Nakamura (Nakamura et al., 1991. "A simple assay for lipid hydroperoxides based on triphenylphosphine Oxidation and high-performance liquid chromatography "Lipids 26:765-768).
  • H 2 O 2 peroxides
  • compositions that may have an extended shelf life relative to compositions having elevated levels of ROS (eg, HPO).
  • ROS eg, HPO
  • shelf life refers to the length of time a product can be stored without becoming unsuitable for medical use.
  • compositions that are unsuitable for medical use include, but are not limited to, compositions that have unacceptably high levels of impurities and/or the presence of physical changes described herein (eg, color changes and/or the presence of insoluble particles).
  • the shelf life of the composition may be 7 days, or 11 days, or 14 days, or 1 month, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 7 months, or 8 months, or 9 months, or 10 months, or 11 months, or 12 months, or 13 months, or 14 months, or 15 months, or 16 months, or 17 months, or 18 months, or 19 months, or 20 months, or 21 months, or 22 months, or 23 months, or 24 months, or 25 months, or 26 months, or 27 months, or 28 months, or 29 months, or 30 months, or 31 months, or 32 months, or 33 months, or 34 months, or 35 months, or 36 months, or 48 months.
  • the shelf life of the composition may be extended by 7 days, or 11 days, or 14 days, or 1 month, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 7 months, or 8 months, or 9 months, or 10 months, or 11 months, or 12 months, or 13 months, or 14 months, or 15 months, or 16 months, or 17 months, or 18 months, or 19 months, or 20 months, or 21 months, or 22 months, or 23 months, or 24 months, or 25 months, or 26 months, or 27 months, or 28 months, or 29 months, or 30 months, or 31 months, or 32 months, or 33 months, or 34 months, or 35 months, or 36 months, or 48 months.
  • shelf life can be determined by measuring certain characteristics of the composition that may indicate that the composition is unsuitable for medical use. In some embodiments, shelf life can be determined by measuring the concentration of impurities in the composition after storage at 25°C and 60% relative humidity. In some embodiments, shelf life can be determined by measuring the concentration of impurities in the composition after storage at 37°C and 65% relative humidity. In some embodiments, shelf life can be determined by measuring the concentration of impurities in the composition after storage at 40°C and 75% relative humidity. In some embodiments, shelf life can be determined by measuring the concentration of impurities in the composition after storage between 50°C and 60°C or between 55°C and 65°C.
  • shelf life can be determined by measuring the concentration of impurities in the composition after storage at: (long-term - 12 months) 25°C ⁇ 2°C/60% RH ⁇ 5% RH or 30°C ⁇ 2°C//65%RH ⁇ 5%RH, or (mid-6 months) 30°C ⁇ 2°C/65%RH ⁇ 5%RH, or (accelerated-6 months) 40°C ⁇ 2°C/75 %RH ⁇ 5%RH.
  • shelf life can be determined by using, for example, the ICH Harmonized Tripartite Guideline: Stability Testing of New Drug Substances and Products Q1A(R2) dated February 6, 2003 (ICH Harmonized Tripartite Guideline: Stability Testing of New Drug Substances and Products Q1A(R2)) to measure the concentration of impurities in the composition to determine.
  • shelf-life in long-term, accelerated, and, if appropriate, intermediate-term (if appropriate) storage conditions can be determined by measuring the concentration of impurities after storage in these conditions, where the composition is packaged in the same packaging as recommended for storage and distribution. or simulated container closure systems.
  • the structural components of oxides or reactive oxygen species such as substances can help to reduce the formation or growth of oxidative degradation impurity B.
  • the present invention provides one of the related substances of OAD2, degrading impurity B, 2-3(-(4-((3,4-dichlorobenzyl)oxy)phenyl)-8-oxo-12-( 1-phenylpropyl)-2,3,6,8,9,10-hexahydro-7H-6,9-imino[1,4]dioxino[2',3':4, 5] benzo[1,2-c]azepin-7-yl)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid, as shown in structural formula B .
  • the molecular formula of degraded impurity B is C 50 H 45 Cl 2 N 3 O 6 , and the molecular weight is 854.82.
  • impurity B is characterized by a relative retention time relative to OAD2 of between 0.45 and 0.66 under certain HPLC or LCMS conditions, such as those described in Sections 18-24 of Examples.
  • the HPLC relative retention time of impurity B is between 0.47 and 0.63 relative to OAD2.
  • the HPLC relative retention time of impurity B is between 0.55 and 0.64 relative to OAD2.
  • Impurity B is the product produced by a process comprising the step of oxidizing OAD2 or a pharmaceutically acceptable salt thereof.
