WO2023051149A1 - Préparation ophtalmique antibiotique, son procédé de préparation et son utilisation - Google Patents

Préparation ophtalmique antibiotique, son procédé de préparation et son utilisation Download PDF

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WO2023051149A1
WO2023051149A1 PCT/CN2022/116433 CN2022116433W WO2023051149A1 WO 2023051149 A1 WO2023051149 A1 WO 2023051149A1 CN 2022116433 W CN2022116433 W CN 2022116433W WO 2023051149 A1 WO2023051149 A1 WO 2023051149A1
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ophthalmic preparation
parts
active ingredient
povidone
polymerization
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PCT/CN2022/116433
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English (en)
Chinese (zh)
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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • 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
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of biomedicine, and in particular relates to an antibiotic ophthalmic preparation and its preparation method and application.
  • cataract, glaucoma, age-related macular degeneration (Age-related Macular Degeneration, AMD), diabetic macular edema (Diabetic Macular Edema, DME) and other fundus angiogenesis diseases have increased significantly.
  • the disease rate is about 47.8%, and surgical treatment is currently the only confirmed and effective method for the treatment of cataracts (Jingjie Xu et al: Advances in pharmacotherapy of cataracts, Ann Transl Med 2020; 8(22):1552).
  • Staphylococcus (mainly Staphylococcus aureus, Staphylococcus epidermidis) is more common in intraocular infections after intraocular surgery or trauma, followed by Streptococcus, and Proteus, Enterobacter, Klebsiella or Pseudomonas aeruginosa Monocellular bacteria, etc., can be treated with antibiotics.
  • antibiotics due to the complex physiological structure and barrier in the eye, it is difficult for drugs such as antibiotics to penetrate the barrier and reach the vitreous body of the posterior segment of the eye through the administration of eye drops, making it difficult to effectively treat infection of the posterior segment of the eye through ocular surface administration.
  • vitreous injection may cause lens opacity, vitreous organization, retinal/optic nerve damage, etc.
  • Antibiotic eye drops are administered locally through the eye, which is a common way to treat conjunctivitis, keratitis and other diseases caused by anterior segment infection. But the administration amount of existing antibiotic eye drops is few, and the dwelling time in ocular surface is short, and concentration is low, even all need multiple administrations to reach better therapeutic effect for the treatment of anterior segment infection, and for the back of eye For segmental infection, it is even more difficult to enter the posterior segment of the eye to achieve an effective therapeutic dose.
  • quinolone antibiotics Moxifloxacin (Moxifloxacin), Ofloxacin (Ofloxacin), Levofloxacin (Levofloxacin), Ciprofloxacin (Ciprofloxacin) and other systemic administration have adverse reactions to the gastrointestinal tract, especially long-term use can Damage the liver, prolong the Q-T interval of the heart to the cardiovascular system, and cause adverse reactions such as insomnia and headache to the nervous system.
  • quinolone antibiotics are often used as active ingredients to make eye drops (such as ofloxacin eye drops, levofloxacin eye drops, ciprofloxacin eye drops, etc.) Cause systemic toxic and side effects.
  • Moxifloxacin (Moxifloxacin, CAS No.: 151096-09-2) is an 8-methoxyfluoroquinolone with antibacterial activity, which is characterized by concentration-dependent bactericidal activity, minimum bactericidal concentration and minimum inhibitory concentration (MIC, Minimal Inhibitory Concentration) are basically the same.
  • concentration-dependent bactericidal activity minimum bactericidal concentration and minimum inhibitory concentration (MIC, Minimal Inhibitory Concentration) are basically the same.
  • the antibacterial effect of moxifloxacin is 4 to 64 times that of levofloxacin eye drops and ciprofloxacin eye drops.
  • moxifloxacin solution still cannot effectively penetrate the cornea into the aqueous humor and vitreous body under normal circumstances.
  • moxifloxacin eye drops for the treatment of anterior segment infection (bacterial conjunctivitis): 0.5% moxifloxacin eye drops (trade name: Approved by the US FDA in 2003, Chinese name: Weimosi ), and 0.5% moxifloxacin eye drops (trade name In 2010, the U.S. FDA approved the listing).
  • Rabbit ocular surface tear absorption test showed that in Vimos After 30 minutes of instillation of eye drops, the concentration of the drug in the tears is 3.6 ⁇ g/mL, and the dosage is 3 times a day according to the instruction manual; under the same conditions, The drug concentration after instillation was 14 ⁇ g/mL, and the instruction manual of the latter stated that the frequency of instillation was 2 times/day, and the compliance was improved.
