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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成都瑞沐生物医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K31/40—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
    • 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
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • 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
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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.

Abstract

一种适于滴眼给药的酪氨酸激酶抑制剂眼用制剂，它含有如下重量份的原辅料制成：活性成分：酪氨酸激酶抑制剂0.5～1.5份；所述眼用制剂中活性成分的含量为0.1～1mg/mL；药学上可接受的辅料：表面活性剂20～300份、增黏剂0.5～70份、增溶剂10～800份，余量为溶剂。该眼用制剂可以将有效将活性成分递送到眼底，治疗眼底血管新生疾病，且吸收利用率高，并且粒径小，稳定性好，适于通过微孔滤膜除菌法或/和高温灭菌法制得无菌制剂。

Description

一种酪氨酸激酶抑制剂眼用制剂及其制备方法和用途 技术领域
本发明属于药物制剂领域，具体涉及一种酪氨酸激酶抑制剂眼用制剂及其制备方法和用途。
背景技术
由于人口老龄化导致白内障、青光眼、年龄相关眼底黄斑病变(Age-related Macular Degeneration,AMD)、糖尿病性黄斑水肿(Diabetic Macular Edema,DME)等眼底血管新生疾病大幅度增多。目前使用对血管内皮生长因子(vascular endothelial growth factor，VEGF)有拮抗作用的药物抑制眼底血管生长是治疗相关的眼底血管新生疾病的主要手段之一。
然而，由于眼内存在复杂的生理结构和屏障，药物难以通过滴眼液给药的方式穿透屏障到达眼后段玻璃体，导致临床难以通过眼表给药的方法有效治疗眼底疾病，长期以来都是采用眼局部注射给药的方法治疗眼底疾病。为克服眼屏障，临床采用是将Bevacizumab(贝伐单抗),ranibizumab(雷珠单抗),Aflibercept(阿柏西普)、康柏西普(Conbercept)和Brolucizumab(布洛赛珠单抗)等抗血管内皮生长因子的大分子生物药通过玻璃体注射给药，治疗眼底新生血管导致的年龄相关眼底黄斑病变(Age-related Macular Degeneration,AMD)、糖尿病性黄斑水肿(Diabetic Macular Edema,DME)等眼底疾病。除上述抗VEGF的单克隆抗体、融合蛋白类等大分子生物药外，小分子化学药物例如酪氨酸激酶抑制剂(Tyrosine Kinases Inhibitors,TKIs)对血管内皮生长因子受体(vascular endothelial growth factor receptor，VEGFR)的酪氨酸激酶有拮抗作用，可以抑制血管生长。TKIs包括阿昔替尼、瑞戈非尼、舒尼替尼和尼达尼布等还对血小板生长因子受体(Platelet derived growth factor receptor，PDGFR)有拮抗作用，抑制新生血管生成，治疗AMD、DME等新生血管相关的眼部疾病(Samanta,et al.,Emerging Therapies in Neovascular Age-Related Macular Degeneration in 2020,Asia Pac J Ophthalmol(Phila)2020；9:250–259)。一项小型的临床前研究把一种TKI阿昔替尼配制的混悬液注射到眼底后部脉络膜上腔治疗wAMD，已在美国启动临床研究(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)。
然而，玻璃体注射或眼底注射是有创给药，长期反复注射致使发生并发症的风险增高。进一步地，替尼类小分子化学药物虽然其稳定性比大分子生物药物好，但在眼球内代谢分布速度更快，要维持眼底病灶有效的药物浓度必须更加频繁注射药物，发生并发症的风险更高，因而不适合玻璃体注射给药。
除了上述的眼局部注射给药方式外，常用的给药手段：例如口服、注射(非眼部注射)等全身给药方式，则全身毒副作用增大，且会因血-眼屏障的阻碍仅可能有极少量的药物分子到达眼后段，无法达到治疗眼底疾病的目的(陈祖基主编《实用眼科药理学》，中国科学技术出版社，p27，1993)。多数口服TKIs类抗肿瘤药会出现系统性不良反应，如口服阿昔替尼片和索拉非尼片，它们的主要不良反应包括腹泻(发生率分别为：55％和53％)、高血压(40％、29％)、疲乏(39％、32％)、食欲减退(34％、29％)、恶心(32％、22％)等(药品说明书，Reference ID:3078397)。一项口服替尼类药物(X-82)治疗老年性黄斑病变的临床2期研究给受试者分别口服不同剂量的X-82片(50mg、100mg、200mg/日)，6个月后视力改善为非劣效，但因其毒性而暂停临床研究(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)。
鉴于口服、注射、眼局部注射等给药方式均存在安全性和有效性的缺陷，亟需研究酪氨酸激酶抑制剂(如替尼类药物)的新的给药方式，治疗眼底新生血管疾病。