  • the oxidizing step may comprise mixing OAD2 or a pharmaceutically acceptable salt thereof with an oxidizing agent.
  • the oxidizing agent can be any reagent capable of removing two electrons and/or H2 from OAD2 or a pharmaceutically acceptable salt thereof.
  • the oxidizing agent can be molecular oxygen ( O2 ), hydrogen peroxide ( H2O2 ), superoxide, hypochlorite, or organic hydroperoxide (ROOH), where R is a carbon atom, such as C1-C6 alkyl .
  • the oxidizing agent is molecular oxygen.
  • the oxidizing agent is hydrogen peroxide.
  • the oxidizing agent is an organic hydroperoxide, such as 3-chloroperoxybenzoic acid (mCPBA).
  • Embodiment A-1 A compound prepared by a process comprising the steps of: oxidation of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl -7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3- g] isoquinolin-8-ylcarboxamido)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propanoic acid (OAD2) or a pharmaceutically acceptable salt thereof,
  • OAD2 oxidation of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl -7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3- g] isoquino
  • Embodiment A-2 A compound of Embodiment A-1, wherein said compound is characterized by a retention time relative to OAD2 of between 0.45 and 0.66 under the gradient mobile phase conditions of reverse phase liquid chromatography: wherein mobile phase A Contains 0.05% TFA in water (v/v), mobile phase B contains 0.05% TFA in acetonitrile:methanol (1:2) (v/v), where used from time zero (50% mobile phase A) to Samples were run with a step gradient of 38 minutes (99% mobile phase B).
  • Embodiment A-3 A composition comprising: (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S )-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxine[2,3-g]isoquinoline- 8-ylcarboxamido)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propanoic acid (OAD2) or a pharmaceutically acceptable salt thereof, according to embodiment A-1
  • OAD2 a pharmaceutically acceptable salt thereof
  • the compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients wherein the compound according to embodiment A-1 or A-2 or its The amount of pharmaceutically acceptable salt is greater than zero and less than 2.5 wt%.
  • Embodiment A-4 A composition comprising: (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S )-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxine[2,3-g]isoquinoline- 8-ylcarboxamido)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propanoic acid (OAD2) or a pharmaceutically acceptable salt thereof, and having an HPO value of less than 50 ppm of disintegrants.
  • Embodiment A-5 The composition of Embodiment A-4, comprising: 10 wt% to 40 wt% OAD2 dihydrochloride, and 0.1 wt% to 20 wt% disintegrant.
  • Embodiment A-6 The composition of Embodiment A-5 wherein the disintegrant is crospovidone and is present in the range of 0.2 wt% to 10 wt%.
  • Embodiment A-7 The composition of Embodiment A-4, wherein the composition comprises a compound according to Embodiment A-1 or A-2, or a pharmaceutically acceptable salt thereof, wherein according to Embodiment A-1 Or the presence of the compound described in A-2 or a pharmaceutically acceptable salt thereof is greater than zero and less than 1.0 wt%.
  • Embodiment A-8 The composition of Embodiment A-7, wherein the composition comprises 0.4 wt% or less of The compound described in Scheme A-1 or A-2 or a pharmaceutically acceptable salt thereof.
  • Embodiment A-9 The composition of Embodiment A-7, wherein said composition comprises 1 wt% or less of the compound according to Embodiment A-1 or A-2 after storage for 14 days at 55°C to 65°C. compound or a pharmaceutically acceptable salt thereof.
  • Embodiment A-10 The composition of Embodiment A-4 comprising 10 wt % to 40 wt % OAD2 dihydrochloride, 1 wt % to 5 wt % disintegrant, wherein the disintegrant comprises crospovidone, 0.1 Wt% to 20wt% binder, 10wt% to 85wt% filler, 0.25wt% to 15wt% surfactant, 0.1wt% to 10wt% lubricant, 0.1wt% to 10wt% glidant , 1 wt% to about 50 wt% of an acidulant; wherein the composition comprises a compound according to embodiment A-1 or A-2, or a pharmaceutically acceptable salt thereof, wherein according to embodiment A-1 or A- The amount of the compound described in 2 or a pharmaceutically acceptable salt thereof is greater than zero and less than or equal to 0.4 wt% after storage at 25°C ⁇ 2°C/60%RH ⁇ 5%RH for 24 months.
  • Embodiment A-11 The composition of any one of Embodiments A-3 to A-10 in the form of a tablet or capsule.
  • Embodiment A-12 The composition of any one of Embodiments A-3 to Embodiment A-10, comprising 1 to 500 mg of OAD2 or a pharmaceutically acceptable salt thereof.
