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WO2023241652A1 - Composition pharmaceutique, son procédé de préparation et son utilisation - Google Patents

Composition pharmaceutique, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2023241652A1
WO2023241652A1 PCT/CN2023/100441 CN2023100441W WO2023241652A1 WO 2023241652 A1 WO2023241652 A1 WO 2023241652A1 CN 2023100441 W CN2023100441 W CN 2023100441W WO 2023241652 A1 WO2023241652 A1 WO 2023241652A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
compound
polyoxyethylene
formula
castor oil
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/100441
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English (en)
Chinese (zh)
Inventor
于垂亮
吴美容
薛亚萍
周胜安
刘欣
于艳春
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Ocusun Ophthalmic Biotechnology Co Ltd
Ocusun Ophthalmic Pharmaceutical Guangzhou Co Ltd
Original Assignee
Guangzhou Ocusun Ophthalmic Biotechnology Co Ltd
Ocusun Ophthalmic Pharmaceutical Guangzhou Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangzhou Ocusun Ophthalmic Biotechnology Co Ltd, Ocusun Ophthalmic Pharmaceutical Guangzhou Co Ltd filed Critical Guangzhou Ocusun Ophthalmic Biotechnology Co Ltd
Priority to CN202380047223.0A priority Critical patent/CN119384280A/zh
Publication of WO2023241652A1 publication Critical patent/WO2023241652A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medical technology, and specifically relates to a pharmaceutical composition and its preparation method and application.
  • Rho associated protein kinase a serine/threonine protein kinase
  • RHO-related protein kinase a serine/threonine protein kinase
  • MLC myosin light chain
  • ROCK inhibitors can also promote the damage repair of corneal endothelial cells and prevent fibrosis, which has huge application prospects.
  • Isoquinoline sulfonamide compounds are an important type of ROCK inhibitors. Fasudil and K-115, which are currently on the market, are both isoquinoline sulfonamide compounds (WO2006057397A1). Among them, fasudil is a new drug with a wide range of pharmacological effects. It is an inhibitor of RHO kinase. It dilates blood vessels by increasing the activity of myosin light chain phosphatase, reduces the tension of endothelial cells, improves brain tissue microcirculation, and does not produce It can also aggravate brain hemorrhage, antagonize inflammatory factors, protect nerves from apoptosis, and promote nerve regeneration.
  • K-115 The approved and potential applications of K-115 are very wide, including glaucoma, intraocular hypertension, complications of diabetic retinal damage, age-related macular degeneration, corneal damage, recovery after cataract and glaucoma surgery, etc., and may be further expanded to the system. Sex drugs.
  • WO2020253882A1 discloses an isoquinolinone derivative as a ROCK protein kinase inhibitor and its application in preparing drugs for ROCK protein kinase inhibitor-related glaucoma or ocular hypertension diseases, and specifically discloses compound 63 in the specification.
  • This compound shows a better intraocular pressure-lowering effect than K-115, but due to its poor water solubility, it may have many adverse effects on drugability, such as: 1) the exposure of the compound is reduced, which affects the efficacy of the drug; 2 ) Affects the metabolism of the drug in the body; 3) The dosage needs to be increased to achieve the drug effect, which will cause the drug to accumulate or crystallize in the body, increasing the risk of toxic side effects; 4) It is not easy to make oral or intravenous or other liquid preparations , resulting in an increase in R&D investment in the later period; especially in the field of ophthalmic preparations, the range of dosage forms to choose from is narrow (mainly liquid preparations, gels, eye ointments, etc.).
  • eye drops are the most ideal dosage form, but due to This compound has poor water solubility, and often only a suspension can be obtained, or the uniformity and stability indicators of the developed liquid preparation are difficult to meet the requirements. It has the disadvantages of large eye irritation and poor patient compliance, and is not suitable for use as a medicine for patients. use.
  • ophthalmic preparations especially liquid preparations, that are suitable for pharmaceuticals and have simple components to improve the solubility of the compounds, preparation stability and patient compliance.
  • the object of the present invention is to provide a pharmaceutical composition and its preparation method and application.
  • the pharmaceutical composition includes a sulfate form of an isoquinolinone derivative, which has higher drug loading capacity, better uniformity and stability.
