WO2023103835A1 - 一种酪氨酸激酶抑制剂眼用制剂及其制备方法和用途 - Google Patents

一种酪氨酸激酶抑制剂眼用制剂及其制备方法和用途 Download PDF

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WO2023103835A1
WO2023103835A1 PCT/CN2022/134961 CN2022134961W WO2023103835A1 WO 2023103835 A1 WO2023103835 A1 WO 2023103835A1 CN 2022134961 W CN2022134961 W CN 2022134961W WO 2023103835 A1 WO2023103835 A1 WO 2023103835A1
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ophthalmic preparation
parts
preparation according
polyethylene glycol
ophthalmic
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French (fr)
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董庆
张舒
薛陆兵
唐欣
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Chengdu Ruimu Biomedical Technology Co Ltd
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Chengdu Ruimu Biomedical Technology Co Ltd
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Priority to EP22903257.8A priority patent/EP4424302A4/en
Priority to US18/717,660 priority patent/US20250064725A1/en
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a tyrosine kinase inhibitor ophthalmic preparation, a preparation method and application thereof.
  • VEGF vascular endothelial growth factor
  • Bevacizumab (bevacizumab), ranibizumab (ranibizumab), Aflibercept (Aflibercept), Conbercept (Conbercept) and Brolucizumab (brolucizumab) are used clinically
  • Macromolecular biological drugs such as anti-vascular endothelial growth factor are administered through vitreous injection to treat age-related macular degeneration (Age-related Macular Degeneration, AMD), diabetic macular edema (Diabetic Macular Edema, DME), etc. Fundus disease.
  • TKIs Tyrosine Kinase Inhibitors
  • VEGFR vascular endothelial growth factor receptor
  • TKIs including axitinib, regorafenib, sunitinib and nintedanib also have antagonistic effects on platelet derived growth factor receptor (PDGFR), inhibit angiogenesis, and treat AMD, DME and other neovascular-related ocular diseases (Samanta, et al., Emerging Therapies in Neovascular Age-Related Macular Degeneration in 2020, Asia Pac J Ophthalmol (Phila) 2020; 9:250–259).
  • PDGFR platelet derived growth factor receptor
  • a small preclinical study injecting a TKI axitinib-prepared suspension into the suprachoroidal space at the back of the eye for the treatment of wAMD has initiated clinical studies in the United States (Kansara VS, Muya LW, Ciulla TA. Evaluation of long -lasting potential of suprachoroidal axitinib suspension via ocular and systemic disposition in rabbits. Transl Vis Sci Technol.2021; 10(7):19).
  • vitreous injection or fundus injection is invasive, and repeated injections over a long period of time increase the risk of complications.
  • small-molecule chemical drugs such as tinib
  • their metabolic distribution in the eyeball is faster.
  • drugs must be injected more frequently, and the risk of complications Higher, and thus not suitable for intravitreal injection.
  • a clinical phase 2 study of oral tinib (X-82) in the treatment of age-related macular degeneration gave subjects oral administration of different doses of X-82 tablets (50mg, 100mg, 200mg/day), and after 6 months, the visual acuity Improved to non-inferiority, but clinical research was suspended due to toxicity (Cohen et al., APEX: a phase II randomised clinical trial evaluating the safety and preliminary efficacy of oral X-82 to treat exudative age-related macular degeneration, Br J Ophthalmol, 2021 May;105(5):716-722).
  • tyrosine kinase inhibitors such as tinib
  • Eye drop administration is the most convenient and safest way of eye administration, which belongs to local administration, with less dosage and less toxic and side effects.
  • the cornea has a multi-layered structure, which is roughly divided from the outside to the inside: a lipid-rich epithelial layer, an aqueous component-rich stroma layer, and a lipid-rich endothelial layer. Eye drops first contact the tear layer of the ocular surface after instillation, and then need to cross the epithelial layer, stroma layer and endothelial layer of the cornea to reach the posterior segment of the eye.