  • Embodiment A-13 A method of preparing the composition of any one of Embodiments A-3 to Embodiment A-10, wherein the method comprises combining OAD2 or a pharmaceutically acceptable salt thereof with one or more mixed with pharmaceutically acceptable excipients.
  • Embodiment A-14 The method of Embodiment A-13, wherein the method is a spray granulation method.
  • Embodiment A-15 A method of treating a condition comprising administering to a human in need thereof the composition of any one of Embodiments A-3 through A-10, wherein the condition is selected from the group consisting of metabolic syndrome, Glucose intolerance, hyperglycemia, dyslipidemia, type 1 diabetes, type 2 diabetes, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), obesity, diabetic dyslipidemia, hyperlipidemia Lipidemia, arteriosclerosis, atherosclerosis, other cardiovascular diseases, hypertension, and complications caused by or associated with diabetes, including but not limited to neuropathy, retinopathy, nephropathy, and poor wound healing.
  • the condition is selected from the group consisting of metabolic syndrome, Glucose intolerance, hyperglycemia, dyslipidemia, type 1 diabetes, type 2 diabetes, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), obesity, diabetic dyslipidemia, hyperlipidemia Lipidemia, arteriosclerosis, at
  • Embodiment A-16 The method of Embodiment A-15, wherein the condition is Type II diabetes.
  • Embodiment A-17 The method of Embodiment A-16, wherein the amount of OAD2 or a pharmaceutically acceptable salt thereof administered is 25 mg to 200 mg per day.
  • active ingredient refers to OAD2 and pharmaceutically acceptable salts thereof.
  • salts refers to a salt of a compound prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base.
  • Representative salts include those of the following: acetate, benzenesulfonate, benzoate, bicarbonate, hydrogensulfate, bitartrate, borate, bromide, calcium edetate, camphor Sulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, ethylenedisulfonate, propionate lauryl sulfate (estolate ), esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolyl arsenate (glycollylarsanilate), hexylresorcinate (hexylresorcinate), hydrabamine, hydrobromide, hydrochloride, xinanate,
  • acidic substituents such as -COOH, ammonium salts, morpholinium salts (morpholinium), sodium salts, potassium salts, barium salts, calcium salts, etc.
  • acidic salts can be formed, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, tris Chloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartrate, fumarate, mandelate, benzoic acid Salt, cinnamate, methanesulfonate, ethanesulfonate, picrate, etc.
  • the GLP-1R agonist is hydrochloride or dihydrochloride.
  • reactive oxygen refers to a class of one-electron reduction products of oxygen in the body, which are produced by electrons leaking out of the respiratory chain and consuming approximately 2% of oxygen before being passed to terminal oxidases, including superoxide, the one-electron reduction product of oxygen Anion (O 2 ⁇ -), two-electron reduction product hydrogen peroxide (H 2 O 2 ), three-electron reduction product hydroxyl radical ( ⁇ OH) and nitric oxide, etc.
  • hydroperoxide or HPO may be organic hydroperoxide (ROOH), where R is a carbon atom, or hydrogen peroxide ( H2O2 ).
  • ROOH organic hydroperoxide
  • H2O2 hydrogen peroxide
  • ROS reactive oxygen species
  • HPO value refers to the amount of HPO.
  • the units of HPO value can be ppm, mEq ⁇ O2/kg, nmole/g or absorbance units, depending on the assay method used to measure HPO.
  • shelf life refers to the length of time that a pharmaceutical composition can be stored without being used under the premise of maintaining effectiveness.
  • compositions that are unsuitable for medical use include, but are not limited to, compositions that have unacceptably high levels of impurities and/or the presence of physical changes described herein (eg, color changes and/or the presence of insoluble particles).
  • shelf life can usually also be understood as “shelf life”.
  • storage may refer to the storage conditions of the composition, such as temperature, light, relative humidity and other conditions for storing pharmaceutical compositions. In some embodiments, unless otherwise stated, storage refers to storing the pharmaceutical composition at a temperature of 25 ⁇ 5° C. and a relative humidity of 50 ⁇ 10%.
  • composition mass or “preparation mass” refers to the mass of active ingredients or other pharmaceutically acceptable excipients calculated from the weight of the tablet core without coating.
  • excipient includes any substance used as a vehicle for the delivery of an active ingredient to a subject, as well as any substance added to an active ingredient, for example to improve its handling properties or to allow the resulting composition to be made orally deliverable A unit dose having the desired shape and consistency.