  • the concentration of the above-mentioned commercially available moxifloxacin eye drops in the vitreous is also very low after administration, which cannot treat the bacterial infection of the posterior segment of the eye, such as secondary endophthalmitis after eye surgery.
  • TASS Toxic Anterior Segment Syndrome
  • FDA US Food and Drug Administration
  • the purpose of the present invention is to provide a safe way of eye drop administration, while treating infectious inflammation of the anterior segment (conjunctivitis, keratitis), it can also effectively deliver antibiotic active ingredients to the back of the eye.
  • the invention provides an antibiotic ophthalmic preparation, which contains the following raw and auxiliary materials in parts by weight:
  • Active ingredient 0.5-1.5 parts of antibiotics; the content of the active ingredient in the ophthalmic preparation is 1-10 mg/mL;
  • auxiliary materials 1-10 parts of surfactant, 0.5-5 parts of emulsion stabilizer, 1-3 parts of thickener, and the balance is solvent.
  • Active ingredient 1 part of antibiotic; the content of active ingredient in the ophthalmic preparation is 1.2 mg/mL;
  • auxiliary materials 6-8 parts of surfactant, 1-4 parts of emulsion stabilizer, 2 parts of thickener, and the balance is solvent.
  • antibiotic is moxifloxacin or its salt, ofloxacin or its salt, or ciprofloxacin or its salt, preferably moxifloxacin or its salt.
  • the above-mentioned surfactant is polysorbate, spans, alkyl glucoside, vitamin E polyethylene glycol succinate, sucrose stearate or azone.
  • the above-mentioned surfactant is polysorbate.
  • the above-mentioned emulsion stabilizer is poloxamer, polyvinyl alcohol, povidone or sodium alginate.
  • the above-mentioned emulsion stabilizer is poloxamer, polyvinyl alcohol or povidone.
  • the above-mentioned thickening agent is carboxymethyl cellulose or its salt, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, carbomer, methyl cellulose , xanthan gum, polyoxyethylene fatty alcohols, hyaluronic acid or a salt thereof.
  • the above-mentioned thickener is hydroxypropylmethylcellulose or carboxymethylcellulose or a salt thereof.
  • the above-mentioned solvent is a polar solvent, preferably water.
  • the present invention also provides another antibiotic ophthalmic preparation, which contains the following raw and auxiliary materials in parts by weight:
  • Active ingredient 0.5-1.5 parts of antibiotics; the content of the active ingredient in the ophthalmic preparation is 1-10 mg/mL;
  • compositions 1 to 10 parts of povidone with a medium degree of polymerization, 0 to 5 parts of povidone with a low degree of polymerization, 0 to 5 parts of povidone with a high degree of polymerization, 0.5 to 3 parts of a tackifier, and the balance for the solvent.
  • Active ingredient 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL, preferably 1.2-5.45 mg/mL;
  • compositions 3-8.3 parts of povidone with a medium degree of polymerization, 0-2 parts of povidone with a low degree of polymerization, 0-2 parts of povidone with a high degree of polymerization, 1-2 parts of a viscosifier, and the balance for the solvent.
  • Active ingredient 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL, preferably 1.2-5.45 mg/mL;
  • auxiliary materials 3-8.3 parts of povidone with a medium degree of polymerization, 1-2 parts of povidone with a low degree of polymerization, 1-2 parts of a tackifier, and the balance is a solvent.
  • Active ingredient 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL, preferably 1.2-5.45 mg/mL, more preferably 5.45 mg/mL;
  • compositions 3-8.3 parts of povidone with medium degree of polymerization, 1.5-2 parts of tackifier, and the balance is solvent.
  • Active ingredient 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL, preferably 1.2-5.45 mg/mL, more preferably 5.45 mg/mL;
  • compositions 3 parts of povidone with medium degree of polymerization, 2 parts of povidone with high degree of polymerization, 1 part of thickener, and the balance is solvent.
  • the above-mentioned antibiotic is moxifloxacin or a salt thereof, ofloxacin or a salt thereof, or ciprofloxacin or a salt thereof, preferably moxifloxacin or a salt thereof.