  • the invention provides a pharmaceutical composition comprising a compound of formula I:
  • the pharmaceutical composition includes a compound of formula I and a pharmaceutically acceptable Acceptable excipients, carriers and/or diluents.
  • the pharmaceutical composition includes a compound of Formula I and a solubilizing agent. In some embodiments of the invention, the pharmaceutical composition includes a compound of Formula I and an osmotic pressure regulator. In some embodiments of the invention, the pharmaceutical composition includes a compound of Formula I and a bacteriostatic agent.
  • the pharmaceutical composition includes a compound of Formula I, a solubilizer, an osmolality regulator, and a bacteriostatic agent.
  • the mass ratio of the compound of formula I to the osmotic pressure regulator can be 1:(4.5-600), such as 1:(10-500), 1:(20-400), 1:(30- 350) etc.
  • the mass ratio of the compound of formula I to the solubilizer can be 1:(2-70), preferably 1:(2-50), such as 1:(2.5-40), 1:(5- 40), 1:(10-40), etc.
  • the solubilizing agent is selected from Tween 80, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 400, poloxamer 188, polyoxyethylene hydrogenated stearate, polyoxyethylene One or more of ethylene castor oil and its derivatives, such as one, two, three or four.
  • the solubilizer is polyoxyethylene hydrogenated castor oil.
  • the polyoxyethylene hydrogenated castor oil is selected from one or more of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, and polyoxyethylene 60 hydrogenated castor oil.
  • the solubilizing agent is Tween 80 and/or polyoxyethylene 40 hydrogenated castor oil.
  • the solubilizer is Tween 80 and polyoxyethylene 40 hydrogenated castor oil.
  • the mass ratio of Tween 80 and polyoxyethylene 40 hydrogenated castor oil is 1:(0.1-30), such as 1:(0.5-20), 1:(1- 10), 1:(2-10), 1:(2-8), etc.
  • the osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, mannitol, glycerin, propylene glycol, dextrose, boric acid and borax, such as a , two, three or four.
  • the osmotic pressure regulator is sodium chloride and/or mannitol. More preferably, the osmotic pressure regulator is sodium chloride and mannitol.
  • the bacteriostatic agent is selected from benzalkonium chloride, thimerosal, dumycin Any combination of one or more of phenylene, xanthanol, chlorobutanol, parabens, and sorbic acid is preferably benzalkonium chloride.
  • the pharmaceutical composition includes the following components: a compound of formula I, and a compound selected from the group consisting of Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride, mannitol and benzalkonium chloride. one or more.
  • the pharmaceutical composition includes the following components: a compound of formula I, and one or more of polyoxyethylene hydrogenated castor oil, sodium chloride, mannitol, and benzalkonium chloride.
  • the pharmaceutical composition includes the following components: a compound of formula I, and polyoxyethylene hydrogenated castor oil.
  • the pharmaceutical composition includes the following components: a compound of formula I, polyoxyethylene hydrogenated castor oil, sodium chloride, mannitol, and benzalkonium chloride.
  • the pharmaceutical composition includes the following components: a compound of formula I, polyoxyethylene 40 hydrogenated castor oil, sodium chloride, mannitol, and benzalkonium chloride.
  • the pharmaceutical composition includes the following components: a compound of formula I, Tween 80, and polyoxyethylene 40 hydrogenated castor oil.
  • the pharmaceutical composition includes the following components: a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, and sodium chloride.
  • the pharmaceutical composition includes the following components: a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride, and benzalkonium chloride.
  • the pharmaceutical composition includes the following components: a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride, and mannitol.
  • the pharmaceutical composition includes the following components: a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride, mannitol, and benzalkonium chloride.
  • the weight parts of the compound of formula I, solubilizer, osmotic pressure regulator and bacteriostatic agent are respectively:
  • the weight portion of the solubilizer in the pharmaceutical composition, can be any value in the range of 2-70 parts, for example, it can be 2 parts, 3 parts, 4 parts, or 5 parts. , 6 servings, 8 servings, 10 servings, 15 servings, 20 servings, 25 servings, 30 servings, 35 servings, 40 servings, 45 servings, 50 servings, 55 servings, 60 servings, 65 servings or 70 servings.
