WO2023051149A1 - Antibiotic ophthalmic preparation, preparation method therefor and use thereof - Google Patents
Antibiotic ophthalmic preparation, preparation method therefor and use thereof Download PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ophthalmic preparation
- parts
- active ingredient
- povidone
- polymerization
- Prior art date
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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
An antibiotic ophthalmic preparation, comprising the following raw materials in parts by weight: an active ingredient: 0.5-1.5 parts of an antibiotic; the content of the active ingredient in the ophthalmic preparation being 1-10 mg/mL; and pharmaceutically acceptable excipients: 1-10 parts of a surfactant, 0.5-5 parts of an emulsion stabilizer, 1-3 parts of a tackifier, and the balance of a solvent. The ophthalmic preparation can deliver antibiotics to the posterior segment of the eye in an eye drop administration manner, so as to solve the problem that it is difficult to treat endophthalmitis by means of eye drop administration. Moreover, a higher drug concentration can also be accumulated in the ocular surface, and an excellent inhibitory effect is also exhibited against some drug-resistant bacteria. A one-off solution and means are provided for endophthalmitis prophylactic treatment after clinical glaucoma surgery, cataract surgery or/and vitreous injection, and anterior segment infection treatment.
Description
本发明属于生物医药领域,具体涉及一种抗生素眼用制剂及其制备方法和用途。The invention belongs to the field of biomedicine, and in particular relates to an antibiotic ophthalmic preparation and its preparation method and application.
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,50岁以上人群白内障患病率约47.8%,而手术治疗是目前唯一确定有效的治疗白内障的方法(Jingjie Xu et al:Advances in pharmacotherapy of cataracts,Ann Transl Med 2020;8(22):1552)。近年来,内眼手术及创伤性玻璃体注射给药大幅度增多,致使发生眼内炎的机率增加(涂海霞、王勇,36107例不同类型内眼手术或操作后感染性眼内炎的发病率及临床特点,中国感染控制杂志,19(10):889-893,2020)。Due to the aging population, 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). In recent years, intraocular surgery and traumatic vitreous injections have increased significantly, leading to an increase in the probability of endophthalmitis (Tu Haixia, Wang Yong, 36107 cases of different types of intraocular surgery or the incidence of infectious endophthalmitis after operation and Clinical features, Chinese Journal of Infection Control, 19(10): 889-893, 2020).
内眼手术后或眼外伤发生的眼内感染以葡萄球菌(主要为金黄色菌葡萄球菌、表皮葡萄球菌)多见,其次为链球菌,和变形杆菌、肠杆菌、克雷伯菌或铜绿假单胞菌等,可采用抗生素类药物予以治疗。然而,由于眼内存在复杂的生理结构和屏障,抗生素等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后段感染导致的眼内炎等眼底疾病,长期以来都是采用玻璃体切割或玻璃体注射抗感染药物到玻璃体内的方法治疗眼内感染。然而,这些手段都是创伤性的,存在潜在危险,例如玻璃体注射可能导致晶状体浑浊,玻璃体机化,视网膜/视神经损害等。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. However, 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. Fundus diseases such as endophthalmitis have been treated with vitrectomy or vitreous injection of anti-infective drugs into the vitreous for a long time. However, these methods are invasive and have potential risks, such as vitreous injection may cause lens opacity, vitreous organization, retinal/optic nerve damage, etc.
目前眼科临床急需安全、给药方便的治疗眼内炎等眼底疾病的抗生素新剂型(Dubald et al.,Ophthalmic Drug Delivery Systems for Antibiotherapy-A Review,Pharmaceutics 2018,10,10,31pages)。抗生素类滴眼液通过眼局部给药,是治疗眼前段感染导致的结膜炎、角膜炎等疾病常用的途径。但现有的抗生素类滴眼液给药量少,在眼表的停留时间短、浓度低,即使对于眼前段感染的治疗都需要多次给药以达到较好的治疗效果,而对于眼后段感染而言,更是难以进入眼后段达到有效治疗剂量。At present, there is an urgent need for safe and convenient new antibiotic formulations for the treatment of endophthalmitis and other fundus diseases in ophthalmology (Dubald et al., Ophthalmic Drug Delivery Systems for Antibiotherapy-A Review, Pharmaceutics 2018, 10, 10, 31 pages). 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.