滴眼给药(结膜囊给药)是最方便、最安全的眼部给药方式，属于局部给药，用药量少，毒副作用小。但是眼角膜有多层结构，从外至内大致分为：富含脂质的上皮层、富含水性成分的基质层和富含脂质的内皮层。滴眼液在滴眼后首先接触眼表泪水层，继而需要跨过角膜的上皮层、基质层和内皮层才可能到达眼后段。在此过程中，由于泪液的稀释、角膜、结膜的眼表屏障和晶状体、玻璃体的解剖位置，滴眼液往往在眼前段的组织中浓度高而产生毒副作用，但仍很难进入眼后段并达到有效的治疗浓度。因此，滴眼给药的方式虽然安全，但是现有药物制剂难以将药物输送至眼后段达到有效治疗眼底疾病的目的。
发明人在之前的研究中，开发了一种纳米晶滴眼剂，利用双溶性大分子、单溶性大分子辅料成功实现了将酪氨酸激酶抑制剂类药物递送到眼底的效果(专利申请CN110664757A)，但是，该方案仍存在如下问题：
滴眼液是直接用于眼部发挥治疗作用的溶液，必须是无菌制剂，为实现药物液体制剂产品的无菌目的，生产制备中常采用产品终端高温灭菌或过程灭菌两类方式(选用0.22μm的微孔滤膜过滤除菌)以达到最终产品无菌的目的(国家药典委员会编《中国药典》2020版四部，中国医药科技出版社，北京，2020；凌沛学主编《眼科药物与制剂学》，中国轻工业出版社，北京，2010)。纳米晶溶液在灭菌过程中因为温度的变化对纳米晶的结构、性质有直接的影响。纳米晶溶液经终端高温灭菌将导致纳米晶溶解，或纳米晶晶型、粒度等重要物化特性改变，甚至导致纳米晶消失，溶液中出现胶状物，因此不能采用类似方法灭菌。
而采用孔径为0.22μm的膜材料过滤除菌的过程灭菌方式，则由于该纳米晶制剂的粒径高达300～800nm，导致过滤后原料药的损失非常高，严重影 响产品有效成分含量，故产品在工业化生产过程中，存在灭菌和除菌方面的困难。
此外，该纳米晶滴眼剂的原料药吸收利用率也偏低，稳定性等性能也有待改进。
因此，提供一种灭菌后有效成分含量损失小，原料药吸收利用率高的酪氨酸激酶抑制剂滴眼液，从而通过滴眼给药方式治疗眼底新生血管疾病，具有非常重要的意义。
发明内容
本发明的目的在于提供一种更稳定的滴眼液能够降低过滤除菌过程或高温灭菌过程中有效成分损失的，眼底吸收利用率高且稳定性优异(比纳米晶更稳定)的滴眼给药眼用制剂。
本发明提供了一种滴眼给药的眼用制剂，它由治疗眼病的活性物质和药学上可接受的载体或辅料组成。所述治疗眼病的活性物质为小分子化合物药物例如酪氨酸激酶抑制剂(Tyrosine Kinases Inhibitors,TKIs)对血管内皮生长因子受体(VEGFR)和/或血小板生长因子受体(PDGFR)的酪氨酸激酶有拮抗作用。替尼类化合物是TKI类药物分子，它们的游离碱多数难溶于水，要将其制备成以水为基质的、可滲透至眼后段的滴眼液，必须要使替尼类药物分散到水溶液，并且稳定。所述药学上可接受的载体或辅料含有如下成分：表面活性剂、增溶剂、增黏剂和溶剂，具体而言面本发明提供了一种酪氨酸激酶抑制剂眼用制剂，它含有如下重量份的原辅料制成：
活性成分：酪氨酸激酶抑制剂0.5～1.5份；所述眼用制剂中活性成分的含量为0.05～1mg/mL，优选为0.1～1mg/mL；
药学上可接受的辅料：表面活性剂20～300份、增黏剂0.5～70份、增溶剂10～800份，余量为溶剂。
进一步地，上述眼用制剂含有如下重量份的原辅料制成：
活性成分：酪氨酸激酶抑制剂1份；
药学上可接受的辅料：表面活性剂25～200份、增黏剂1～60份、增溶剂27.5～500份，余量为溶剂。
优选地，所述眼用制剂中活性成分的含量为0.05～0.5mg/mL，优选为0.1～0.5mg/mL。
进一步地，上述酪氨酸激酶抑制剂为替尼类原料药或其药学上可接受的盐，所述替尼类原料药(Active Pharmaceutical Ingredient,API)为阿昔替尼(axitinib)、索拉菲尼(sorafenib)、瑞戈非尼(regorafenib)、帕唑帕尼(pazopanib)、尼达尼布(nintedanib)、博卡替尼(carbozantinib)、乐伐替尼(lenvatinib)、和舒尼替尼(sunitinib)中的至少一种。
进一步地，上述表面活性剂的HLB值(亲水亲脂平衡常数，Hydrophile Lipophilic Balance value，HLB值)大于10，优选为13～29。
更进一步地，上述非离子型表面活性剂为聚山梨酯(吐温类，Tween)、 脱水山梨醇脂肪酸酯(司盘类)、聚氧乙烯脂肪酸酯(卖泽类，Myrij)、聚氧乙烯脂肪醇醚(苄泽类，Brij)、泊洛沙姆中的至少一种。
更进一步地，上述表面活性剂为聚山梨酯和/或泊洛沙姆。
更进一步地，上述表面活性剂为聚山梨酯和泊洛沙姆，所述聚山梨酯和泊洛沙姆的重量比为(1～5):1。
更进一步地，上述聚山梨酯为聚山梨酯80。
进一步地，上述增黏剂为甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素或其盐、透明质酸或其盐、黄原胶、卡波姆或固态聚乙二醇中的至少一种。
所述固态聚乙二醇为分子量不低于1000的聚乙二醇，优选为聚乙二醇4000(PEG 4K)、聚乙二醇5000(PEG 5K)或聚乙二醇6000(PEG 6K)，更优选为PEG 6K。
更进一步地，上述增黏剂为甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、透明质酸或其盐、羧甲基纤维素或其盐或固态聚乙二醇中的至少一种。
进一步地，上述增溶剂为液态聚乙二醇、环糊精、羟丙基环糊精、泰洛沙泊、蓖麻油聚氧乙烯醚、聚氧乙烯氢化蓖麻油中的至少一种。
更进一步地，上述增溶剂为液态聚乙二醇、蓖麻油聚氧乙烯醚和/或聚氧乙烯氢化蓖麻油。
更进一步地，上述增溶剂为聚乙二醇300(PEG 300)、聚乙二醇400(PEG 400)、蓖麻油聚氧乙烯醚EL-40、聚氧乙烯氢化蓖麻油PEG-60中的任意一种，所述蓖麻油聚氧乙烯醚EL-40的HLB值为13～14。