  • eye drops often have a high concentration in the tissues of the anterior segment and cause toxic side effects, but it is still difficult to enter the posterior segment of the eye. and achieve effective therapeutic concentrations. Therefore, although the method of eye drop administration is safe, it is difficult for the existing pharmaceutical preparations to deliver the drug to the posterior segment of the eye to effectively treat fundus diseases.
  • Eye drops are solutions that are directly used for the treatment of the eyes, and must be sterile preparations.
  • two types of product terminal high-temperature sterilization or process sterilization are often used in production and preparation (choose 0.22 ⁇ m microporous membrane filtration sterilization) to achieve the purpose of final product sterility (four volumes of the 2020 edition of the Chinese Pharmacopoeia compiled by the State Pharmacopoeia Committee, China Medical Science and Technology Press, Beijing, 2020; ", China Light Industry Press, Beijing, 2010).
  • the nanocrystal solution has a direct impact on the structure and properties of the nanocrystal due to temperature changes during the sterilization process.
  • Terminal high-temperature sterilization of the nanocrystal solution will lead to the dissolution of the nanocrystals, or changes in important physical and chemical properties such as the crystal form and particle size of the nanocrystals, and even lead to the disappearance of the nanocrystals and the appearance of jelly in the solution. Therefore, similar methods cannot be used for sterilization.
  • the absorption and utilization rate of the crude drug of the nanocrystalline eye drops is also low, and the properties such as stability also need to be improved.
  • the object of the present invention is to provide a more stable eye drop that can reduce the loss of active ingredients in the filtration sterilization process or high temperature sterilization process, and has high fundus absorption and utilization rate and excellent stability (more stable than nanocrystals) Administration of ophthalmic formulations.
  • the invention provides an ophthalmic preparation for eye drop administration, which consists of active substances for treating eye diseases and pharmaceutically acceptable carriers or auxiliary materials.
  • the active substance for the treatment of eye diseases is small molecular compound drugs such as tyrosine kinase inhibitors (Tyrosine Kinases Inhibitors, TKIs) to vascular endothelial growth factor receptor (VEGFR) and/or platelet growth factor receptor (PDGFR) tyrosine Acid kinase is antagonistic.
  • TKIs tyrosine Kinases Inhibitors
  • VEGFR vascular endothelial growth factor receptor
  • PDGFR platelet growth factor receptor
  • Tini compounds are TKI drug molecules, and most of their free bases are insoluble in water. To prepare them into water-based eye drops that can penetrate into the posterior segment of the eye, it is necessary to disperse the TKIs. to aqueous solution and is stable.
  • the pharmaceutically acceptable carrier or adjuvant contains the following components: surfactant, solubilizer, thickener and solvent.
  • the present invention provides a tyrosine kinase inhibitor ophthalmic preparation, which contains the following The raw and auxiliary materials of weight portion are made:
  • Active ingredient 0.5-1.5 parts of a tyrosine kinase inhibitor; the content of the active ingredient in the ophthalmic preparation is 0.05-1 mg/mL, preferably 0.1-1 mg/mL;
  • compositions 20-300 parts of surfactant, 0.5-70 parts of thickener, 10-800 parts of solubilizer, and the balance is solvent.
  • the above-mentioned ophthalmic preparation contains the following raw and auxiliary materials in parts by weight:
  • Active ingredient 1 part of tyrosine kinase inhibitor
  • compositions 25-200 parts of surfactant, 1-60 parts of thickener, 27.5-500 parts of solubilizer, and the balance is solvent.
  • the content of the active ingredient in the ophthalmic preparation is 0.05-0.5 mg/mL, preferably 0.1-0.5 mg/mL.
  • tyrosine kinase inhibitors are tinib-based raw materials or pharmaceutically acceptable salts thereof
  • the tinib-based raw materials (Active Pharmaceutical Ingredient, API) are axitinib, sola Sorafenib, regorafenib, pazopanib, nintedanib, carbozantinib, lenvatinib, and sunitinib At least one of sunitinib.