  • Excipients may include, by way of illustration and not limitation, fillers, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, substances added to mask or counteract unpleasant taste or odor, Flavoring agents, dyes, substances added to improve the appearance of the dosage form, and any other substance other than active ingredients usually used in the preparation of oral dosage forms.
  • the excipient may be an excipient having a peroxide content of less than 50 ppm, or less than 40 ppm, or less than 30 ppm, or less than 20 ppm.
  • the peroxide content may be a measure of H2O2 .
  • subject refers to any mammal such as, but not limited to, humans, horses, cows, sheep, pigs, mice, rats, dogs, cats, and primates such as chimpanzees, gorillas, and rhesus monkey.
  • a "subject” is a human.
  • a "subject” is a human being exhibiting one or more symptomatic properties of a disease, disorder or condition.
  • the term "subject” does not require a human being to have any particular status with respect to a hospital, clinic, or research institution (eg, as an admitted patient, research participant, etc.).
  • the subject is a human having an HbA1c level greater than 6.0%, 6.5%, 7.0%, 7.5%, or 8.0%.
  • the subject is a human subject in need of administration of a GLP1R agonist.
  • the nature of the need depends on the goals of treatment.
  • the subject exhibits an elevated level of glycated hemoglobin in his blood, eg, an elevated level of HbA1c in his blood.
  • the administration of the GLP1R agonist is performed to reduce the HbA1c level in the subject.
  • the subject exhibits one or more symptoms consistent with type II diabetes.
  • the administration of the GLP1R agonist is for the treatment of type II diabetes or type I diabetes (including treatment of one or more symptoms associated therewith).
  • the subject has gained weight, or in some cases is obese.
  • the administration of the GLP1R agonist is for reducing body weight, treating obesity (including treating one or more symptoms associated therewith), or delaying gastric emptying.
  • the subject exhibits one or more symptoms consistent with poor glycemic control.
  • the administration of the GLP1R agonist is performed to improve glycemic control (including treating one or more symptoms associated therewith).
  • administer/administering refers to introducing, eg, introducing a compound or composition to a subject.
  • the term is not limited to any particular mode of delivery, but preferably refers to oral delivery.
  • administration can be by various individuals including, for example, a health care professional (eg, physician, nurse, etc.), a pharmacist, or a subject (ie, self-administration).
  • treat/treating/treatment may refer to one or more of the following: delaying the progression of a disease, disorder or condition; controlling the disease, disorder or condition; delaying the onset of the disease, disorder or condition; ameliorating the disease, disorder or condition.
  • One or more symptomatic properties of a disorder or delaying the recurrence of a disease, disorder or condition or its characteristic symptoms, depending on the nature of the disease, disorder or condition and its characteristic symptoms.
  • Fig. 1 is the mass spectrum (MS) figure of impurity B
  • Fig. 2 is the hydrogen nuclear magnetic resonance spectrum ( 1 H-NMR) figure of impurity B
  • Fig. 3 is the carbon nuclear magnetic resonance spectrum ( 13 C-NMR) figure of impurity B
  • Figure 4 is the NMR DEPT 135° spectrum of impurity B
  • Fig. 5 is the NMR carbon-hydrogen correlation spectrum (HSQC) figure of impurity B
  • Fig. 6 is the nuclear magnetic resonance carbon-hydrogen long-range correlation spectrum (HMBC) figure of impurity B
  • Figure 7 is the NMR hydrogen-hydrogen correlation spectrum ( 1 H- 1 H COZY) diagram of impurity B
  • the dihydrochloride of OAD2 can be obtained according to the method described in patent CN102378574A or related international publication WO 2010/114824, which is hereby incorporated by reference in its entirety.
  • Free state OAD2 can be obtained according to the method described in patent CN102378574A or related international publication WO 2010/114824, which is hereby incorporated by reference in its entirety.
  • hydroxypropyl beta-cyclodextrin The prescribed amounts of hydroxypropyl beta-cyclodextrin, poloxamer 188, and polyvinylpyrrolidone were added to purified water. Add API to the above solution and stir to dissolve it completely. Transfer the prescribed amount of microcrystalline cellulose, lactose, and low-substituted hydroxypropyl cellulose to a fluidized bed for spray granulation. After passing the prepared granules through a 40-mesh sieve for granulation, mix with the prescribed amount of microcrystalline cellulose, Low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, and anhydrous citric acid are mixed, and pressed into tablets to control the hardness of the tablet to 10-14kg.