进一步地，上述溶剂为极性溶剂，优选为水。
进一步地，上述的眼用制剂还含有如下重量份的药学上可接受的辅料：乳化稳定剂5～60份。
更进一步地，它还含有如下重量份的药学上可接受的辅料：乳化稳定剂6～50份。
更进一步地，上述乳化稳定剂为聚维酮、羟乙基纤维素和/或聚乙烯醇。
更进一步地，上述乳化稳定剂为聚维酮。
更进一步地，上述聚维酮为重均分子量10000～50000Dalton的聚维酮。
更进一步地，上述的眼用制剂还含有如下药学上可接受的辅料中的一种或多种：渗透压调节剂、pH调节剂、防腐剂；
所述渗透压调节剂为葡萄糖、氯化钠、氯化钾、甘露醇、山梨醇、枸橼酸钠、枸橼酸钾和甘油中的任意一种或多种；
所述pH调节剂为盐酸、氢氧化钠、醋酸或其盐、枸橼酸或其盐、富马酸、琥珀酸、山梨酸、磷酸、磷酸二氢钠、磷酸氢二钠、硼酸、硼砂、酒石酸或其盐中的任意一种或多种；
所述防腐剂为山梨酸、三氯叔丁醇、亚氯酸钠、过硼酸钠、季铵盐类、羟苯酯类、硝酸苯汞中的任意一种或多种；优选地，所述季铵盐类包括苯扎氯铵、苯扎溴铵、聚季铵盐-1和/或溴化十六烷基三甲铵，所述羟苯酯类包括 羟苯甲酯、羟苯乙酯和/或羟苯丙酯。
进一步地，上述制剂的pH值为5～8。
更进一步地，上述制剂的pH值为6～8。
更进一步地，上述制剂的pH值为6～7。
更进一步地，上述的眼用制剂是滴眼剂。
本发明还提供了上述的眼用制剂的制备方法，它是将所述活性成分和药学上可接受的辅料混合分散均匀，再进行搅拌分散和/或均质分散。
进一步地，上述制备方法包括如下步骤：
(1)将表面活性剂分散在溶剂中得溶液A，另将乳化稳定剂和增黏剂分散在溶剂中得溶液B；
(2)将活性成分分散在增溶剂中，再加入步骤(1)得到的溶液B中分散均匀，得溶液C；
(3)将溶液C加入溶液A中分散均匀，然后高压均质分散，即得。
更进一步地，上述步骤(2)和/或步骤(3)中所述分散选自机械搅拌分散、磁力搅拌分散、涡旋振摇分散、剪切分散、研磨分散、超声分散中的至少一种。
更进一步地，上述步骤(3)所述的高压均质分散是先在不高于1000Bar的压力下均质1～5次循环，再提高压力到1300Bar以上均质10～20次循环，再次减压至1000Bar以下均质1～5次循环。
(4)加入或不加渗透压调节剂和/或pH调节剂调节步骤(3)得到的溶液的渗透压至等渗、pH值至5～8，再加入或不加防腐剂；即得。
本发明还提供了上述的眼用制剂在制备治疗眼部疾病的药物中的用途。
进一步地，上述治疗眼部疾病的药物是治疗眼表疾病和/或眼底疾病的药物。
更进一步地，上述治疗眼底疾病的药物是抑制新生血管生成的药物。
更进一步地，上述治疗眼底疾病的药物是治疗年龄相关眼底黄斑病变、视网膜静脉阻塞黄斑水肿、视网膜静脉阻塞、糖尿病性视网膜病变、糖尿病性黄斑水肿、继发于病理性近视的脉络膜新生血管引起的视力下降、新生血管性青光眼中的任意一种的药物。
更进一步地，上述治疗眼表疾病的药物是治疗眼表新生血管疾病的药物。
更进一步地，上述治疗眼表疾病的药物是治疗角膜炎、机械损伤、化学损伤和/或生物性损伤导致角膜新生血管、对翼状胬肉并发的角膜新生血管、角膜移植排斥性角膜新生血管、角膜干细胞缺乏症中的任意一种的药物。
本发明的有益效果：
1、本发明滴眼液为澄明液，稳定性好且粒径显著降低(可低至0.1μm及更小)，适于通过0.22μm微孔滤膜过滤除菌或/和高温灭菌(121℃)制备无菌制剂产品，除菌后有效成分损失小，且除菌后不影响原料药递送与眼后段对原料药的吸收。
2、在原料药用量减少90％的基础上，原料药在玻璃体的吸收量与专利 申请CN110664757A的记载相当甚至更高(本发明滴眼液中原料药浓度为0.1～0.5mg/mL，而专利申请CN110664757A中实施例的原料药浓度达到了1mg/mL)，说明本发明滴眼液药物的眼底吸收利用率提高；
同时，由于多数情况滴眼给药后80～90％的药液随泪液从泪小管排出或经眼睑及结膜血管吸收入血液系统，可能产生系统毒副作用。在保证将治疗量的药物递送到眼底的条件下，减少总给药量有利于减少全身毒副作用，因此本发明滴眼液的毒副作用更小。
本发明所述HLB值是亲水亲脂平衡常数。
本发明所述聚乙二醇4000(PEG 4K)是指聚乙二醇重均分子量为4000，以此类推，其它聚乙二醇后的数值表示的是其重均分子量。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为实施例2制得的样品的透射电镜图(标尺＝200nm)。
图2为实施例3制得的样品的透射电镜图(标尺＝100nm)。
具体实施方式
本发明所用试剂或仪器可以通过市售购买获得，未注明具体条件的，按照常规条件或制造商建议的条件使用。
部分仪器设备如下：
ES225SM-DR(E)电子分析天平，Precisa公司(瑞士)；
DF-101S集热式恒温加热磁力搅拌器，巩义市英峪高科仪器厂(河南，中国)；
WH-2微型涡旋混合仪，上海沪西分析仪器厂有限公司(上海，中国)；
分散机：T25 easy clean digital，IKA公司(德国)；
KQ-500型超声清洗仪，昆山市超声波仪器有限公司(昆山，中国)；
AH-NANO Plus高压均质机，安拓思纳米技术(苏州)有限公司(中国)；
PM-DK2行星式球磨机，卓的仪器设备(上海)有限公司(上海，中国)；
Mettler Toledo FE20pH meter，梅特勒-托利多公司(瑞士)；
NS-90纳米粒度分析仪，珠海欧美克仪器有限公司(珠海，中国)；
安捷伦1100HPLC高效液相色谱仪，安捷伦科技有限公司(美国)；
API 4000三重四极杆质谱仪(美国Applied Biosystems公司)；
STY-1A渗透压测定仪，天津市天大天发科技有限公司(天津，中国)。
本发明制剂的性质检测方法如下：
粒径检测方法：