  • HLB value Hydrophilic Balance value, HLB value
  • nonionic surfactant is polysorbate (Tween class, Tween), sorbitan fatty acid ester (Span class), polyoxyethylene fatty acid ester (Maize class, Myrij), poly At least one of oxyethylene fatty alcohol ether (Benzazol, Brij) and poloxamer.
  • the above-mentioned surfactant is polysorbate and/or poloxamer.
  • the above-mentioned surfactant is polysorbate and poloxamer, and the weight ratio of polysorbate and poloxamer is (1-5):1.
  • polysorbate 80 Furthermore, the above-mentioned polysorbate is polysorbate 80.
  • the above-mentioned thickening agent is methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose or its salt, hyaluronic acid or its salt, xanthan gum, carbomer Or at least one of solid polyethylene glycol.
  • the solid polyethylene glycol is polyethylene glycol with a molecular weight of not less than 1000, preferably polyethylene glycol 4000 (PEG 4K), polyethylene glycol 5000 (PEG 5K) or polyethylene glycol 6000 (PEG 6K) , more preferably PEG 6K.
  • PEG 4K polyethylene glycol 4000
  • PEG 5K polyethylene glycol 5000
  • PEG 6K polyethylene glycol 6000
  • the above-mentioned thickening agent is methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hyaluronic acid or its salt, carboxymethyl cellulose or its salt or solid polyethylene glycol at least one of .
  • solubilizing agent is at least one of liquid polyethylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, tyloxapol, castor oil polyoxyethylene ether, and polyoxyethylene hydrogenated castor oil.
  • solubilizer is liquid polyethylene glycol, castor oil polyoxyethylene ether and/or polyoxyethylene hydrogenated castor oil.
  • solubilizer is any one of polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), castor oil polyoxyethylene ether EL-40, polyoxyethylene hydrogenated castor oil PEG-60 One, the HLB value of the castor oil polyoxyethylene ether EL-40 is 13-14.
  • the above-mentioned solvent is a polar solvent, preferably water.
  • the above ophthalmic preparation also contains the following pharmaceutically acceptable excipients in parts by weight: 5-60 parts of emulsion stabilizer.
  • emulsion stabilizer also contains the following pharmaceutically acceptable auxiliary materials in parts by weight: 6-50 parts of emulsion stabilizer.
  • the above-mentioned emulsion stabilizer is povidone, hydroxyethyl cellulose and/or polyvinyl alcohol.
  • the above-mentioned emulsion stabilizer is povidone.
  • the above-mentioned povidone is a povidone with a weight average molecular weight of 10000-50000 Dalton.
  • the above ophthalmic preparation also contains one or more of the following pharmaceutically acceptable excipients: osmotic pressure regulator, pH regulator, preservative;
  • the osmotic pressure regulator is any one or more of glucose, sodium chloride, potassium chloride, mannitol, sorbitol, sodium citrate, potassium citrate and glycerol;
  • the pH regulator is hydrochloric acid, sodium hydroxide, acetic acid or its salt, citric acid or its salt, fumaric acid, succinic acid, sorbic acid, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, Any one or more of tartaric acid or its salts;
  • the preservative is any one or more of sorbic acid, chlorobutanol, sodium chlorite, sodium perborate, quaternary ammonium salts, hydroxyphenyl esters, phenylmercuric nitrate; preferably, the Quaternary ammonium salts include benzalkonium chloride, benzalkonium bromide, polyquaternium-1 and/or cetyltrimethylammonium bromide, and the paraben esters include methylparaben, ethylparaben and and/or propylparaben.
  • pH value of the above preparation is 5-8.
  • pH value of the above preparation is 6-8.
  • the above-mentioned ophthalmic preparations are eye drops.
  • the present invention also provides the preparation method of the above-mentioned ophthalmic preparation, which is to mix and disperse the active ingredient and the pharmaceutically acceptable auxiliary material uniformly, and then carry out stirring and/or homogeneous dispersing.