  • the prescribed amounts of poloxamer 188 and polyvinylpyrrolidone were added to purified water, respectively. Add API to the above solution and stir to dissolve it completely. Transfer the prescribed amount of microcrystalline cellulose, lactose, and low-substituted hydroxypropyl cellulose to a fluidized bed for spray granulation. After passing the prepared granules through a 40-mesh sieve for granulation, mix with the prescribed amount of microcrystalline cellulose, Low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, and anhydrous citric acid are mixed, and pressed into tablets to control the hardness of the tablet to 10-14kg.
  • composition was prepared according to the formulation and method described in Examples 1-11, and the prepared composition was placed under the conditions of temperature 25°C and humidity, and the initial, 1 month, 2 month and 3 months were recorded respectively. The total mass change of each tablet during the month, the results are recorded as shown in Table 12.1.
  • impurity B is the only shelf-life impurity among all related substances, that is, the content of impurity B will gradually increase with the prolongation of storage time. Therefore, the researchers analyzed the growth of impurity B separately.
  • the composition was prepared according to the formulation prescription and method described in Examples 1-11, and the prepared composition was placed under the conditions of temperature 25°C and normal humidity. Record the content of impurity B in each pharmaceutical composition at the beginning, 1 month, 2 months and 3 months respectively, and the result records are shown in Table 12.2.
  • Undestroyed test solution Take about 25 mg of OAD2 or its pharmaceutically acceptable salt, put it in a 50ml measuring bottle, add diluent to dissolve and dilute to the mark, shake well, and use it as the test solution.
  • Acid-base blank Take 2ml of 1mol/L sodium hydroxide solution, put it in a 50ml measuring bottle, neutralize it with 1mol/L hydrochloric acid solution, then dilute to the mark with diluent, shake well, and use it as an acid-base destruction blank solution.
  • Oxidative damage to the test solution take 28.10 mg of OAD2 or its pharmaceutically acceptable salt, put it in a 50 ml measuring bottle, add 2 ml of 15% hydrogen peroxide, leave it at room temperature for 9 hours, and then dilute to the mark with a diluent , Shake well, as the oxidative destruction test solution.
  • Oxidative destruction blank take 2ml of 15% hydrogen peroxide, put it in a 50ml measuring bottle, then dilute to the mark with a diluent, shake well, and use it as a oxidative destruction blank.
  • High-temperature destruction of the test solution take 26.07 mg of OAD2 or its pharmaceutically acceptable salt, weigh it accurately, put it in a 50ml measuring bottle, place it at a high temperature of 105°C for 72 hours, dissolve it with a diluent and dilute to the mark, shake Evenly, as a high-temperature destruction test solution.
  • Illumination destroys the test solution: take OAD2 or its pharmaceutically acceptable salt 25.12mg, weigh it accurately, put it in a 50ml measuring bottle, place it under the condition of light 4500Lx ⁇ 500Lx for 6 days, dissolve it with a diluent and dilute to Scale, shake well, as light damage the test solution.
  • Determination method Take 2 ⁇ l of each of the above solutions (1)-(10), inject them into a liquid chromatograph, and record the chromatograms. Among them, the results of the forced degradation experiment are shown in Table 13.1, and the results of the changes of various impurity components after the forced degradation are shown in Table 13.2.
  • the structural components of oxides or reactive oxygen species such as substances can help to reduce the formation or growth of oxidative degradation impurity B.
  • Determination method Weigh a certain amount of oxidative degradation impurity B (batch number: RD181112), dissolve it in DMSO-d6, and measure 1 H-NMR, 13 C-NMR, DEPT135°, HSQC, HMBC, 1 H- 1 H COZY.
  • Table 14.1 records the 1 H-NMR and 1 H- 1 H COZY spectrum data of impurity B
  • Table 14.2 records the 13 C-NMR, DEPT135°, HSQC, and HMBC spectrum data of impurity B.
  • Example 4 and Example 5 Through the screening of the pharmaceutical composition of each component prescription in Examples 1-11, the stability test described in Example 12, and the screening of the total impurity content and impurity B content, the preferred compositions are further obtained as Example 4 and Example 5 . The researchers further measured the situation of related substances in the prescription of the compositions of Example 4 and Example 5.
  • each pharmaceutical preparation is worth, the preparation is placed under different storage conditions, and the content of impurity B and the total content of impurities in the preparation are detected according to the plan.
  • the specific stability test results of Example 4 are shown in Tables 16.1 and 16.2.
  • the specific stability test results of Example 5 are shown in Tables 16.3 and 16.4.
  • a stock solution was prepared by dissolving 12.90 mg of OAD2 2HCl in acetonitrile:water (70:30) to a final volume of 25 mL (0.442 mg/mL).
  • test solutions were prepared by mixing 2 mL of stock solution and 2 mL of water.