例如,喹诺酮类抗生素:莫西沙星(Moxifloxacin)、氧氟沙星(Ofloxacin)、左氧氟沙星(Levofloxacin)、环丙沙星(Ciprofloxacin)等全身给药对胃肠道有不良反应,特别是长期使用可以损伤肝脏,对心血管系统可以延长心脏Q-T间期,对神经系统有失眠,头痛等不良反应。临床上常以喹诺酮类抗生素为活性成分制成滴眼液(如氧氟沙星滴眼液、左氧氟沙星滴眼液、环丙沙星滴眼液等),用以局部治疗眼科疾病,避免口服所致全身毒副反应。然而,据报 道,环丙沙星滴眼液(0.3%)、氧氟沙星滴眼液(0.3%)滴眼后在玻璃体浓度无法达到有效浓度,所以它们只能用于治疗眼前段的感染(陈祖基主编《眼科临床药理学》(第二版)化学工业出版社,2011,p112-3)。For example, 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. Clinically, 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. However, it has been reported that ciprofloxacin eye drops (0.3%) and ofloxacin eye drops (0.3%) cannot reach effective concentrations in the vitreous after eye drops, so they can only be used to treat infections of the anterior segment (Ophthalmic Clinical Pharmacology (Second Edition) Chemical Industry Press, edited by Chen Zuji, 2011, p112-3).
莫西沙星(Moxifloxacin,CAS号:151096-09-2)是具有抗菌活性的8-甲氧基氟喹诺酮,其特点是具有浓度依赖性杀菌活性,最低杀菌浓度和最低抑菌浓度(MIC,Minimal Inhibitory Concentration)基本一致。莫西沙星的抗菌作用是左氧氟沙星滴眼液和环丙沙星滴眼液的4~64倍,但文献报道,莫西沙星溶液在通常情况下依然不能有效透过角膜进入房水和玻璃体,只有在眼屏障不完整的情况下才能大量进入房水,但在玻璃体里仍达不到有效治疗浓度(Miller D.,Review of moxifloxacin hydrochloride ophthalmic solution in the treatment of bacterial eye infections,Clinical Ophthalmology 2008:2(1)77–91)。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. The antibacterial effect of moxifloxacin is 4 to 64 times that of levofloxacin eye drops and ciprofloxacin eye drops. However, according to literature reports, moxifloxacin solution still cannot effectively penetrate the cornea into the aqueous humor and vitreous body under normal circumstances. Only when the eye barrier is incomplete can it enter the aqueous humor in large quantities, but it still cannot reach the effective therapeutic concentration in the vitreous (Miller D., Review of moxifloxacin hydrochloride ophthalmic solution in the treatment of bacterial eye infections, Clinical Ophthalmology 2008:2( 1) 77–91).