将1mL实施例或对比例制备得到的样品转移至样品池中，检测温度设置为40℃，将样品池放入NS-90纳米粒度分析仪，开始检测。每个样品重复检测3次，取3次检测结果的平均值为该样品检测结果为粒度(以主要粒径分布及其占比)和多分散指数(PdI，Polydispersity Index)表示。
渗透压摩尔浓度检测方法：
测量溶液的冰点下降来测定其渗透压摩尔浓度。操作：清洗STY-1A渗透压测定仪探头：取三份100μL蒸馏水至3只样品管中，待仪器预热后，将装有100μL蒸馏水的样品管旋上仪器探头，选择清洗3次，点击“清洗”，重复三次。检测：在仪器信息表中填入样品信息后，点击“测试”；用移液枪移取100μL样品至样品管中，轻轻旋上仪器，点击“启动”检测。重复检测三次，取3次检测结果的平均值为检测结果。
pH值检测方法：
FE20型酸度计分别用pH缓冲溶液(pH分别为4.00、6.86和9.18)校准，电极用纯净水冲洗后，用无纤维纸吸去多余水份，浸入待检测液体样品中按读数键开始测量，在读数稳定后所得数据，即为样品pH值。
除另有说明外，递送药物到达眼后段的效果验证方法如下：
试验仪器设备：高效液相色谱仪，型号：LC-20AD(日本岛津)；质谱仪：型号：API4000三重四极杆质谱仪(美国Applied Biosystems公司)；色谱柱：Fortis Pace C18 5μm,2.1X30mm(英国Fortis公司)。
大鼠眼试验方法：选用健康成年Sprague Dawley(SD)大鼠，分为受试剂组和对照组，每组4只眼，受试剂组滴加本发明实施例制备的眼用制剂，每只眼睛20μL。给药后按预定的时间点安乐死处理动物，迅速采集玻璃体或/和房水，玻璃体样品匀浆处理后，于-80℃保存。
样品处理及检测方法：取大鼠玻璃体样品匀浆后，取5μL，加入45μL70％甲醇-水，超声2min，涡旋1min后，加入内标25μL，甲醇150μL，涡旋混合2min，4℃ 12000rpm离心10min，取上清液用于LC-MS/MS分析(正离子模式，MRM SCAN)分析。房水样品不需匀浆，按同样方法处理后用LC-MS/MS分析检测。
兔眼试验方法：选用健康成年新西兰兔，分为受试剂组和对照组，每组4只眼，受试剂组滴加本发明实施例制备的眼用制剂，每只眼睛50μL。给药后按预定的时间点安乐死处理动物，迅速采集眼组织(视网膜、脉络膜、巩膜)，样品匀浆处理后，于-80℃保存。
样品处理及检测方法：参照大鼠眼组织样品处理及检测方法。
实施例1、本发明眼用制剂的制备
制备方法：称取75mg聚山梨酯-80(TW-80)加到含有10mL纯化水的玻璃三角瓶中，开启磁力搅拌0.5h，得溶液1；分别称取18mg聚维酮K12(PVP K12)和18mg羟丙基甲基纤维素(HPMC)加到含有10mL纯化水的 玻璃三角瓶中，磁力搅拌60min，得溶液2；称取2.5mg阿昔替尼投入到装有1.2g蓖麻油聚氧乙烯醚EL-40的50mL聚丙烯管中，加入溶液2，搅拌30min，加入溶液1，加水至25mL，搅拌30min，得混合液；将混合液用分散机在10000rpm分散3min，停机待泡沫消失后，将分散液转移至高压均质机，控制温度15±5℃，在压力400Bar左右均质循环3次，然后提高压力至1300Bar均质循环15次，减压至300Bar均质循环2次后排出，得到均质液，检测pH值和渗透压，用枸橼酸钠或/和稀盐酸溶液调节至pH7.0；加氯化钠调节渗透压至：272mOsmol/kg。加入防腐剂后搅拌分散，溶液经0.45μm滤膜减压过滤，得产品为溶液。
HPLC检测：安捷伦HPLC1100系统配置DAD检测单元，色谱条件：色谱柱为Waters XBridge C18，5μm,4.6x250mm；
流动相A:0.1％H 3PO 4溶液,流动相B:ACN(乙腈)。Temp.：35℃,检测波长：360nm，Flowrate:0.8mL/min；梯度洗脱程序：0’:85％A-15％B,15’:50％A-50％B,20-21’:30％A-70％B,25’:85％A-15％B。HPLC含量检测结果：0.078mg/mL。
粒径检测结果(主要粒径分布及其占比)，粒径：13.0nm(92.1％)，PdI：0.227；
溶液经孔径0.22μm膜过滤除菌后，粒径检测结果：粒径14.4nm(100.0％)，PdI：0.080；HPLC含量检测结果：0.077mg/mL。
大鼠眼部吸收实验结果：给大鼠滴眼20μL，0.5h API在动物玻璃体的浓度为19.9±3.2ng/g，在房水的浓度为237.5±47.6ng/g。
兔眼组织吸收实验结果：给新西兰兔滴眼50μL，0.5h API在视网膜的浓度为0.92±0.64ng/g，在脉络膜的浓度为1.22±0.60ng/g，在巩膜的浓度为10.3±5.61ng/g。
实施例2、本发明眼用制剂的制备
所用物料及比例如表1所示，制备过程(pH调节至6.5)与含量检测同实施例1，得到溶液；调节渗透压至：332mOsmol/kg；
粒径检测结果，粒径：12.8nm(76.0％)，PdI：0.283；HPLC含量检测结果：0.181mg/mL。
溶液经孔径0.22μm膜过滤除菌后，粒径检测结果，粒径：15.2nm(93.5％)，PdI：0.234；HPLC含量检测结果：0.178mg/mL。
大鼠眼部吸收实验结果：给大鼠滴眼20μL，0.5h API在大鼠玻璃体的浓度为17.3±9.0ng/g。
透射电镜分析粒径为球状(图1)
实施例3、本发明眼用制剂的制备
所用物料及比例如表1所示，制备过程(pH调节至5.7)与含量检测同实施例1，得到溶液；调节渗透压至：338mOsmol/kg；
粒径检测结果：粒径：13.8nm(67.2％)，72.6nm(21.5％)，PdI：0.249；HPLC检测结果含量：0.391mg/mL。
溶液经121℃；20min灭菌后，粒径检测结果，粒径：12.7nm(68.6％)，76.7nm(31.4％)，PdI：0.286；HPLC含量检测结果：0.387mg/mL。