  • test solutions were prepared by mixing 2 mL of stock solution and 2 mL of 0.1 N HCl solution.
  • test groups 5 and 6 test solutions were prepared by mixing 2 mL of stock solution and 2 mL of 0.1 N NaOH solution.
  • Test groups 1, 3 and 5 were protected from light by wrapping them in aluminum foil.
  • a stock solution was prepared by dissolving 5.37 mg of OAD2 2HCl in acetonitrile:water (40:60) to a final volume of 10 mL (0.46 mg/mL).
  • the test solution was prepared by mixing 2 mL of the stock solution with 2 mL of 3% aqueous H2O2 .
  • test solutions were prepared by dissolving 5.58 mg to 5.64 mg of OAD2 2HCl in acetonitrile:water (40:60) to a final volume of 25 mL.
  • Samples in each test group were stored at room temperature or at 60°C and observed after the time periods indicated in the table below.
  • test Group 7 In any of these forced degradation studies, with the exception of Test Group 7, no substantial increase in impurities or loss of active ingredient was found by HPLC analysis. In test group 7, a significant increase in impurities was found after 90 minutes, accompanied by a loss of 10% of the active ingredient. Additionally, the largest impurity had a relative retention time consistent with impurity B by HPLC analysis.
  • the assay (amount of active ingredient) was determined using a validated reversed-phase liquid chromatography gradient method.
  • the column used was Supelco Ascentis Express RP-Amide, 150X 3.0mm, 2.7 ⁇ or equivalent.
  • Mobile phase A contained 0.05% TFA in water (v/v).
  • Mobile phase B contained 0.05% TFA (v/v) in acetonitrile:methanol (1:2).
  • Samples were run using a step gradient from time zero (50% mobile phase A) to 38 minutes (99% mobile phase B).
  • the diluent used to dissolve standards and samples was a 60:40 mixture of acetonitrile and water.
  • Chromatographic peaks were detected at 280 nm using a UV detector. Measurements are obtained by comparing the peak response expressed as the peak area of a sample preparation of known concentration with the peak area obtained from a standard preparation of known concentration.
  • Impurities were quantified using the assay methods described above.
  • the method uses an area normalization method to determine the percent level of each impurity.
  • Step 1 Dissolve Polysorbate 80, Vitamin E TPGS, Poloxamer 188, and Copovidone in a volume of water using an overhead stirrer until dissolved.
  • the amount of water may be equal to between 50% and 100% (by combined weight of polysorbate 80/vitamin E TPGS/poloxamer 188/copovidone). Heat water to 50°C to speed up dissolution.
  • Step 2 Add OAD2 dihydrochloride to the above polysorbate 80/vitamin E TPGS/poloxamer 188/copovidone solution and mix until dissolved.
  • Step 3 Pass the microcrystalline cellulose, pregelatinized starch and crospovidone through a #20 sieve and charge into the fluid bed dryer and mix.
  • Step 4 Spray the solution of step 2 onto the mixture of step 3 to form a spray granulation.
  • Step 5 Grind spray granulate and pass through a #40 screen.
  • Step 6 Determine the potency of OAD2 dihydrochloride in the spray granulated material and adjust all extragranular material to achieve the desired potency of 75 mg per tablet.
  • Step 7 In a separate polyethylene bag, pass the colloidal silicon dioxide, microcrystalline cellulose, crospovidone, and citric acid through a #30 mesh.
  • Step 8 Charge the sieved granulation and the sieved excipients in step 6 into a V-shell blender and mix for 15-20 minutes.
  • Step 9 In a polyethylene bag, add an equal amount of the mixture to the sieved magnesium stearate and mix for a few minutes.
  • Step 10 Add the sieved magnesium stearate to the V-shell blender and blend for several minutes.
  • Step 11 Remove the powder and compress the powder into tablets containing 75 mg of OAD2 dihydrochloride and a total tablet weight of approximately 620-640 mg.
  • Step 12 After compression, coat the tablets with Opadry II white 85F18422 to a 3% weight gain.
  • microcrystalline cellulose Avicel PH 133, NF, Ph. Eur., JP Pregelatinized Corn Starch Starch 1500, USP/NF Crospovidone, Kollidon CL, USP/NF citric acid Anhydrous powder, USP Colloidal silica Cab-O-Sil M5P, NF Magnesium stearate Non-bovine #5712, NF/EP coating Opadry II White 85F18422 purified water USP/EP
  • the manufacturer's certificate of analysis for the crospovidone batch used in formulation CF1 showed a peroxide level (expressed as H2O2 ) of 58 ppm as determined by European Pharmacopoeia 8th edition for "Crospovidone" class A, The method described in USP37/NF32, Japanese Pharmacopoeia 16th edition Supplement 1 is used for measurement.