  • the weight parts of the osmotic pressure regulator can be any value in the range of 13-600 parts, for example, it can be 13 parts, 14 parts, 15 parts, 16 copies, 18 copies, 20 copies, 25 copies, 30 copies, 40 copies, 50 copies, 60 copies, 70 copies, 80 copies, 90 copies, 100 copies, 120 copies, 150 copies, 180 copies, 200 copies, 250 copies, 300 copies, 350 copies, 400 copies, 450 copies, 500 copies, 550 copies or 600 copies.
  • the weight part of the bacteriostatic agent in the pharmaceutical composition, can be any value in the range of 0.05-3.2 parts, for example, it can be 0.05, 0.1 part, 0.2 part, 0.3 part, 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1 part, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts, 1.5 parts, 1.6 parts, 1.7 parts, 1.8 parts, 1.9 parts, 2 parts , 2.1 parts, 2.2 parts, 2.3 parts, 2.4 parts, 2.5 parts, 2.6 parts, 2.7 parts, 2.8 parts, 2.9 parts, 3 parts, 3.1 parts or 3.2 parts.
  • the pharmaceutical composition includes the following components by weight:
  • Tween 80 0.3-3.5 parts (such as 0.3 parts, 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1 part, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts, 1.5 parts, 1.6 parts , 1.7 parts, 1.8 parts, 1.9 parts, 2 parts, 2.1 parts, 2.2 parts, 2.3 parts, 2.4 parts, 2.5 parts, 2.6 parts, 2.7 parts, 2.8 parts, 2.9 parts, 3 parts, 3.2 parts, etc.); and
  • Polyoxyethylene hydrogenated castor oil such as polyoxyethylene 40 hydrogenated castor oil 2-35 parts (such as 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 servings, 13 servings, 14 servings, 15 servings, 16 servings, 17 servings, 18 servings, 19 servings, 20 servings, 21 servings, 22 servings, 23 servings, 24 servings, 25 servings, 26 servings, 27 servings, 28 servings , 29 copies, 30 copies, 32 copies, etc.).
  • the pharmaceutical composition includes the following components by weight:
  • Tween 80 0.3-3.5 parts (such as 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1 part, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts, 1.5 parts, 1.6 parts, 1.7 parts, 1.8 parts, 1.9 parts, 2 parts, 2.1 parts, 2.2 parts, 2.3 parts , 2.4 parts, 2.5 parts, 2.6 parts, 2.7 parts, 2.8 parts, 2.9 parts, 3 parts, 3.2 parts, etc.);
  • Polyoxyethylene hydrogenated castor oil such as polyoxyethylene 40 hydrogenated castor oil 2-35 parts (such as 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 servings, 13 servings, 14 servings, 15 servings, 16 servings, 17 servings, 18 servings, 19 servings, 20 servings, 21 servings, 22 servings, 23 servings, 24 servings, 25 servings, 26 servings, 27 servings, 28 servings , 29 copies, 30 copies, 32 copies, etc.);
  • Sodium chloride 9-110 parts (such as 9 parts, 10 parts, 13 parts, 15 parts, 18 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 50 parts, 60 parts, 70 parts, 80 parts , 90 copies, 100 copies or 107 copies, etc.);
  • Mannitol 4-200 parts (such as 4 parts, 5 parts, 8 parts, 10 parts, 12 parts, 15 parts, 18 parts, 20 parts, 25 parts, 30 parts, 40 parts, 50 parts, 60 parts, 80 parts, 100 copies, 120 copies, 150 copies, 170 copies, 190 copies, 195 copies, etc.).
  • the pharmaceutical composition includes the following components by weight:
  • the dosage form of the pharmaceutical composition is a solution, suspension, emulsion, gel, micelle or any pharmaceutically applicable ophthalmic topical dosage form.