即使直接将莫西沙星溶液注射到玻璃体中,莫西沙星也难以在玻璃体内保留有效浓度,例如:Bronner1等将莫西沙星溶液注射到新西兰兔玻璃体(兔平均体重为3.8kg,药物量以5mg/kg计算,总注射量为19mg),0.5h后检测到兔玻璃体中莫西沙星的浓度为0.43±0.10μg/mL,药物在玻璃体里保留的浓度远低于注射量(Bronner1et al.,Moxifloxacin Efficacy and Vitreous Penetration in a Rabbit Model of Staphylococcus aureus Endophthalmitis and Effect on Gene Expression of Leucotoxins and Virulence Regulator Factors,Antimicrobial Agents and Chemotherapy,47(5),2003,Pages 1621-1629)。如果为了维持玻璃体里的药物浓度而持续注射给药有引发并发症风险,临床实践中难以采用。Even if the moxifloxacin solution is directly injected into the vitreous, moxifloxacin is also difficult to retain an effective concentration in the vitreous, for example: Bronner1 etc. injected the moxifloxacin solution into the vitreous of New Zealand rabbits (the average body weight of the rabbit is 3.8kg, and the drug dose is 5mg /kg calculation, the total injection amount is 19mg), after 0.5h, it is detected that the concentration of moxifloxacin in the rabbit vitreous is 0.43 ± 0.10μg/mL, and the concentration of the medicine retained in the vitreous is far lower than the injection amount (Bronner1 et al., Moxifloxacin Efficacy and Vitreous Penetration in a Rabbit Model of Staphylococcus aureus Endophthalmitis and Effect on Gene Expression of Leucotoxins and Virulence Regulator Factors, Antimicrobial Agents and Chemotherapy, 47(5), 2003, Pages 12921-1). If continuous injections are required to maintain the drug concentration in the vitreous, there is a risk of complications, which is difficult to adopt in clinical practice.
进一步地,即使将盐酸莫西沙星作为药物活性成分(Active Pharmaceutical Ingredient,API),添加药学上可接受的辅料制备成滴眼液,现有报道的莫西沙星滴眼液也难以通过滴眼给药的方式在玻璃体内达到有效抑菌浓度,因此目前这类抗生素滴眼液只能用于治疗眼前段的感染。Further, even if moxifloxacin hydrochloride is used as the active pharmaceutical ingredient (Active Pharmaceutical Ingredient, API), adding pharmaceutically acceptable excipients to prepare eye drops, the existing reported moxifloxacin eye drops are also difficult to administer through eye drops. The effective antibacterial concentration can be achieved in the vitreous by the way of medicine, so at present, this kind of antibiotic eye drops can only be used to treat the infection of the anterior segment.
例如,一项临床观察性研究有20例玻璃体切割患者,术前用0.5%莫西沙星滴眼液滴眼(分别为1次/2h或1次/6h,连续3天),术后房水药物浓度分别为2.28和0.88μg/mL,超过大多数致病菌的MIC
90;在连续滴眼3天(次/2h)后玻璃体内的药物浓度为0.11μg/mL,对部分感染菌有抑制作用;而滴眼频率为1次/6h,则玻璃体里药物浓度为0.06μg/mL,达不到抑菌所需浓度(陈祖基主编《眼科临床药理学》(第二版)化学工业出版社,2011,116-117;Hariprasad,et al.,Penetration Pharmacokinetics of Topically Administered 0.5%Moxifloxacin Ophthalmic Solution in Human Aqueous and Vitreous,Arch Ophthalmol.2005;123:39-44;Miller D.,2008)。
For example, in a clinical observational study, 20 patients with vitrectomy were treated with 0.5% moxifloxacin eye drops before operation (1 time/2h or 1 time/6h, respectively, for 3 consecutive days). The drug concentrations are 2.28 and 0.88 μg/mL respectively, exceeding the MIC90 of most pathogenic bacteria; the drug concentration in the vitreous is 0.11 μg/mL after continuous eye drops for 3 days (times/2h), which can inhibit some infectious bacteria effect; while the frequency of eye drops is 1 time/6h, the drug concentration in the vitreous is 0.06 μg/mL, which cannot reach the concentration required for antibacterial (Chen Zuji editor-in-chief "Ophthalmic Clinical Pharmacology" (Second Edition) Chemical Industry Press, 2011, 116-117; Hariprasad, et al., Penetration Pharmacokinetics of Topically Administered 0.5% Moxifloxacin Ophthalmic Solution in Human Aqueous and Vitreous, Arch Ophthalmol. 2005; 123:39-44; Miller D., 2008).