  • the above-mentioned preparation method comprises the following steps:
  • the dispersion in the above step (2) and/or step (3) is at least one selected from mechanical stirring dispersion, magnetic stirring dispersion, vortex shaking dispersion, shear dispersion, grinding dispersion, ultrasonic dispersion .
  • the high-pressure homogeneous dispersion described in the above step (3) is to homogenize for 1 to 5 cycles at a pressure not higher than 1000 Bar, then increase the pressure to more than 1300 Bar and homogenize for 10 to 20 cycles, and reduce the pressure again. Press down to below 1000 Bar for 1 to 5 cycles of homogenization.
  • step (3) adding or not adding osmotic pressure regulator and/or pH regulator to adjust the osmotic pressure of the solution obtained in step (3) to isotonicity and pH value to 5-8, and then adding or not adding preservative;
  • the present invention also provides the use of the above ophthalmic preparation in the preparation of medicines for treating eye diseases.
  • the above-mentioned medicine for treating eye diseases is a medicine for treating ocular surface diseases and/or fundus diseases.
  • the above-mentioned drugs for treating fundus diseases are drugs for inhibiting neovascularization.
  • the above-mentioned drugs for treating fundus diseases are for the treatment of age-related fundus macular degeneration, retinal vein occlusion macular edema, retinal vein occlusion, diabetic retinopathy, diabetic macular edema, and choroidal neovascularization secondary to pathological myopia. Any of the medicines for vision loss and neovascular glaucoma.
  • drugs for treating ocular surface diseases are drugs for treating ocular surface neovascular diseases.
  • the above-mentioned medicine for treating ocular surface diseases is for treating keratitis, mechanical injury, chemical injury and/or biological injury leading to corneal neovascularization, corneal neovascularization complicated by pterygium, corneal neovascularization due to corneal transplantation rejection, Any of the medicines for corneal stem cell deficiency.
  • the eye drops of the present invention are clear liquids with good stability and significantly reduced particle size (can be as low as 0.1 ⁇ m and less), and are suitable for sterilization by 0.22 ⁇ m microporous membrane filtration or/and high temperature sterilization (121 ⁇ m) °C) to prepare sterile preparation products, the loss of active ingredients after sterilization is small, and the delivery of raw materials and the absorption of raw materials in the posterior segment of the eye are not affected after sterilization.
  • the absorption of the raw material drug in the vitreous body is equivalent to or even higher than the record of the patent application CN110664757A (the concentration of the raw material drug in the eye drops of the present invention is 0.1 ⁇ 0.5mg/mL, while The concentration of the bulk drug in the example of the patent application CN110664757A has reached 1 mg/mL), which shows that the fundus absorption utilization rate of the eye drop medicine of the present invention is improved;
  • the HLB value described in the present invention is a hydrophilic-lipophilic balance constant.
  • Polyethylene glycol 4000 (PEG 4K) of the present invention refers to polyethylene glycol weight-average molecular weight is 4000, and by analogy, what the numerical value behind other polyethylene glycol represents is its weight-average molecular weight.
  • the reagents or instruments used in the present invention can be obtained from commercial purchases. If no specific conditions are specified, use them according to conventional conditions or conditions suggested by the manufacturer.
  • Dispersing machine T25 easy clean digital, IKA company (Germany);
  • API 4000 triple quadrupole mass spectrometer (Applied Biosystems, USA);
  • the property detection method of preparation of the present invention is as follows:
  • the freezing point depression of a solution is measured to determine its osmolarity.
  • Operation Clean the probe of the STY-1A osmometer: take three portions of 100 ⁇ L distilled water into 3 sample tubes, and after the instrument is preheated, screw the sample tube containing 100 ⁇ L distilled water onto the instrument probe, choose to clean 3 times, and click " Wash", repeat three times.