  • the above-mentioned high degree of polymerization povidone is a weight-average molecular weight greater than 100000Dalton Povidone, preferably PVP K60 or PVP K90;
  • the polyvidone of above-mentioned degree of polymerization is the polyvidone of weight-average molecular weight 35000 ⁇ 50000Dalton, is preferably PVP K30;
  • Above-mentioned low degree of polymerization povidone is the povidone of weight average molecular weight 3500 ⁇ 15000Dalton, is preferably PVP K12, PVP K15 or PVP K17.
  • the above-mentioned thickening agent is carboxymethyl cellulose or its salt, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, carbomer, methyl cellulose , xanthan gum, polyoxyethylene fatty alcohols, hyaluronic acid or a salt thereof.
  • the above-mentioned thickener is at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose.
  • the above-mentioned solvent is a polar solvent, preferably water.
  • the pharmaceutically acceptable excipients in the above preparation also include any one or more of osmotic pressure regulators, pH regulators, and preservatives;
  • the osmotic pressure regulator is any one or more of glucose, sodium chloride, potassium chloride, mannitol, sorbitol, sodium citrate, potassium citrate and glycerin;
  • 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, tartaric acid any one or more of its salts;
  • Described preservative is sorbic acid, chlorobutanol, sodium chlorite, sodium perborate, quaternary ammonium salts (comprising benzalkonium chloride, benzalkonium bromide, polyquaternium-1, cetyl bromide Alkyltrimethylammonium), paraben esters (including methylparaben, ethylparaben, propylparaben), any one or more of phenylmercuric nitrate; preferably, the quaternary ammonium salts include Benzalkonium chloride, benzalkonium bromide, polyquaternium-1 and/or cetyltrimethylammonium bromide, the paraben esters include methylparaben, ethylparaben and/or propylparaben ester.
  • quaternary ammonium salts comprising benzalkonium chloride, benzalkonium bromide, polyquaternium-1, cetyl bromide Al
  • the pH value of the above preparation is 5-8, preferably 6.5-7.5.
  • the above-mentioned preparation is eye drops.
  • the present invention also provides a preparation method of the above-mentioned 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:
  • step (2) Disperse the active ingredient in the solution obtained in step (1), then add a surfactant or a solution formed by dissolving it in a solvent, and disperse and mix to obtain an initial suspension;
  • step (3) stirring and dispersing and/or homogeneously dispersing the primary suspension obtained in step (2), to obtain final product;
  • step (b) disperse the active ingredient for treating eye diseases in the solution obtained in step (a), or add povidone with a low degree of polymerization or a solution formed by dissolving it in a solvent, or add povidone with a high degree of polymerization or its solution
  • the solution formed by dissolving in the solvent is dispersed and mixed to obtain the primary suspension;
  • step (c) Grinding and/or homogeneously dispersing the mixed solution obtained in step (b), to obtain.
  • the dispersion in step (2) or step (b) is selected from at least one of mechanical stirring dispersion, magnetic stirring dispersion, vortex shaking dispersion, shear dispersion, homogeneous dispersion, grinding dispersion, ultrasonic dispersion .
  • the present invention provides the use of the above-mentioned ophthalmic preparation in the preparation of medicines for treating eye diseases.
  • the above-mentioned medicine for treating eye diseases is a medicine for treating fundus diseases and/or treating diseases of the anterior segment.
  • the above-mentioned medicine for treating eye diseases is a medicine for treating infectious inflammation of the eye.
  • the above-mentioned medicine for treating ocular infectious inflammation is a medicine for treating endophthalmitis, conjunctivitis and/or keratitis.
  • the above-mentioned medicine for treating ocular infectious inflammation is a medicine against intraocular bacterial infection.
  • the eye drop technology of the present invention overcomes the anatomical and physiological barrier system of the eyeball, and can penetrate the anterior segment of the drug into the vitreous body. Taking moxifloxacin eye drops as an example, it can not only deliver the drug to the posterior segment of the eye, but also in animal experiments. Eye drops 1 time, the concentration of the back part of the eye reaches 4-4.5 times of the staphylococcus bacteriostatic concentration MIC 90 , 2 times of Klebsiella pneumoniae (embodiment 12), and solves the problem that endophthalmitis cannot be treated by eye drops problem.
  • the ocular surface concentration of the novel moxifloxacin eye drops prepared by the present invention was twice as high as that of the commercially available second-generation product of the same kind under the same medication conditions after giving eye drops to the test rabbits. It provides a one-time solution and means for clinical glaucoma, preventive treatment after cataract intraocular surgery or/and vitreous injection, and treatment of anterior segment infection.