目前有二款莫西沙星滴眼液用于治疗眼前段感染(细菌性结膜炎):0.5%莫西沙星滴眼液(商品名:
2003年美国FDA批准上市,中文名:维莫思
),和0.5%莫西沙星滴眼液(商品名
2010年美国FDA批准上市)。兔眼表泪液吸收试验表明,在维莫思
滴眼液滴眼30分钟后, 泪液里药物浓度为3.6μg/mL,依照其使用说明书使用量为每天滴眼3次;在相同情况下,
滴眼滴眼后的药物浓度为14μg/mL,后者使用说明书为滴眼次数为2次/天,依从性提高。然而,上述市售莫西沙星滴眼液滴眼给药后在玻璃体内的浓度也很低,无法治疗眼后段的细菌感染,如眼术后继发的眼内炎。临床上也曾尝试将莫西沙星滴眼液(主要是
滴眼液)注射到玻璃体,结果发生了中毒性眼前节综合症(TASS,Toxic Anterior Segment Syndrome),可能是由
滴眼液中所含高分子多糖聚合物黄原胶所导致,为此美国食品药品管理局(FDA)于2020年发出了警告(FDA alerts health care professionals of risks associated with intraocular use of compounded moxifloxacin,August 12,2020)。
Currently there are two 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 μg/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 μg/mL, and the instruction manual of the latter stated that the frequency of instillation was 2 times/day, and the compliance was improved. However, 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. Clinically, it has also been tried to use moxifloxacin eye drops (mainly eye drops) into the vitreous, resulting in Toxic Anterior Segment Syndrome (TASS, Toxic Anterior Segment Syndrome), which may be caused by Xanthan gum, a high-molecular polysaccharide polymer contained in eye drops, for which the US Food and Drug Administration (FDA) issued a warning in 2020 (FDA alerts health care professionals of risks associated with intraocular use of compounded moxifloxacin, August 12, 2020).
通过安全、有效、无创地通过传统的滴眼方式,将药物递送到眼后段,不但必须克服眼球的解剖学、生理学屏障系统,而且还要确保递送有效浓度的药物到眼底,一直是眼后段药物递送系统非常重大技术难题。研发一种能够通过滴眼给药的方式,将抗生素类活性成分递送到眼后段,并且在较低的用药量下实现高的眼表、眼底有效治疗浓度,为眼前段和眼后段细菌感染提供安全有效的一次性解决方案和手段,具有非常重要的意义和价值。To deliver drugs to the posterior segment of the eye safely, effectively, and non-invasively through the traditional eye drop method, not only must overcome the anatomical and physiological barrier system of the eyeball, but also ensure the delivery of effective concentrations of drugs to the fundus, always the posterior segment of the eye. The segment drug delivery system is a very significant technical problem. Develop a method that can deliver antibiotic active ingredients to the posterior segment of the eye through eye drops, and achieve a high effective therapeutic concentration on the ocular surface and fundus at a lower dosage, and provide bacteria in the anterior segment and posterior segment of the eye. Infection provides a safe and effective one-time solution and means, which is of great significance and value.
发明内容Contents of the invention
由于眼球结构的特殊性,现有技术中的给药方式均无法兼顾安全给药和有效给药,能够有效给药的方式存在安全问题,能够安全给药的方式无法有效给药。比如,针对眼细菌感染,玻璃体注射抗生素虽然能够有效给药,但是存在并发感染、眼内出血、疼痛等严重的并发症风险,目前滴眼给药的方式虽然非常安全,但是现有的抗生素滴眼液无法透过眼球眼前段的屏障,导致抗生素难以到达眼后段,有效浓度不够,无法达到有效治疗眼内感染的目的。Due to the particularity of the eyeball structure, none of the drug delivery methods in the prior art can take into account both safe drug delivery and effective drug delivery. The effective drug delivery methods have safety problems, and the safe drug delivery methods cannot be effectively delivered. For example, for eye bacterial infection, although vitreous injection of antibiotics can be effectively administered, there are risks of serious complications such as concurrent infection, intraocular hemorrhage, and pain. Although the current eye drop administration method is very safe, the existing antibiotic eye drops The liquid cannot pass through the barrier of the anterior segment of the eyeball, making it difficult for antibiotics to reach the posterior segment of the eye, and the effective concentration is not enough to achieve the purpose of effectively treating intraocular infection.