  • Detection After filling in the sample information in the instrument information form, click "Test”; pipette 100 ⁇ L of sample into the sample tube with a pipette gun, gently screw on the instrument, and click "Start” for detection. The detection was repeated three times, and the average value of the three detection results was taken as the detection result.
  • FE20 acidity meter is calibrated with pH buffer solution (pH is 4.00, 6.86 and 9.18 respectively), rinses the electrode with pure water, absorbs excess water with cellulose-free paper, immerses in the liquid sample to be tested and press the read button to start measurement, The data obtained after the reading is stable is the pH value of the sample.
  • Test equipment high performance liquid chromatography, model: LC-20AD (Shimadzu, Japan); mass spectrometer: model: API4000 triple quadrupole mass spectrometer (Applied Biosystems, USA); chromatographic column: Fortis Pace C18 5 ⁇ m, 2.1X30mm (Fortis, UK).
  • Rat eye test method select healthy adult Sprague Dawley (SD) rats for use, and be divided into a reagent group and a control group, with 4 eyes in each group, and the reagent group is dripped with the ophthalmic preparation prepared by the embodiment of the present invention, and each eye 20 ⁇ L. After administration, the animals were euthanized according to the predetermined time point, and the vitreous body or/and aqueous humor were collected rapidly, and the vitreous body samples were homogenized and stored at -80°C.
  • Sample processing and detection method After homogenizing the rat vitreous body sample, take 5 ⁇ L, add 45 ⁇ L of 70% methanol-water, sonicate for 2 minutes, vortex for 1 minute, add internal standard 25 ⁇ L, methanol 150 ⁇ L, vortex mix for 2 minutes, centrifuge at 12000 rpm at 4 °C After 10 min, the supernatant was taken for LC-MS/MS analysis (positive ion mode, MRM SCAN) analysis. Aqueous humor samples do not need to be homogenized, and are analyzed and detected by LC-MS/MS after being processed in the same way.
  • Rabbit eye test method select healthy adult New Zealand rabbits and divide them into a test group and a control group, with 4 eyes in each group.
  • the test group is dripped with the ophthalmic preparation prepared in the embodiment of the present invention, 50 ⁇ L per eye.
  • the animals were euthanized at a predetermined time point, and eye tissues (retina, choroid, sclera) were collected rapidly, and the samples were homogenized and stored at -80°C.
  • Sample processing and detection methods refer to rat eye tissue sample processing and detection methods.
  • Embodiment 1 the preparation of ophthalmic preparation of the present invention
  • Preparation method Weigh 75mg of polysorbate-80 (TW-80) into a glass Erlenmeyer flask containing 10mL of purified water, turn on magnetic stirring for 0.5h to obtain solution 1; weigh 18mg of povidone K12 (PVP K12) respectively and 18mg of hydroxypropylmethylcellulose (HPMC) were added to a glass conical flask containing 10mL of purified water, and magnetically stirred for 60min to obtain solution 2; 2.5mg of axitinib was weighed and put into a glass flask containing 1.2g of castor oil polyoxygen Add solution 2 to a 50mL polypropylene tube of vinyl ether EL-40, stir for 30 minutes, add solution 1, add water to 25mL, and stir for 30 minutes to obtain a mixed solution; use a disperser to disperse the mixed solution at 10000rpm for 3 minutes, stop the machine until the foam disappears , transfer the dispersion to a high-pressure homogenizer, control
  • HPLC detection Agilent HPLC1100 system is equipped with DAD detection unit, chromatographic conditions: chromatographic column is Waters XBridge C18, 5 ⁇ m, 4.6x250mm;
  • Mobile phase A 0.1% H 3 PO 4 solution
  • mobile phase B ACN (acetonitrile).
  • Temp. 35°C
  • detection wavelength 360nm
  • Flowrate 0.8mL/min
  • gradient elution program 0': 85%A-15%B, 15': 50%A-50%B, 20-21': 30%A-70%B, 25':85%A-15%B.
  • HPLC content detection result 0.078mg/mL.