  • the eye drop technology of the present invention improves the bioavailability of such antibiotic eye drops, can obtain higher antibacterial concentration in the body under the same dosage, improves the antibacterial effect, and reduces the risk of inducing drug resistance.
  • the eye drops of the present invention also has the following advantages:
  • the MIC 90 of moxifloxacin against sensitive Staphylococcus aureus and Staphylococcus epidermidis was 0.06 ⁇ g/mL
  • the MIC 90 against Escherichia coli, Klebsiella pneumoniae and Proteus were 0.06 ⁇ g/mL and 0.12 respectively.
  • the concentration of moxifloxacin in the vitreous body is 0.27 ⁇ g/mL, which is 2-4 times higher than the MIC 90 of the main pathogenic bacteria of intraocular infection, and can kill the main pathogenic bacteria of intraocular infection, effectively Treats deep eye infections.
  • the in vitro antibacterial test results of the eye drops of the present invention show that some drug-resistant strains (comprising Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus) still have Compared with the better antibacterial effect of the control drug (see Table 1). It shows that the ophthalmic preparation of the present invention has strong permeability to these bacterial strains, so that moxifloxacin can exert antibacterial and bactericidal effects.
  • the eye drop administration of the present invention is: a method of administration by dripping a medicinal solution into the eye, which belongs to the ocular surface administration route.
  • Fig. 1 is the scanning electron microscope picture of the sample of embodiment 4.
  • Fig. 2 is the in vitro bacteriostasis test result of the sample of Example 4 (the drug and drug concentration corresponding to the number number in the figure are as follows: No. 0-blank control (physiological saline); No. 1-commercially available reference substance (trade name Weimosi) , moxifloxacin hydrochloride concentration 5.45mg/mL; No. 2-Example 4 test article 1.2mg/mL; No. 3-Example 4 test article 1.25mg/mL; No. 4-Example 4 test article 2.5mg /mL; No. 5-embodiment 4 test article 5mg/mL).
  • 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.
  • API4000 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. If the solution has not reached isotonicity, add an appropriate amount of osmotic pressure regulator to make it reach or approach isotonicity.
  • 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.
  • pH of the detected solution is ⁇ 5, or >9, it needs to be adjusted to pH 6-8 with acid or alkali.
  • pH regulators are NaOH and HCl, phosphoric acid and phosphates (such as sodium dihydrogen phosphate, disodium hydrogen phosphate ), citric acid and citrates (such as sodium citrate), boric acid and borax, etc.
  • 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).
  • SD rats Select healthy adult Sprague Dawley (SD) rats and divide them into a reagent group and a control group, with 6 eyes in each group.
  • the reagent group is instilled with the ophthalmic preparation prepared by the embodiment of the present invention, and each eye of the control group is instilled with the test product.
  • vitreous homogenate Take 10 ⁇ L vitreous homogenate, add 90 ⁇ L 95% ethanol, sonicate for 2 minutes, and vortex mix for 1 minute to obtain vitreous homogenate; take 50 ⁇ L homogenate, add 175 ⁇ L methanol, vortex mix for 3 minutes, centrifuge at 12000 rpm at 4°C for 10 minutes, and take the supernatant
  • the solution was filtered with a 0.45 ⁇ m syringe filter, and the filtrate was used to detect the API content by LC/MS/MS (positive ion mode, MRM SCAN).
  • Healthy 3-4 month-old male New Zealand rabbits were selected and divided into two groups with 4 eyes in each group. Grab the New Zealand rabbits and place them on the operating table. After the animals are quiet, 30 ⁇ L of normal saline is instilled in the eyes of animals in one group (blank control); 30 ⁇ L of the test substance is instilled in the eyes of animals in the other group, and the animals are euthanized at the set time point. The aqueous humor and vitreous body of both eyes were quickly collected and stored at -80°C.
  • One male New Zealand rabbit was given 50 ⁇ L of different test preparations in both eyes, and 5 ⁇ L of tear fluid was collected with a capillary tube 0.5 hours after administration, and stored at -80°C.
  • Tear fluid sample Take 2 ⁇ L of tear fluid sample, add 48 ⁇ L of normal saline, 25 ⁇ L of internal standard (midazolam 20 ng/ml acetonitrile solution), 150 ⁇ L of methanol, vortex and mix for 2 min, centrifuge at 12000 rpm at 4 °C for 10 min, take the supernatant and use the above LC-MS/MS The method was used to determine the content of API in tear fluid.