  • An independent analysis of this batch of crospovidone using the method in the NF 33 monograph, before use in the CF1 formulation, the determination of H2O2 showed an absorbance of 0.13 against a suitable compensation liquid, where an absorbance of 0.35 corresponds to 400 ppm of H 2 O 2 .
  • An absorbance of 0.13 translates to about 148 ppm H2O2 in Class A of the European Pharmacopoeia.
  • ICH conditions tablets of formulation CF1 from three independent batches (batches 1, 2 and 3) were packed in PVC/aluminum foil blisters, and the tablets of formulation CF1 were stored at 5°C, 25°C/ The stability program was performed at 60% relative humidity (RH) and 40°C/75%RH.
  • Tables 20.1-A, 20.2-A, 20.3-A provide a complete list of impurities in each batch after 3 months under different storage conditions, where the retention time is relative to that of OAD2 dihydrochloride and the impurity B is highlighted in bold.
  • the relative retention time of impurity B at time zero (initial) in Tables 20.1-A, 20.2-A and 20.3-A is 0.56-0.60.
  • the assay uses the high performance liquid chromatography method described herein.
  • Step 1 Dissolve Polysorbate 80, Vitamin E TPGS, and Copovidone in a volume of water using an overhead stirrer until dissolved. Heat water to 50°C to speed up dissolution.
  • Step 2 Add OAD2 dihydrochloride to the above polysorbate 80/vitamin E TPGS/copovidone solution and mix until dissolved.
  • Step 3 Pass the microcrystalline cellulose, pregelatinized starch and crospovidone through a #30 sieve and charge into the fluid bed dryer and mix.
  • Step 4 Spray the solution of step 2 onto the mixture of step 3 to form a spray granulation.
  • Step 5 Grind spray granulate and pass through a #40 screen.
  • Step 6 Determine the potency of OAD2 dihydrochloride in the spray granulated material and adjust all extragranular material to achieve the desired potency at 100 mg per tablet.
  • Step 7 In a separate polyethylene bag, pass the colloidal silicon dioxide, microcrystalline cellulose, crospovidone, poloxamer 188, and citric acid through a #30 mesh.
  • Step 8 Charge the sieved granulation and the sieved excipients in step 6 into a V-shell blender and mix for 15-20 minutes.
  • Step 9 In a polyethylene bag, add an equal amount of the mixture to the sieved magnesium stearate and mix for a few minutes.
  • Step 10 Add the sieved magnesium stearate to the V-shell blender and blend for several minutes.
  • Step 11 Remove the powder and compress the powder into tablets containing 100 mg of OAD2 dihydrochloride and a total tablet weight of approximately 820-840 mg.
  • the manufacturer's certificate of analysis for the crospovidone batch used in formulation CF2 showed a peroxide level (expressed as H2O2 ) of 50 mg/kg (or ppm) as determined by the European Pharmacopoeia 6th edition , supplement 6.3 ( Class A), the method described in "crospovidone", USP32/NF37, JPE 2004 is measured.
  • An independent analysis of the same batch of crospovidone using the method in the European Pharmacopoeia 2013 (category A) prior to formulation CF2 found that the amount of H2O2 did not exceed 400 ppm.
  • Tablet batches of formulation CF2 were placed in a stability program under the conditions and time points listed in Table 22.1.
  • the tablets were packaged and capped in 75cc high density polyethylene bottles with rayon coils and desiccant.
  • Tables 22.1-A and 22.1-B provide a complete list of impurities in batches of Formulation CF2 at months 3, 12, and 24 under different storage conditions, where retention times are relative to that of OAD2 dihydrochloride, And impurity B is highlighted in bold.
  • the relative retention time of impurity B at time zero (initial) in Tables 22.1-A and 22.2-B is 0.56.
  • the assay uses the high performance liquid chromatography method described herein.
  • Formulation LPO uses a grade of crospovidone (PolyplasdoneTM Ultra from Ashland Chemical) with a maximum of 30 ppm peroxide (H 2 O 2 ) depending on its product specification, and Formulation LPO may have as low as 9.2 ppm H 2 O 2 levels (see Pharmaceutical Technology Report (PTR-097), Ashland Specialty Ingredients "Utility of Polyplasdone TM crospovidone as a Superdisintegrant" pp. 1-5 (2014)).
  • the crospovidone used in formulation CF1 had a H2O2 level of 148 ppm as described in 19 above.