  • the particle size test result particle size 14.4 nm (100.0%), PdI: 0.080; HPLC content test result: 0.077 mg/mL.
  • Rat eye absorption test results 20 ⁇ L was given to the eyes of rats, and the concentration of API in the animal vitreous was 19.9 ⁇ 3.2ng/g, and the concentration in the aqueous humor was 237.5 ⁇ 47.6ng/g after 0.5h.
  • Rabbit eye tissue absorption test results New Zealand rabbits were instilled with 50 ⁇ L, and the concentration of API in the retina was 0.92 ⁇ 0.64ng/g, the concentration in the choroid was 1.22 ⁇ 0.60ng/g, and the concentration in the sclera was 10.3 ⁇ 5.61ng in 0.5h /g.
  • Embodiment 2 the preparation of ophthalmic preparation of the present invention
  • the particle size test results were: particle size: 15.2 nm (93.5%), PdI: 0.234; HPLC content test result: 0.178 mg/mL.
  • Rat eye absorption test results 20 ⁇ L was given to rat eyes, and the concentration of API in rat vitreous was 17.3 ⁇ 9.0ng/g after 0.5h.
  • Embodiment 3 the preparation of ophthalmic preparation of the present invention
  • Particle size test results particle size: 13.8nm (67.2%), 72.6nm (21.5%), PdI: 0.249; HPLC test result content: 0.391mg/mL.
  • particle size test results were: particle size: 12.7nm (68.6%), 76.7nm (31.4%), PdI: 0.286; HPLC content test result: 0.387mg/mL.
  • the solution was sterilized by filtration through a membrane with a pore size of 0.22 ⁇ m.
  • the particle size test results were: 16.2nm (70.0%), 126.5nm (23.7%), PdI: 0.513; HPLC content test result: 0.389mg/mL.
  • Rat vitreous body absorption test results 20 ⁇ L was given to rats, the concentration of API in rat vitreous body was 37.2 ⁇ 25.1ng/g, and the concentration in aqueous humor was 370 ⁇ 92.4ng/g after 0.5h.
  • Rabbit eye tissue absorption test results New Zealand rabbits were instilled with 50 ⁇ L, and the concentration of API in the retina was 1.66 ⁇ 2.08ng/g, the concentration in the choroid was 0.98 ⁇ 0.76ng/g, and the concentration in the sclera was 9.40 ⁇ 6.41ng in 0.5h /g.
  • Embodiment 4 the preparation of ophthalmic preparation of the present invention
  • Particle size detection results particle size: 284.6nm (53.5%), 15.2nm (46.5%) PdI: 0.500; HPLC content detection result: 0.077mg/mL.
  • particle size test results were: particle size: 12.3 nm (89.8%), PdI: 0.179; HPLC content test result: 0.076 mg/mL.
  • Rat eye absorption test results 20 ⁇ L was instilled in the eyes of the rats, and the concentration of API in the vitreous body of the rats was 46.8 ⁇ 36.1ng/g after 0.5h.
  • Embodiment 5 the preparation of ophthalmic preparation of the present invention
  • particle size test results were: particle size: 97.8nm (98.9%), PdI: 0.247; HPLC content test result: 0.078mg/mL.
  • Embodiment 6 the preparation of ophthalmic preparation of the present invention
  • particle size test results were: particle size: 20.0 nm (98.6%), PdI: 0.218; HPLC content test result: 0.081 mg/mL.
  • the solution was left at 40°C for 1 month. The appearance and content of the solution did not change significantly, the particle size test result: 19.6nm (99.2%), PdI: 0.236, and the HPLC content test result: 0.080mg/mL.
  • Embodiment 7 the preparation of ophthalmic preparation of the present invention
  • Particle size test results particle size: 20.3nm (95.2%), PdI: 0.246; HPLC content test results: 0.082mg/mL.
  • particle size test results were: particle size: 19.2 nm (98.3%), PdI: 0.198; HPLC content test result: 0.081 mg/mL.