溶液经孔径0.22μm膜过滤除菌，粒径检测结果，粒径：16.2nm(70.0％)，126.5nm(23.7％)，PdI：0.513；HPLC含量检测结果：0.389mg/mL。
大鼠玻璃体吸收实验结果：给大鼠滴眼20μL，0.5h API在大鼠玻璃体的浓度为37.2±25.1ng/g，在房水的浓度为370±92.4ng/g。
兔眼组织吸收实验结果：给新西兰兔滴眼50μL，0.5h API在视网膜的浓度为1.66±2.08ng/g，在脉络膜的浓度为0.98±0.76ng/g，在巩膜的浓度为9.40±6.41ng/g。
透射电镜分析粒径为雪花状(图2)
实施例4、本发明眼用制剂的制备
所用物料及比例如表1所示，制备过程(pH调节至6.1)与含量检测同实施例1，得到溶液；调节渗透压至：288mOsmol/kg；
粒径检测结果，粒径：284.6nm(53.5％)，15.2nm(46.5％)PdI：0.500；HPLC含量检测结果：0.077mg/mL。
溶液经孔径0.22μm膜过滤除菌后，粒径检测结果，粒径：12.3nm(89.8％)，PdI：0.179；HPLC含量检测结果：0.076mg/mL。
大鼠眼部吸收实验结果：给大鼠滴眼20μL，0.5h API在大鼠玻璃体的浓度为46.8±36.1ng/g。
实施例5、本发明眼用制剂的制备
所用物料及比例如表1所示，制备过程(pH调节至6.7)与含量检测同实施例1，得到溶液；
粒径检测结果，粒径：106.0nm(91.2％)，PdI：0.288；HPLC含量检测结果：0.081mg/mL。
溶液经孔径0.22μm膜过滤除菌后，粒径检测结果，粒径：97.8nm(98.9％)，PdI：0.247；HPLC含量检测结果：0.078mg/mL。
溶液在40℃放置1月。溶液外观及含量无明显变化，粒径检测：93.1nm(99.6％)，PdI:0.255，HPLC含量检测结果：0.076mg/mL。
实施例6、本发明眼用制剂的制备
所用物料及比例如表1所示，制备过程(pH调节至6.1)与含量检测同实施例1，得到溶液；
粒径检测结果，粒径：19.8nm(99.3％)，PdI：0.186；HPLC含量检测结果：0.082mg/mL。
溶液经孔径0.22μm膜过滤除菌后，粒径检测结果，粒径：20.0nm (98.6％)，PdI：0.218；HPLC含量检测结果：0.081mg/mL。
溶液在40℃放置1月。溶液外观及含量无明显变化，粒径检测结果：19.6nm(99.2％)，PdI:0.236，HPLC含量检测结果：0.080mg/mL。
实施例7、本发明眼用制剂的制备
所用物料及比例如表1所示，制备过程(pH调节至6.3)与含量检测同实施例1，得到溶液；
粒径检测结果，粒径：20.3nm(95.2％)，PdI：0.246；HPLC含量检测结果：0.082mg/mL。
溶液经孔径0.22μm膜过滤除菌后，粒径检测结果，粒径：19.2nm(98.3％)，PdI：0.198；HPLC含量检测结果：0.081mg/mL。
溶液在40℃放置1月。溶液外观及含量无明显变化，粒径检测结果：18.6nm(98.8％)，PdI:0.210，HPLC含量检测结果：0.081mg/mL。
实施例8、本发明眼用制剂的制备
所用物料及比例如表1所示，制备过程(pH调节至6.1)与含量检测同实施例1，得到溶液；
粒径检测结果，粒径：13.3nm(99.4％)，PdI：0.305；HPLC含量检测结果：0.083mg/mL。
溶液经孔径0.22μm膜过滤除菌后，粒径检测结果，粒径：12.7nm(99.3％)，PdI：0.237；HPLC含量检测结果：0.082mg/mL。
实施例9、本发明眼用制剂的制备
所用物料及比例如表1所示，制备过程(pH调节至6.1)与含量检测同实施例1，加氯化钠和山梨醇调节渗透压至284mOsmol/kg，得到溶液；
粒径检测结果，粒径：15.6nm(78.2％)，PdI：0.454；HPLC含量检测结果：0.084mg/mL。
溶液经孔径0.22μm膜过滤除菌后，粒径检测结果，粒径：14.3nm(89.6％)，PdI：0.317；HPLC含量检测结果：0.082mg/mL。
大鼠眼部吸收实验结果：给大鼠滴眼20μL，0.5h API在大鼠玻璃体的浓度为39.5±26.3ng/g。
实施例10、本发明眼用制剂的制备
所用物料及比例如表1所示，API为瑞戈非尼，制备过程与含量检测同实施例1(HPLC检测波长：265nm)，得到溶液；含量检测结果：0.048mg/mL。
粒径检测结果，粒径：17.4nm(81.2％)，PdI：0.387；
溶液经孔径0.22μm膜过滤除菌后，粒径检测结果，粒径：16.3nm(91.2％)，PdI：0.342；HPLC含量检测结果：0.046mg/mL。
实施例11、本发明眼用制剂的制备
所用物料及比例如表1所示，API为对甲苯磺酸索拉菲尼，制备过程与含量检测同实施例1(HPLC检测波长：255nm)，得到溶液；含量检测结果：0.089mg/mL。
粒径检测结果，粒径：19.6nm(88.2％)，PdI：0.406；
溶液经孔径0.22μm膜过滤除菌后，粒径检测结果，粒径：17.9nm(92.6％)，PdI：0.265；HPLC含量检测结果：0.087mg/mL。
对比例1、
所用物料及比例如表1所示，制备过程与含量检测同实施例1，得到溶液；
粒径检测结果，粒径：2105nm(100.0％)，PdI：0.645；
室温静置过夜后制剂中物质凝聚成团产生水油分离现象，说明此制剂稳定性较差。
大鼠眼部吸收实验结果：给大鼠滴眼20μL，0.5h API在大鼠玻璃体的浓度为7.87±2.83ng/g，说明此制剂在眼底浓度较低。
对比例2、