  • the crospovidone used in formulation CF2 had a H2O2 level of at least 50 ppm and no more than 400 ppm .
  • Step 1 Dissolve polysorbate 80, vitamin E TPGS, poloxamer 188, and copovidone in a volume of water using an overhead stirrer until dissolved, possibly warming to 50°C to speed up dissolution.
  • Step 2 Add OAD2 dihydrochloride to the above polysorbate 80/vitamin E TPGS/poloxamer 188/copovidone solution and mix until dissolved.
  • Step 3 Pass the microcrystalline cellulose and pregelatinized starch through a #30 sieve and load into the fluid bed dryer and mix.
  • Step 4 Spray the solution from step 2 onto the mixture from step 3 to form a spray granulation.
  • Step 5 Screen the spray granulate and pass it through a #40 screen.
  • Step 6 Determine the potency of OAD2 dihydrochloride in the spray granulated material and adjust all extragranular material to achieve the desired potency per tablet.
  • Step 7 In a separate polyethylene bag, pass the Colloidal Silicon Dioxide, Microcrystalline Cellulose, Polyplasdone Ultra, and Citric Acid through a #30 mesh.
  • Step 8 Charge the sieved granulation and the sieved excipients in step 6 into a V-shell blender and mix for 15-20 minutes.
  • Step 9 Add an equal amount of the mixture to the sieved magnesium stearate in a polyethylene bag and mix for a few minutes.
  • Step 10 Add the sieved magnesium stearate to the V-shell blender and blend for several minutes.
  • Step 11 Remove the powder and compress the powder into tablets with the following specifications: total weight: 500 mg, containing 150 mg of OAD2 dihydrochloride; total weight: 250 mg, containing 75 mg of OAD2 dihydrochloride.
  • Tables 24.1 and 24.2 summarize the growth of impurity B under these conditions and at the indicated time points.
  • Tables 24.1-A and 24.2-A provide a complete list of impurities in each formulation at the indicated time points under these conditions, where retention times are relative to that of OAD2 dihydrochloride and impurity B is highlighted in bold.
  • the relative retention time of impurity B at time zero (initial) in Tables 24.1-A and 24.2-A is 0.47 or 0.59.
  • the assay uses the high performance liquid chromatography method described herein.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
WO2025158275A1 (en) 2024-01-24 2025-07-31 Pfizer Inc. Combination therapy using glucose-dependent insulinotropic polypeptide receptor antagonist compounds and glp-1 receptor agonist compounds
WO2025189141A1 (en) 2024-03-08 2025-09-12 Annapurna Bio, Inc. Methods for treating obesity and increasing weight loss

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010114824A1 (en) 2009-03-30 2010-10-07 Transtech Pharma Inc Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010114824A1 (en) 2009-03-30 2010-10-07 Transtech Pharma Inc Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof
CN102378574A (zh) 2009-03-30 2012-03-14 转化技术制药公司 取代的偶氮蒽衍生物、药物组合物及其使用方法

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Crospovidone", vol. 6, 2004, JAPANESE PHARMACOPOEIA, pages: 3
"ICH Harmonized Tripartite Guideline", STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Q1A(R2, 6 February 2003 (2003-02-06)
GAY ET AL.: "Hydroperoxide assay with the ferric-xylenol orange complex", ANAL. BIOCHEM, vol. 273, 1999, pages 149 - 155, XP002314653, DOI: 10.1006/abio.1999.4208
NAKAMURA ET AL.: "A simple assay for lipid hydroperoxides based on triphenylphosphine oxidation and high-performance liquid chromatography", LIPIDS, vol. 26, 1991, pages 765 - 768, XP035173827, DOI: 10.1007/BF02535628
See also references of EP4410793A4
WASYLASCHUK ET AL.: "Evaluation of hydroperoxides in common pharmaceutical excipients", J. PHARM. SCI, vol. 96, 2007, pages 106 - 116, XP055281352, DOI: 10.1002/jps.20726
ZHAO, PEISHEN ET AL.: "Activation of the GLP-1 Receptor by a Non-Peptidic Agonist", NATURE, vol. 577, 8 January 2020 (2020-01-08), XP036988521, DOI: 10.1038/s41586-019-1902-z *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
WO2025158275A1 (en) 2024-01-24 2025-07-31 Pfizer Inc. Combination therapy using glucose-dependent insulinotropic polypeptide receptor antagonist compounds and glp-1 receptor agonist compounds
WO2025189141A1 (en) 2024-03-08 2025-09-12 Annapurna Bio, Inc. Methods for treating obesity and increasing weight loss

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