  • the solution was left at 40°C for 1 month. The appearance and content of the solution did not change significantly, the particle size test result: 18.6nm (98.8%), PdI: 0.210, the HPLC content test result: 0.081mg/mL.
  • Embodiment 8 the preparation of ophthalmic preparation of the present invention
  • Particle size test results particle size: 13.3nm (99.4%), PdI: 0.305; HPLC content test results: 0.083mg/mL.
  • the particle size test results were: particle size: 12.7 nm (99.3%), PdI: 0.237; HPLC content test result: 0.082 mg/mL.
  • Embodiment 9 the preparation of ophthalmic preparation of the present invention
  • the particle size test results were: particle size: 14.3 nm (89.6%), PdI: 0.317; HPLC content test result: 0.082 mg/mL.
  • Rat eye absorption test results 20 ⁇ L was given to rat eyes, and the concentration of API in rat vitreous was 39.5 ⁇ 26.3ng/g after 0.5h.
  • Embodiment 10 the preparation of ophthalmic preparation of the present invention
  • Example 1 The materials and ratios used are shown in Table 1, the API is regorafenib, the preparation process and content detection are the same as in Example 1 (HPLC detection wavelength: 265nm), and the solution is obtained; the content detection result: 0.048mg/mL.
  • particle size test results were: particle size: 16.3 nm (91.2%), PdI: 0.342; HPLC content test result: 0.046 mg/mL.
  • Embodiment 11 the preparation of ophthalmic preparation of the present invention
  • the materials and ratios used are shown in Table 1.
  • the API is sorafenib p-toluenesulfonate.
  • the preparation process and content detection are the same as in Example 1 (HPLC detection wavelength: 255nm) to obtain a solution; content detection result: 0.089mg/mL.
  • the particle size test results were: particle size: 17.9 nm (92.6%), PdI: 0.265; HPLC content test result: 0.087 mg/mL.
  • Rat eye absorption test results 20 ⁇ L of the rat was instilled in the eye, and the concentration of API in the vitreous body of the rat was 7.87 ⁇ 2.83ng/g after 0.5h, indicating that the concentration of this preparation in the fundus was low.
  • Preparation method Weigh 500mg TW-80 and 500mg hydroxypropyl cellulose (HPC) into a conical flask filled with 40mL purified water, stir for 30min to obtain solution 1, weigh 50mg Add axitinib to 100mL polypropylene plastic, add solution 1, stir for 10min, add purified water to 50ml, stir for 30min to obtain a mixed solution, use a disperser to disperse the mixed solution at 10000rpm for 3min, (1) adopt ball milling method : Transfer the dispersion into a ball milling tank, add 80g of wet zirconium beads (0.3-0.4mm in particle size), add 1mL of purified water to rinse the polypropylene plastic tube, then pour it into the ball milling tank, then cover the ball milling tank tightly, and put it under the condition of 0°C Grinding at 300 rpm for 2 hours, after grinding, filter with a G2 glass sand core funnel to obtain a milk
  • the particle size test results were: particle size: 310.0 nm (100.0%), PdI: 0.248; HPLC content test result: 0.736 mg/mL.
  • the solution was sterilized at 121°C; after 20 minutes, the solution separated, indicating that the preparation was unstable when heated at high temperature.
  • (2) adopt the high-pressure homogenization method, disperse the mixed liquid with a disperser at 10000rpm for 3 minutes, stop the machine until the foam disappears, transfer the dispersion liquid to the high-pressure homogenizer, control the temperature at 15 ⁇ 5°C, and disperse the mixed liquid at a pressure of about 400 Bar. Homogeneous cycle 3 times, then increase the pressure to >1300Bar homogeneous cycle 15 times, depressurize to 300Bar homogeneous cycle 2 times, then discharge to obtain a homogeneous liquid, which is a white suspension.
  • Particle size test results particle size: 295.0nm (100.0%), PdI: 0.443; HPLC content test results: 0.830mg/mL.