  • the content of the compound of formula I in the pharmaceutical composition is 0.01-2 mg/mL, specifically, it can be any value in the range of 0.01-2 mg/mL, for example, it can be 0.01 mg/mL. , 0.02mg/mL, 0.05mg/mL, 0.08mg/mL, 0.1mg/mL, 0.2mg/mL, 0.3mg/mL, 0.5mg/mL, 0.8mg/mL, 1mg/mL, 1.2mg/mL, 1.5 mg/mL, 1.8 mg/mL or 2 mg/mL, etc.; preferably any value within the range of 0.05-1 mg/mL.
  • the crystal form of the compound of formula I is crystal form A or crystal form B.
  • the crystal form of the compound of formula I is crystal form B.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.33 ⁇ 0.20°, 10.62 ⁇ 0.20°, and 13.11 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 3.30 ⁇ 0.20°, 6.33 ⁇ 0.20°, 6.55° ⁇ 0.20°, 10.62 ⁇ 0.20°, 12.57 ⁇ 0.20°, 13.11 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.30 ⁇ 0.20°, 6.33 ⁇ 0.20°, 10.62 ⁇ 0.20°, 12.57 ⁇ 0.20°, 13.11 ⁇ 0.20°, 17.85 ⁇ 0.20°, 18.51 ⁇ 0.20°, 20.99 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.30 ⁇ 0.20°, 6.33 ⁇ 0.20°, 6.55 ⁇ 0.20°, 10.62 ⁇ 0.20°, 12.57 ⁇ 0.20°, 13.11 ⁇ 0.20°, 14.20 ⁇ 0.20°, 16.37 ⁇ 0.20°, 17.85 ⁇ 0.20°, 18.51 ⁇ 0.20°, 19.56 ⁇ 0.20°, 20.99 ⁇ 0.20°, 25.53 ⁇ 0.20°, 26.35 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.69 ⁇ 0.20°, 12.12 ⁇ 0.20°, 16.48 ⁇ 0.20°, 16.95 ⁇ 0.20°, 17.94 ⁇ 0.20°, 19.23 ⁇ 0.20°, 20.37 ⁇ 0.20°, 21.87 ⁇ 0.20°.
  • the invention provides the B crystal form of the compound of formula I, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2 ⁇ angles: 16.48 ⁇ 0.20°, 16.95 ⁇ 0.20°, and/or 21.87 ⁇ 0.20°, and/or 12.12 ⁇ 0.20°, and/or 17.94 ⁇ 0.20°, and/or 9.69 ⁇ 0.20°, and/or 20.37 ⁇ 0.20°, and/or 21.87 ⁇ 0.20°, and/or 4.80 ⁇ 0.20°, and/or 14.61 ⁇ 0.20 °, and/or 19.23 ⁇ 0.20°, and/or 27.53 ⁇ 0.20°, and/or 28.72 ⁇ 0.20°, and/or 33.61 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.80 ⁇ 0.20°, 9.69 ⁇ 0.20°, 12.12 ⁇ 0.20°, 14.61 ⁇ 0.20°, 16.48 ⁇ 0.20°, 16.95 ⁇ 0.20°, 17.94 ⁇ 0.20°, 19.23 ⁇ 0.20°, 20.37 ⁇ 0.20°, 21.87 ⁇ 0.20°, 27.53 ⁇ 0.20°, 28.72 ⁇ 0.20°, 33.61 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.80 ⁇ 0.20°, 9.69 ⁇ 0.20°, 12.12 ⁇ 0.20°, 16.48 ⁇ 0.20°, 16.95 ⁇ 0.20°, 17.94 ⁇ 0.20°, 19.23 ⁇ 0.20°, 20.37 ⁇ 0.20°, 21.87 ⁇ 0.20°.
  • the pH of the pharmaceutical composition is 4.0-6.0, specifically, it can be any value in the range of 4.0-6.0, for example, it can be 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0.
  • Tween 80 and/or polyoxyethylene 40 hydrogenated castor oil as solubilizers, and/or selecting sodium chloride and mannitol as osmotic pressure regulators for synergy, further improving
  • the solubility of the compound of formula I and the stability of the liquid preparation containing the compound can help solve the shortcomings of low drug loading, poor uniformity and stability of the preparation, etc. caused by the poor water solubility of the compound of formula I.