  • Embodiment 1 the preparation of ophthalmic preparation of the present invention
  • 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% formic acid aqueous solution
  • mobile phase B ACN.
  • Temp. 35°C
  • detection wavelength 296nm
  • Flowrate 0.8mL/min
  • gradient elution program 0-2': 95%A-5%B, 15': 55%A-45%B, 18-21 ': 35%A-65%B, 23': 95%A-5%B.
  • HPLC content detection result 1.18mg/mL.
  • Particle size test results particle size 11.9nm (100.0%), PdI: 0.150;
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • the particle size test result 12.7nm (98.2%), PdI: 0.190, and the HPLC content test result: 1.16mg/mL.
  • Rat eye absorption test results 20 ⁇ L of eye drop was given to rats, and the concentration of 0.5hAPI in the animal vitreous was 315 ⁇ 93ng/mL.
  • Embodiment 2 the preparation of ophthalmic preparation of the present invention
  • Particle size test result particle size 13.4nm (89.4%), PdI: 0.210; HPLC content test result: 1.22mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • the particle size test result 12.9nm (98.5%), PdI: 0.159, and the HPLC content test result: 1.21mg/mL.
  • Rat eye absorption test results 20 ⁇ L of eye drop was given to rats, and the concentration of 0.5hAPI in rat vitreous was 538 ⁇ 175ng/mL.
  • Embodiment 3 the preparation of ophthalmic preparation of the present invention
  • Particle size test result particle size 14.4nm (96.6%), PdI: 0.199; HPLC test result content: 1.19 mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • the particle size test result 14.2nm (99.1%), PdI: 0.156, and the HPLC content test result: 1.14mg/mL;
  • Rat vitreous body absorption test results 20 ⁇ L of eyedrops were given to rats, and the concentration of 0.5hAPI in the rat vitreous body was 401 ⁇ 167 ng/mL.
  • Embodiment 4 the preparation of ophthalmic preparation of the present invention
  • Particle size test result particle size 16.3nm (86.5%), PdI: 0.475; HPLC content test result: 5.09mg/mL.
  • Embodiment 5 the preparation of ophthalmic preparation of the present invention
  • Particle size test result particle size 16.05nm (79.5%), PdI: 0.237; HPLC content test result: 1.18mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • Rat vitreous absorption test results 20 ⁇ L of eyedrops was given to rats, and the concentration of 0.5hAPI in rat vitreous was 379 ⁇ 228ng/mL.
  • Embodiment 6 the preparation of ophthalmic preparation of the present invention
  • Particle size test result particle size 16.0nm (64.8%), PdI: 0.378; HPLC content test result: 1.19 mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • Rat eye absorption test results 20 ⁇ L of eye drop was given to rats, and the concentration of 0.5hAPI in rat vitreous was 470 ⁇ 259ng/mL.
  • Embodiment 7 the preparation of ophthalmic preparation of the present invention
  • Example 1 The materials and ratios used are shown in Table 1, the preparation process (pH adjusted to 6.9) and detection are the same as in Example 4 to obtain a light yellow clear solution, and the content detection is the same as in Example 1;
  • Particle size test results particle size 16.1nm (79.5%), PdI: 0.237; HPLC content: 1.17mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • the particle size test result 15.1nm (78.0%), PdI: 0.206, and the HPLC content test result: 1.14mg/mL;
  • Rat eye absorption test results 20 ⁇ L of eye drop was given to rats, and the concentration of 0.5hAPI in rat vitreous was 498 ⁇ 142ng/mL.
  • Embodiment 8 the preparation of ophthalmic preparation of the present invention
  • Particle size test results particle size 11.1nm (83.8%), PdI: 0.286; HPLC content: 5.43mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • the particle size test result 13.1nm (90.4%), PdI: 0.329, and the HPLC content test result: 5.21mg/mL.
  • Embodiment 9 the preparation of ophthalmic preparation of the present invention
  • Particle size test results particle size 11.6nm (81.8%), PdI: 0.359; HPLC content: 5.45mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • the particle size test result 13.5nm (77.1%), PdI: 0.284, and the HPLC content test result: 5.24mg/mL.
  • Embodiment 10 the preparation of ophthalmic preparation of the present invention
  • Particle size test results particle size 15.0nm (75.7%), PdI: 0.236; HPLC content: 4.90mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • the particle size test result 15.1nm (75.3%), PdI: 0.243, and the HPLC content test result: 4.88mg/mL.