  • the particle size test results were: particle size: 815.7 nm (80.7%), PdI: 0.736; HPLC content test result: 0.025 mg/mL.
  • the weight average molecular weight of PVP K12 is 2500Dalton
  • the weight average molecular weight of PVP K15 is 8000Dalton
  • the weight average molecular weight of PVP K17 is 10000Dalton
  • the weight average molecular weight of PVP K30 is 50000Dalton.
  • the eye drops of the examples of the present invention have significantly better stability than the eye drops prepared by using a weakly hydrophilic solubilizer (HLB value not greater than 10) (Comparative Example 1); and , under the API dosage equivalent to that of Comparative Example 1, the absorption amount in the rat vitreous body is higher after the eye drops of the embodiment are administered, that is, the drug utilization rate of the eye drops of the present invention is significantly higher;
  • HLB value weakly hydrophilic solubilizer
  • the eye drops of the examples of the present invention have significantly better stability
  • the eye drop of the present invention is a solution, the preparation properties and stability are better, and the loss of API content after sterilization is lower; while the preparation of Comparative Example 2 is a suspension of nanocrystals liquid, there is a risk of crystal transformation during the production process, which affects the absorption and distribution of the drug in the body; there is a risk of aggregation during storage, which affects product quality; and, the suspension of Comparative Example 2 has a higher loss of API content after filtration sterilization , after high-temperature sterilization, it is unstable and stratified, and it is difficult to prepare sterile preparations.
  • the comparison of the eye drops of the examples of the present invention with those of Comparative Example 4 and Comparative Example 5 shows that in the present invention, under the API dosage (axitinib concentration 0.1 mg/mL) equivalent to that of the comparative example, axitinib is in the vitreous
  • the absorption amount of the eye drops of the present invention is significantly improved compared with Comparative Example 4 and Comparative Example 5, indicating that the drug utilization rate of the eye drops of the present invention is significantly improved.
  • Contain nonionic surfactant in the preparation of the present invention have fixed hydrophilic lipophilic group in their chemical structure, the ratio of its hydrophilic lipophilic group has determined their HLB value, the lipophilic or lipophilicity of surfactant
  • the degree of hydrophilicity can be judged by the HLB value (Chapter 3 of "Pharmaceutics” edited by Pan Weisan, Chemical Industry Press, Beijing, 2017; M.R.Shah et al., original work, translated by Liu Ying "Lipid-based nanocarriers in drug delivery S.
  • Described surfactant comprises polysorbate 80 (molecular weight is 1130Dalton), poloxamer 407 (molecular weight is 11.5KDalton), PEG-40 hydrogenated castor oil (molecular weight is 2500Dalton) and solubilizer polyoxyethylene hydrogenated castor oil EL- 40 (molecular weight is 2500Dalton), etc., their HLB value is 13-29.
  • the inventors have found through many tests that the ophthalmic solution obtained by using more than one surfactant with similar HLB values but significantly different molecular weights will be more stable than using one surfactant.
  • the present invention have excellent stability, be suitable for filtration through a 0.22 ⁇ m microporous membrane or/and high temperature (121° C.) aseptic treatment, and the raw materials Eye drops with high drug availability.
  • the present invention provides an ophthalmic preparation of a tyrosine kinase inhibitor suitable for eye drop administration, which can effectively deliver active ingredients to the fundus and treat fundus angiogenesis diseases.
  • the ophthalmic preparation of the present invention has high absorption and utilization rate, small particle size and good stability, is suitable for preparing aseptic preparations by microporous membrane sterilization method or/and high temperature sterilization method, and has very good clinical application prospects.

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WO2025169089A1 (en) 2024-02-05 2025-08-14 Sun Pharmaceutical Industries Limited Ophthalmic compositions of tyrosine kinase inhibitors and their uses
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WO2025169089A1 (en) 2024-02-05 2025-08-14 Sun Pharmaceutical Industries Limited Ophthalmic compositions of tyrosine kinase inhibitors and their uses

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