  • the present invention provides a method for preparing the pharmaceutical composition as described in the first aspect, comprising the following steps:
  • the compound of formula I is mixed with pharmaceutically acceptable excipients, carriers and/or diluents (such as solubilizers, osmotic pressure regulators and/or bacteriostatic agents) in corresponding parts by weight to obtain the pharmaceutical composition.
  • pharmaceutically acceptable excipients such as solubilizers, osmotic pressure regulators and/or bacteriostatic agents
  • the preparation method includes: mixing the compound of formula I with a solubilizer, an osmotic pressure regulator and a bacteriostatic agent in corresponding parts by weight to obtain the pharmaceutical composition.
  • the preparation method includes: adding the compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, optionally an osmotic pressure regulator and optionally a bacteriostatic agent in corresponding parts by weight. Mix evenly to obtain the composition.
  • the preparation method includes the following steps:
  • the present invention provides the pharmaceutical composition as described in the first aspect or the pharmaceutical composition prepared by the preparation method as described in the second aspect in the preparation of medicines for preventing and/or treating glaucoma or ocular hypertension. application.
  • the present invention has the following beneficial effects:
  • the compound of formula I of the present invention is in the form of a sulfate salt. Compared with its non-salt form, the water solubility is improved, and the obtained composition has a higher drug loading capacity, better uniformity and stability.
  • the solubility of the compound of formula I and the stability of the pharmaceutical preparation containing the compound are further improved, and the problem of formula I is solved.
  • the poor water solubility of the compound results in low drug loading, poor uniformity and stability of the preparation, and other defects that lead to poor finished drugs.
  • composition thus obtained is capable of completely dissolving the compound of formula I for 12 months long term (25°C ⁇ 2°C; RH 40% ⁇ 5%, 5 ⁇ 3°C) and 6 months accelerated (40°C ⁇ 2°C; RH 25% ⁇ 5 %) conditions, the preparation always remains colorless and clear, and the osmotic pressure, pH value, relative content of the compound of formula I, and the content of related substances are all relatively stable.
  • Test method About 10mg sample is used for XRPD detection.
  • Light tube voltage 40kV
  • light tube current 40mA
  • Control the temperature inside the reaction kettle to be lower than 30°C, and slowly add concentrated sulfuric acid (13.36L) into the 50L reaction kettle. Control the internal temperature below 50°C, and slowly add compound 1-4b (2500g) into the reaction kettle using a constant pressure dropping funnel. Control the internal temperature of the reaction kettle to -10 ⁇ 0°C and slowly add N-bromosuccinimide (3070.25g) in batches to the reaction kettle, and stir the reaction solution in the range of -10 ⁇ 8°C for 13 hours. Control the internal temperature below 50°C and slowly pour the reaction solution into ice water (8L). Control the internal temperature below 50°C, slowly add sodium hydroxide aqueous solution dropwise to the reaction solution, and adjust pH 9.
  • the reaction solution was separated, and the upper organic phase was filtered to obtain a solid.
  • the solid was beaten with methyl tert-butyl ether/ethyl acetate (4.4L, 10:1), and the beaten liquid was filtered to obtain a white solid.
  • the white solid was dried in an oven to obtain crude product 1-4 (371.52g).
  • the crude product is quickly filtered through silica gel and rinsed with dichloromethane until no product remains.
  • the eluate was concentrated under reduced pressure to about 1.2L, washed with 1% sodium bicarbonate aqueous solution (3L), the organic phase was dried over anhydrous sodium sulfate (500g), filtered, and then concentrated under reduced pressure until no fraction was found. Until flowing out, the intermediate 1-3 was obtained and used directly in the next step without purification.
  • methyl tert-butyl ether (8.48L) into the reaction kettle, control the internal temperature at 20-30°C and stir for 0.5 hours.
  • SMS DVS intrinsic dynamic gas adsorption meter SMS DVS intrinsic dynamic gas adsorption meter.
  • the hygroscopic weight gain of the crystal form B of compound I at 25° C. and 80% RH is 0.736%, and it is slightly hygroscopic.
  • the crystal form B of the compound of formula I was placed for 6 months under the conditions of 40°C/75%RH (relative humidity) (double-layer LDPE bag was sealed and then aluminum foil bag was heat-sealed). Double-layer LDPE bags are sealed and then heat-sealed with aluminum foil bags) and stored for 12 months. The crystal form was tested separately at each sampling point to determine the crystal form stability of the sample.