所用物料及比例如表1所示，制备方法：称取500mg TW-80和500mg羟丙基纤维素(HPC)加入装有40mL纯化水的三角瓶中，搅拌30min，得溶液1，称取50mg阿昔替尼加入100mL的聚丙烯塑料中，加入溶液1，搅拌10min后，加纯化水至50ml，搅拌30min，得混合液，使用分散机将混合液在10000rpm分散3min，(1)采用球磨法：将分散液转入球磨罐加80g湿锆珠(粒径为0.3～0.4mm)，再加1mL纯化水冲洗聚丙烯塑料管后汇入球磨罐，然后盖紧球磨罐，在0℃的条件下，转速300rpm研磨2h，研磨结束后，使用G2的玻璃砂芯漏斗过滤，得到乳白色混悬液。
粒径检测结果，粒径：280.9nm(100.0％)，PdI：0.274；HPLC含量检测结果：0.879mg/mL。
溶液经孔径0.22μm微孔滤膜加压过滤除菌后，粒径检测结果，粒径：310.0nm(100.0％)，PdI：0.248；HPLC含量检测结果：0.736mg/mL。
溶液经121℃灭菌；20min后，溶液分层，说明此制剂经高温加热不稳定。
或，(2)采用高压均质法，将混合液用分散机在10000rpm分散3min，停机待泡沫消失后，将分散液转移至高压均质机，控制温度15±5℃，在压力400Bar左右均质循环3次，然后提高压力至>1300Bar均质循环15次，减压至300Bar均质循环2次后排出，得到均质液，均质液为白色混悬液。
粒径检测结果，粒径：295.0nm(100.0％)，PdI：0.443；HPLC含量检测结果：0.830mg/mL。
溶液经孔径0.22μm微孔滤膜加压过滤除菌后，粒径检测结果，粒径： 815.7nm(80.7％)，PdI：0.736；HPLC含量检测结果：0.025mg/mL。
对比例3、
所用物料及比例如表1所示，制备过程(pH调节至7.0)同对比例1，得到溶液。室温放置3天，产生沉淀，说明所制备溶液不稳定。
对比例4、
按照专利申请CN110664757A表8中序号12的记载制备的滴眼剂：5mg阿昔替尼；2mg吐温80；2mg HPMC E5，加水至50mL，高压均质法，所得滴眼液做大鼠玻璃体滴眼吸收试验，滴眼0.5h API在大鼠玻璃体含量为1.7ng/mL。
对比例5、
按照专利申请CN110664757A表8中序号13的记载制备的滴眼剂：10mg阿昔替尼；2mg吐温80；2mg HPMC E5，加水至50mL，高压均质法，所得滴眼液做大鼠玻璃体滴眼吸收试验，滴眼0.5hAPI在大鼠玻璃体含量为6.3ng/mL。
表1
Figure PCTCN2022134961-appb-000001
Figure PCTCN2022134961-appb-000002
说明：PVP K12重均分子量为2500Dalton，PVP K15重均分子量为8000Dalton，PVP K17重均分子量为10000Dalton，PVP K30重均分子量为50000Dalton。
从上述结果可以看出：本发明实施例滴眼液与采用亲水性弱的增溶剂(HLB值不大于10)制备的滴眼剂(对比例1)相比，稳定性显著更优；并且，在与对比例1相当的API用量下，实施例滴眼给药后在大鼠玻璃体内吸收量更高，即本发明滴眼液的药物利用率显著更高；
本发明实施例滴眼液与缺少表面活性剂的制剂(对比例3)相比，稳定性也显著更好；
本发明实施例滴眼液与对比例2相比，本发明滴眼液是溶液，制剂性状、稳定性更优异，除菌后API含量损失较低；而对比例2的制剂是纳米晶混悬液，生产过程中有晶型转变的风险，影响药物在体内的吸收分布；存放期间有聚集的风险，影响产品质量；并且，对比例2的混悬液在过滤除菌后API含量损失较高，经高温除菌则不稳定出现分层，难以制备得到无菌制剂。
进一步地，本发明实施例滴眼液与对比例4和对比例5比较可知，本发明在与对比例相当的API用量(阿昔替尼浓度0.1mg/mL)下，阿昔替尼在玻璃体的吸收量比对比例4和对比例5显著提升，说明本发明滴眼液的药物利用率显著提高。
本发明制剂中含有非离子型表面活性剂，它们的化学结构中具有固定的亲水亲脂基团，其亲水亲脂基团的比例决定了它们的HLB值，表面活性剂的亲油或亲水程度可以用HLB值的大小判别(潘卫三主编《药剂学》第三章，化学工业出版社，北京，2017；M.R.Shah et al.,原著，刘颖主译《基于脂质的纳米载体在药物递送和诊断中的应用》第四章，科学出版社，北京，2019；S.S.Smail et al.,Studies on Surfactants,Cosurfactants,and Oils for Prospective Use in Formulation of Ketorolac Tromethamine Ophthalmic Nanoemulsions, Pharmaceutics 2021,13,467)。本发明人在研究中发现表面活性剂HLB值>10时，在其他条件相同或相似的情况下制备得到的含有API的滴眼液稳定性更好。所述表面活性剂包括聚山梨酯80(分子量为1130Dalton)、泊洛沙姆407(分子量为11.5KDalton)、PEG-40氢化蓖麻油(分子量为2500Dalton)和增溶剂聚氧乙烯氢化蓖麻油EL-40(分子量为2500Dalton)等，它们的HLB值为13～29。本发明人经过多次试验发现，使用HLB值相近，但分子量有明显差异的一种以上表面活性剂，所得到的滴眼液会比使用一种表面活性剂更稳定。
因此，只有在本发明特定的辅料种类和用量组合的基础上，才能得到本发明具有优异稳定性，适于通过0.22μm微孔滤膜过滤或/和高温(121℃)无菌处理，且原料药利用率高的滴眼液。
综上，本发明提供了一种适于滴眼给药的酪氨酸激酶抑制剂眼用制剂，可以有效将活性成分递送到眼底，治疗眼底血管新生疾病。本发明眼用制剂吸收利用率高，并且粒径小，稳定性好，适于通过微孔滤膜除菌法或/和高温灭菌法制得无菌制剂，具有非常好的临床应用前景。

Claims (33)

  1. 一种酪氨酸激酶抑制剂眼用制剂，其特征在于，它含有如下重量份的原辅料制成：
    活性成分：酪氨酸激酶抑制剂0.5～1.5份；所述眼用制剂中活性成分的含量为0.05～1mg/mL；