针对上述问题,本发明的目的在于提供一种能够通过安全的滴眼给药的方式,治疗眼前段感染性炎症(结膜炎、角膜炎)的同时,还能够将抗生素活性成分有效输送到眼后段达到有效浓度,从而治疗眼后段感染性炎症(眼内炎)的抗生素眼用制剂。In view of the above problems, 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. Antibiotic ophthalmic preparations for the treatment of infectious inflammation of the posterior segment of the eye (endophthalmitis) at concentrations effective in the segment.
本发明提供了一种抗生素眼用制剂,它含有如下重量份的原辅料制成:The invention provides an antibiotic ophthalmic preparation, which contains the following raw and auxiliary materials in parts by weight:
活性成分:抗生素0.5~1.5份;所述眼用制剂中活性成分的含量为1~10mg/mL;Active ingredient: 0.5-1.5 parts of antibiotics; the content of the active ingredient in the ophthalmic preparation is 1-10 mg/mL;
药学上可接受的辅料:表面活性剂1~10份、乳化稳定剂0.5~5份、增粘剂1~3份,余量为溶剂。Pharmaceutically acceptable auxiliary materials: 1-10 parts of surfactant, 0.5-5 parts of emulsion stabilizer, 1-3 parts of thickener, and the balance is solvent.
进一步地,它含有如下重量份的原辅料制成:Further, it contains the following raw and auxiliary materials in parts by weight:
活性成分:抗生素1份;所述眼用制剂中活性成分的含量为1.2mg/mL;Active ingredient: 1 part of antibiotic; the content of active ingredient in the ophthalmic preparation is 1.2 mg/mL;
药学上可接受的辅料:表面活性剂6~8份、乳化稳定剂1~4份、增粘剂2份,余量为溶剂。Pharmaceutically acceptable auxiliary materials: 6-8 parts of surfactant, 1-4 parts of emulsion stabilizer, 2 parts of thickener, and the balance is solvent.
进一步地,上述抗生素为莫西沙星或其盐、氧氟沙星或其盐,或环丙沙 星或其盐,优选为莫西沙星或其盐。Further, above-mentioned antibiotic is moxifloxacin or its salt, ofloxacin or its salt, or ciprofloxacin or its salt, preferably moxifloxacin or its salt.
进一步地,上述表面活性剂为聚山梨酯、司盘类、烷基葡萄糖苷、维生素E聚琥珀酸乙二醇酯、蔗糖硬脂酸酯或氮酮。Further, the above-mentioned surfactant is polysorbate, spans, alkyl glucoside, vitamin E polyethylene glycol succinate, sucrose stearate or azone.
更进一步地,上述表面活性剂为聚山梨酯。Furthermore, the above-mentioned surfactant is polysorbate.
进一步地,上述乳化稳定剂为泊洛沙姆、聚乙烯醇、聚维酮或海藻酸钠。Further, the above-mentioned emulsion stabilizer is poloxamer, polyvinyl alcohol, povidone or sodium alginate.
更进一步地,上述乳化稳定剂为泊洛沙姆、聚乙烯醇或聚维酮。Furthermore, the above-mentioned emulsion stabilizer is poloxamer, polyvinyl alcohol or povidone.
进一步地,上述增粘剂为羧甲基纤维素或其盐、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、聚乙二醇、卡波姆、甲基纤维素、黄原胶、聚氧乙烯脂肪醇类、透明质酸或其盐中的至少一种。Further, 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.
更进一步地,上述增粘剂为羟丙基甲基纤维素或羧甲基纤维素或其盐。Furthermore, the above-mentioned thickener is hydroxypropylmethylcellulose or carboxymethylcellulose or a salt thereof.
进一步地,上述溶剂为极性溶剂,优选为水。Further, the above-mentioned solvent is a polar solvent, preferably water.