  • the experimental results of solid stability research on the crystalline form B of compound I are shown in Table 4.
  • Crystal form B of the compound of formula I has good stability under accelerated and long-term tests.
  • a high-performance liquid phase detector (Agilent 1260PDA/UV detector) was used to detect the content of the compound of formula I.
  • the chromatographic conditions are as follows in Table 5.
  • Example 1 The solubility test of the crystalline form B of compound I is shown in Table 6.
  • the compound of Formula I and the solubilizing agent were dissolved in water and prepared into different formulations to examine the effects of different solubilizing agents on the solubility of the compound of Formula I.
  • the specific formulation ingredients and experimental results are shown in Table 7 below.
  • Tween 80 and polyoxyethylene 40 hydrogenated castor oil are used as solubilizers, and an osmotic pressure regulator is further added to prepare different prescriptions.
  • the compatibility of the osmotic pressure regulator and the solubilizer is investigated.
  • the specific prescription ingredients and experiments are The results are shown in Table 8 below:
  • the content detection result refers to the percentage of the detected content of the compound of formula I in the prescription to the calibrated content.
  • This embodiment provides several preparations including compounds of formula I.
  • the specific prescription ingredients are shown in Table 10 below:
  • the preparation method of the above prescription preparation is as follows:
  • Compliance with regulations refers to compliance with the requirements for visible foreign matter in ophthalmic preparations of the Chinese Pharmacopoeia.
  • the relative content of the compound of formula I refers to the percentage of the detected content of the compound of formula I in the prescription to the calibrated content.
  • This embodiment provides several preparations including the compound of formula I.
  • the auxiliary materials in the preparation prescription are polyoxyethylene 40 hydrogenated castor oil, mannitol, sodium chloride, benzalkonium chloride and water for injection.
  • the preparation method of the above prescription preparation is as follows:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique, son procédé de préparation et son utilisation. La composition pharmaceutique comprend un composé représenté par la formule I. La composition pharmaceutique de la présente invention a une capacité de charge de médicament élevée, une bonne uniformité et une bonne stabilité, et peut être utilisée pour préparer un médicament pour prévenir et/ou traiter le glaucome ou l'hypertension oculaire.
PCT/CN2023/100441 2022-06-16 2023-06-15 Composition pharmaceutique, son procédé de préparation et son utilisation Ceased WO2023241652A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380047223.0A CN119384280A (zh) 2022-06-16 2023-06-15 一种药物组合物及其制备方法和应用

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CN202210680912 2022-06-16
CN202210680912.2 2022-06-16

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WO2023241652A1 true WO2023241652A1 (fr) 2023-12-21

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Citations (10)

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US5061714A (en) * 1989-03-28 1991-10-29 Nisshin Flour Milling Co., Ltd. Isoquinoline composition for the treatment of glaucoma or ocular hypertension
JPH08198746A (ja) * 1995-01-18 1996-08-06 Lion Corp 可溶化点眼剤
KR0185294B1 (ko) * 1997-03-17 1999-05-01 김선진 투명액상 이부프로펜 조성물 및 이를 함유하는 연질캅셀제
US20110152264A1 (en) * 2008-05-30 2011-06-23 Santen Pharmaceutical Co., Ltd. Method and composition for treating ocular hypertension and glaucoma
CN105085478A (zh) * 2014-04-28 2015-11-25 南京明德新药研发股份有限公司 异喹啉磺胺衍生物及其药物组合物和制药用途
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CN106310285A (zh) * 2015-06-15 2017-01-11 江苏吉贝尔药业股份有限公司 一种新的盐酸利舒地尔滴眼液及其制备方法
WO2020253882A1 (fr) * 2019-06-21 2020-12-24 中山大学中山眼科中心 Dérivés d'isoquinolinone servant d'inhibiteurs de protéine kinase rock et leur utilisation
CN114129575A (zh) * 2020-09-03 2022-03-04 广州润尔眼科生物科技有限公司 一种药物组合物的制备方法和应用
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