  • Embodiment 11 the preparation of ophthalmic preparation of the present invention
  • Particle size test results particle size 17.1nm (67.8%), PdI: 0.295; HPLC content: 4.92mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • the particle size test result 13.8nm (80.5%), PdI: 0.321, and the HPLC content test result: 4.88mg/mL.
  • Embodiment 12 the preparation of ophthalmic preparation of the present invention
  • Particle size test results particle size 15.5nm (82.3%), PdI: 0.335; HPLC content: 4.93mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • the particle size test result 14.1nm (85.3%), PdI: 0.220, and the HPLC content test result: 4.89mg/mL.
  • Embodiment 13 the preparation of ophthalmic preparation of the present invention
  • Particle size test results particle size 14.8nm (73.1%), PdI: 0.221; HPLC content: 4.85mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance and content did not change significantly.
  • Particle size test results particle size 2424nm (77.9%); PdI: 1.000, HPLC content: 0.009mg/mL.
  • the product was placed in the dark at 40°C for 30 days, and the appearance did not change significantly.
  • the API content decreased by up to 55.5% as detected by HPLC, indicating that the stability is poor, and the conversion rate of the active ingredient in this example is low.
  • PVP povidone
  • CMC-Na sodium carboxymethylcellulose
  • PVA polyvinyl alcohol
  • HPMC hydroxypropylmethylcellulose
  • HPC hydroxypropylcellulose
  • HEC hydroxyethylcellulose
  • the sample prepared in Example 4 was used to detect the antibacterial effect of the prepared sample by the disc diffusion method.
  • Routinely culture the tested bacteria take 100uL of the diluted bacterial solution in a 96-well plate, and measure the OD600 to 0.120 (the middle value of 0.10-0.13) with a microplate reader, which is the McFarland 0.5 concentration, and the bacterial content reaches 1*10 8 to 2 *10 8 CFU/mL.
  • the eye drops prepared by the present invention have the same antibacterial effect as the commercially available product at the same concentration (5mg/mL), and the eye drops prepared by the present invention are effective against partial drug-resistant Klebsiella pneumoniae Bacteria, Escherichia coli, and Acinetobacter baumannii still have significantly more obvious inhibitory effects than commercially available products.
  • the present invention provides an antibiotic ophthalmic preparation, which overcomes the anatomical and physiological barrier system of the eyeball, and can penetrate the anterior segment of the antibiotic into the vitreous body through eye drops.
  • the ophthalmic preparation of the present invention can not only deliver antibiotics to the posterior segment of the eye, and achieve a higher concentration in the posterior segment of the eye, which solves the problem that endophthalmitis is difficult to treat by eye drops, but also accumulates a higher concentration on the ocular surface, It also shows excellent inhibitory effect on some drug-resistant bacteria.
  • the invention provides a one-time solution and means for clinical glaucoma, preventive treatment of endophthalmitis after cataract surgery or/and vitreous injection, and treatment of anterior segment infection.

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Abstract

L'invention concerne une préparation ophtalmique antibiotique, comprenant les matières premières suivantes en parties en poids : un ingrédient actif : 0,5 à 1,5 parties d'un antibiotique ; la teneur en ingrédient actif dans la préparation ophtalmique étant de 1 à 10 mg/mL ; et des excipients pharmaceutiquement acceptables : 1 à 10 parties d'un tensioactif, 0,5 à 5 parties d'un agent de stabilisation d'émulsion, 1 à 3 parties d'un agent donnant du collant, et l'équilibre d'un solvant. La préparation ophtalmique peut administrer des antibiotiques au segment postérieur de l'œil de manière à administrer un collyre, de manière à résoudre le problème de la difficulté de traiter l'endophtalmie par l'administration d'un collyre. En outre, une concentration plus élevée de médicament peut également être accumulée dans la surface oculaire, et un excellent effet inhibiteur est également présenté contre certaines bactéries résistantes aux médicaments. Une solution unique et des moyens sont fournis pour le traitement prophylactique de l'endophtalmie après une chirurgie clinique du glaucome, une chirurgie de la cataracte ou/et une injection dans le vitré, et le traitement des infections du segment antérieur.
PCT/CN2022/116433 2021-09-29 2022-09-01 Préparation ophtalmique antibiotique, son procédé de préparation et son utilisation WO2023051149A1 (fr)

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