本发明还提供另一种抗生素眼用制剂,它含有如下重量份的原辅料制成:The present invention also provides another antibiotic ophthalmic preparation, which contains the following raw and auxiliary materials in parts by weight:
活性成分:抗生素0.5~1.5份;所述眼用制剂中活性成分的含量为1~10mg/mL;Active ingredient: 0.5-1.5 parts of antibiotics; the content of the active ingredient in the ophthalmic preparation is 1-10 mg/mL;
药学上可接受的辅料:中聚合度聚维酮1~10份、低聚合度聚维酮0~5份、高聚合度聚维酮0~5份、增粘剂0.5~3份,余量为溶剂。Pharmaceutically acceptable excipients: 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.
进一步地,它含有如下重量份的原辅料制成:Further, it contains the following raw and auxiliary materials in parts by weight:
活性成分:抗生素1份;所述眼用制剂中活性成分的含量为1~6mg/mL,优选为1.2~5.45mg/mL;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;
药学上可接受的辅料:中聚合度聚维酮3~8.3份、低聚合度聚维酮0~2份、高聚合度聚维酮0~2份、增粘剂1~2份,余量为溶剂。Pharmaceutically acceptable excipients: 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.
进一步地,它含有如下重量份的原辅料制成:Further, it contains the following raw and auxiliary materials in parts by weight:
活性成分:抗生素1份;所述眼用制剂中活性成分的含量为1~6mg/mL,优选为1.2~5.45mg/mL;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;
药学上可接受的辅料:中聚合度聚维酮3~8.3份、低聚合度聚维酮1~2份、增粘剂1~2份,余量为溶剂。Pharmaceutically acceptable 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.
进一步地,它含有如下重量份的原辅料制成:Further, it contains the following raw and auxiliary materials in parts by weight:
活性成分:抗生素1份;所述眼用制剂中活性成分的含量为1~6mg/mL,优选为1.2~5.45mg/mL,更优选为5.45mg/mL;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;
药学上可接受的辅料:中聚合度聚维酮3~8.3份、增粘剂1.5~2份,余量为溶剂。Pharmaceutically acceptable excipients: 3-8.3 parts of povidone with medium degree of polymerization, 1.5-2 parts of tackifier, and the balance is solvent.
进一步地,它含有如下重量份的原辅料制成:Further, it contains the following raw and auxiliary materials in parts by weight:
活性成分:抗生素1份;所述眼用制剂中活性成分的含量为1~6mg/mL,优选为1.2~5.45mg/mL,更优选为5.45mg/mL;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;
药学上可接受的辅料:中聚合度聚维酮3份、高聚合度聚维酮2份、增粘剂1份,余量为溶剂。Pharmaceutically acceptable excipients: 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.
进一步地,上述抗生素为莫西沙星或其盐、氧氟沙星或其盐,或环丙沙星或其盐,优选为莫西沙星或其盐。Further, 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.
进一步地,上述高聚合度聚维酮为重均分子量大于100000Dalton的聚维 酮,优选为PVP K60或PVP K90;Further, the above-mentioned high degree of polymerization povidone is a weight-average molecular weight greater than 100000Dalton Povidone, preferably PVP K60 or PVP K90;
上述中聚合度聚维酮为重均分子量为35000~50000Dalton的聚维酮,优选为PVP K30;The polyvidone of above-mentioned degree of polymerization is the polyvidone of weight-average molecular weight 35000~50000Dalton, is preferably PVP K30;
上述低聚合度聚维酮为重均分子量为3500~15000Dalton的聚维酮,优选为PVP K12、PVP K15或PVP K17。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.
进一步地,上述增粘剂为羧甲基纤维素或其盐、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、聚乙二醇、卡波姆、甲基纤维素、黄原胶、聚氧乙烯脂肪醇类、透明质酸或其盐中的至少一种。Further, 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.
更进一步地,上述增粘剂为羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素中的至少一种。Furthermore, the above-mentioned thickener is at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose.
进一步地,上述溶剂为极性溶剂,优选为水。Further, the above-mentioned solvent is a polar solvent, preferably water.