    药学上可接受的辅料：表面活性剂20～300份、增黏剂0.5～70份、增溶剂10～800份，余量为溶剂。
  2. 如权利要求1所述的眼用制剂，其特征在于，它含有如下重量份的原辅料制成：
    活性成分：酪氨酸激酶抑制剂0.5～1.5份；所述眼用制剂中活性成分的含量为0.1～1mg/mL；
    药学上可接受的辅料：表面活性剂20～300份、增黏剂0.5～70份、增溶剂10～800份，余量为溶剂。
  3. 如权利要求1或2所述的眼用制剂，其特征在于，它含有如下重量份的原辅料制成：
    活性成分：酪氨酸激酶抑制剂1份；
    药学上可接受的辅料：表面活性剂25～200份、增黏剂1～60份、增溶剂27.5～500份，余量为溶剂；优选地，所述眼用制剂中活性成分的含量为0.05～0.5mg/mL，更优选为0.1～0.5mg/mL。
  4. 如权利要求1～3任一项所述的眼用制剂，其特征在于，所述酪氨酸激酶抑制剂为替尼类原料药或其药学上可接受的盐，所述替尼类原料药包括但不限于阿昔替尼、索拉菲尼、瑞戈非尼、帕唑帕尼、尼达尼布、博卡替尼、乐伐替尼和舒尼替尼中的至少一种。
  5. 如权利要求1～3任一项所述的眼用制剂，其特征在于，所述表面活性剂的HLB值大于10，优选为13～29。
  6. 如权利要求5所述的眼用制剂，其特征在于，所述非离子型表面活性剂为聚山梨酯、脱水山梨醇脂肪酸酯、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、泊洛沙姆中的至少一种。
  7. 如权利要求6所述的眼用制剂，其特征在于，所述表面活性剂为聚山梨酯和/或泊洛沙姆。
  8. 如权利要求7所述的眼用制剂，其特征在于，所述表面活性剂为聚山梨酯和泊洛沙姆，所述聚山梨酯和泊洛沙姆的重量比为(1～5):1。
  9. 如权利要求7或8所述的眼用制剂，其特征在于，所述聚山梨酯为聚山梨酯-80。
  10. 如权利要求1～3任一项所述的眼用制剂，其特征在于，所述增黏剂为甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素或其盐、透明质酸或其盐、黄原胶、卡波姆或固态聚乙二醇中的至少一种；
    所述固态聚乙二醇为分子量不低于1000的聚乙二醇，优选为聚乙二醇4000、聚乙二醇5000或聚乙二醇6000，更优选为聚乙二醇6000。
  11. 如权利要求10所述的眼用制剂，其特征在于，所述增黏剂为甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、透明质酸或其盐、羧甲基纤维素或其盐、卡波姆或固态聚乙二醇中的至少一种。
  12. 如权利要求1～3任一项所述的眼用制剂，其特征在于，所述增溶剂为液态聚乙二醇、环糊精、羟丙基环糊精、泰洛沙泊、蓖麻油聚氧乙烯醚、聚氧乙烯氢化蓖麻油中的至少一种。
  13. 如权利要求12所述的眼用制剂，其特征在于，所述增溶剂为液态聚乙二醇、蓖麻油聚氧乙烯醚和/或聚氧乙烯氢化蓖麻油。
  14. 如权利要求13所述的眼用制剂，其特征在于，所述增溶剂为聚乙二醇300、聚乙二醇400、蓖麻油聚氧乙烯醚EL-40、聚氧乙烯氢化蓖麻油PEG-60中的任意一种，所述蓖麻油聚氧乙烯醚EL-40的HLB值为13～14。
  15. 如权利要求1～3任一项所述的眼用制剂，其特征在于，所述溶剂为极性溶剂，优选为水。
  16. 如权利要求1～3任一项所述的眼用制剂，其特征在于，它还含有如下重量份的药学上可接受的辅料：乳化稳定剂5～60份。
  17. 如权利要求16所述的酪氨酸激酶抑制剂眼用制剂，其特征在于，它含有如下重量份的药学上可接受的辅料：乳化稳定剂6～50份。
  18. 如权利要求17所述的眼用制剂，其特征在于，所述乳化稳定剂为聚维酮、羟乙基纤维素、聚乙烯醇中的至少一种。
  19. 如权利要求18所述的眼用制剂，其特征在于，所述乳化稳定剂为聚维酮。
  20. 如权利要求19所述的眼用制剂，其特征在于，所述聚维酮为重均分子量3500～50000Dalton的聚维酮，优选为重均分子量10000～50000Dalton的聚维酮。
  21. 如权利要求1～20任一项所述的眼用制剂，其特征在于，它还含有如下药学上可接受的辅料中的一种或多种：渗透压调节剂、pH调节剂、防腐剂；
    所述渗透压调节剂为葡萄糖、氯化钠、氯化钾、甘露醇、山梨醇、枸橼酸钠、枸橼酸钾和甘油中的任意一种或多种；
    所述pH调节剂为盐酸、氢氧化钠、醋酸或其盐、柠檬酸或其盐、富马酸、琥珀酸、山梨酸、磷酸、磷酸二氢钠、磷酸氢二钠、硼酸、硼砂、酒石酸或其盐中的任意一种或多种；
    所述防腐剂为山梨酸、三氯叔丁醇、亚氯酸钠、过硼酸钠、季铵盐类、羟苯酯类、硝酸苯汞中的任意一种或多种；优选地，所述季铵盐类包括苯扎氯铵、苯扎溴铵、聚季铵盐-1和/或溴化十六烷基三甲铵，所述羟苯酯类包括羟苯甲酯、羟苯乙酯和/或羟苯丙酯。
  22. 如权利要求1～21任一项所述的眼用制剂，其特征在于，所述制剂的pH值为5～8；优选为6～8；更优选为6～7。
  23. 如权利要求1～22任一项所述的眼用制剂，其特征在于，它是滴眼 剂。
  24. 权利要求1～23任一项所述的眼用制剂的制备方法，其特征在于，它是将所述活性成分和药学上可接受的辅料混合分散均匀，再进行搅拌分散和/或均质分散。
  25. 如权利要求24所述的眼用制剂的制备方法，其特征在于，包括如下步骤：
    (1)将表面活性剂分散在溶剂中得溶液A，另将乳化稳定剂和增黏剂分散在溶剂中得溶液B；
    (2)将活性成分分散在增溶剂中，再加入步骤(1)得到的溶液B中分散均匀，得溶液C；
    (3)将溶液C加入溶液A中分散均匀，然后高压均质分散；
    (4)加入或不加渗透压调节剂和/或pH调节剂调节步骤(3)得到的溶液的渗透压至等渗、pH值至5～8，再加入或不加防腐剂；即得。
  26. 如权利要求25所述的制备方法，其特征在于，步骤(2)和/或步骤(3)中所述分散选自机械搅拌分散、磁力搅拌分散、涡旋振摇分散、剪切分散、研磨分散、超声分散中的至少一种。
  27. 如权利要求25所述的制备方法，其特征在于，步骤(3)所述的高压均质分散是先在不高于800Bar的压力下均质1～5次循环，再提高压力到不高于1300Bar均质5～20次循环，再次减压至800Bar以下均质1～5次循环。
  28. 权利要求1～23任一项所述的眼用制剂在制备治疗眼部疾病的药物中的用途。
  29. 如权利要求28所述的用途，其特征在于，所述治疗眼部疾病的药物是治疗眼表疾病和/或眼底疾病的药物。
  30. 如权利要求29所述的用途，其特征在于，所述治疗眼底疾病的药物是抑制新生血管生成的药物。
  31. 如权利要求30所述的用途，其特征在于，所述治疗眼底疾病的药物是治疗年龄相关眼底黄斑病变、视网膜静脉阻塞性黄斑水肿、视网膜静脉阻塞、糖尿病性视网膜病变、糖尿病性黄斑水肿、继发于病理性近视的脉络膜新生血管引起的视力下降、新生血管性青光眼中的任意一种的药物。
  32. 如权利要求29所述的用途，其特征在于，所述治疗眼表疾病的药物是治疗眼表新生血管疾病的药物。
  33. 如权利要求32所述的用途，其特征在于，所述治疗眼表疾病的药物是治疗角膜炎、机械损伤、化学损伤和/或生物性损伤导致角膜新生血管、对翼状胬肉并发的角膜新生血管、角膜移植排斥性角膜新生血管、角膜干细胞缺乏症中的任意一种的药物。
PCT/CN2022/134961 2021-12-09 2022-11-29 一种酪氨酸激酶抑制剂眼用制剂及其制备方法和用途 WO2023103835A1 (zh)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117666A2 (en) * 2005-04-29 2006-11-09 Pfizer Inc. Dosage forms, pharmaceutical compositions and methods for sub-tenon delivery
CN102340993A (zh) * 2009-03-03 2012-02-01 爱尔康研究有限公司 向眼部递送受体酪氨酸激酶抑制性(RTKi)化合物的药物组合物
CN103110597A (zh) * 2013-02-02 2013-05-22 浙江华海药业股份有限公司 盐酸厄洛替尼片及其制备方法
US20150196649A1 (en) * 2014-01-16 2015-07-16 Retinal Therapies LLC Compositions and Methods for the Treatment of Intraocular Neovascularization and/or Leakage
CN107708664A (zh) * 2015-06-22 2018-02-16 新源生物科技股份有限公司 酪胺酸激酶抑制剂的眼用调配物、其使用方法、及其制备方法
US20190015409A1 (en) * 2016-06-02 2019-01-17 Cloudbreak Therapeutics, Llc Compositions and methods of using nintedanib for improving glaucoma surgery success
CN110664757A (zh) * 2018-11-19 2020-01-10 成都瑞沐生物医药科技有限公司 纳米晶滴眼剂、其制备方法及其应用
CN112770724A (zh) * 2018-08-28 2021-05-07 克劳德布雷克医疗有限责任公司 多激酶抑制剂的乳液制剂

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117666A2 (en) * 2005-04-29 2006-11-09 Pfizer Inc. Dosage forms, pharmaceutical compositions and methods for sub-tenon delivery
CN102340993A (zh) * 2009-03-03 2012-02-01 爱尔康研究有限公司 向眼部递送受体酪氨酸激酶抑制性(RTKi)化合物的药物组合物
CN103110597A (zh) * 2013-02-02 2013-05-22 浙江华海药业股份有限公司 盐酸厄洛替尼片及其制备方法
US20150196649A1 (en) * 2014-01-16 2015-07-16 Retinal Therapies LLC Compositions and Methods for the Treatment of Intraocular Neovascularization and/or Leakage
CN107708664A (zh) * 2015-06-22 2018-02-16 新源生物科技股份有限公司 酪胺酸激酶抑制剂的眼用调配物、其使用方法、及其制备方法
US20190015409A1 (en) * 2016-06-02 2019-01-17 Cloudbreak Therapeutics, Llc Compositions and methods of using nintedanib for improving glaucoma surgery success
CN112770724A (zh) * 2018-08-28 2021-05-07 克劳德布雷克医疗有限责任公司 多激酶抑制剂的乳液制剂
CN110664757A (zh) * 2018-11-19 2020-01-10 成都瑞沐生物医药科技有限公司 纳米晶滴眼剂、其制备方法及其应用

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