进一步地,上述制剂中药学上可接受的辅料还包括渗透压调节剂、pH调节剂、防腐剂中的任意一种或多种;Further, the pharmaceutically acceptable excipients in the above preparation also include any one or more of osmotic pressure regulators, pH regulators, and preservatives;
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;The osmotic pressure regulator is any one or more of glucose, sodium chloride, potassium chloride, mannitol, sorbitol, sodium citrate, potassium citrate and glycerin;
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;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;
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(包括苯扎氯铵、苯扎溴铵、聚季銨盐-1、溴化十六烷基三甲铵)、羟苯酯类(包括羟苯甲酯、羟苯乙酯、羟苯丙酯)、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。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.
进一步地,上述制剂的pH值为5~8,优选为6.5~7.5。Further, the pH value of the above preparation is 5-8, preferably 6.5-7.5.
进一步地,上述制剂是滴眼剂。Further, the above-mentioned preparation is eye drops.
本发明还提供上述制剂的制备方法,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。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.
进一步地,上述制备方法包括如下步骤:Further, the above-mentioned preparation method comprises the following steps:
(1)将乳化稳定剂和/或增粘剂分散在溶剂中;(1) disperse the emulsion stabilizer and/or tackifier in the solvent;
(2)将活性成分分散在步骤(1)得到的溶液中,再加入表面活性剂或其溶于溶剂中形成的溶液,分散混合得到初悬液;(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;
(3)将步骤(2)得到的初悬液搅拌分散和/或均质分散,即得;(3) stirring and dispersing and/or homogeneously dispersing the primary suspension obtained in step (2), to obtain final product;
或包括以下步骤:or include the following steps:
(a)将中聚合度聚维酮、增粘剂加入溶剂中配制成溶液;(a) adding medium degree of polymerization povidone and tackifier into solvent to prepare solution;
(b)将治疗眼病的活性成分分散在步骤(a)得到的溶液中,或再加入低聚合度聚维酮或其溶于溶剂中形成的溶液,或再加入高聚合度聚维酮或其溶于溶剂中形成的溶液分散混合得到初悬液;(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;
(c)将步骤(b)得到的混合液研磨和/或均质分散,即得。(c) Grinding and/or homogeneously dispersing the mixed solution obtained in step (b), to obtain.
进一步地,步骤(2)或步骤(b)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、均质分散、研磨分散、超声分散中的至少一种。Further, 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 .
本发明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。The present invention provides the use of the above-mentioned ophthalmic preparation in the preparation of medicines for treating eye diseases.
进一步地,上述治疗眼部疾病的药物是治疗眼底疾病和/或治疗眼前段疾病的药物。Further, the above-mentioned medicine for treating eye diseases is a medicine for treating fundus diseases and/or treating diseases of the anterior segment.
进一步地,上述治疗眼部疾病的药物是治疗眼部感染性炎症的药物。Further, the above-mentioned medicine for treating eye diseases is a medicine for treating infectious inflammation of the eye.
更进一步地,上述治疗眼部感染性炎症的药物是治疗眼内炎、结膜炎和/或角膜炎的药物。Furthermore, the above-mentioned medicine for treating ocular infectious inflammation is a medicine for treating endophthalmitis, conjunctivitis and/or keratitis.
进一步地,上述治疗眼部感染性炎症的药物是的抗眼内细菌感染的药物。Further, the above-mentioned medicine for treating ocular infectious inflammation is a medicine against intraocular bacterial infection.
本发明的有益效果包括:The beneficial effects of the present invention include:
本发明滴眼液技术克服了眼球的解剖学、生理学屏障系统,可以将药物穿透眼前段进入玻璃体,以莫西沙星滴眼液为例,不仅能将药物递送到眼后段,在动物实验中滴眼1次,眼后段浓度达到葡萄球菌抑菌浓度MIC
90的4-4.5倍,肺炎克雷伯菌的2倍(实施例12),解决了眼内炎不能通过滴眼方式治疗的难题。特别是,给试验兔滴眼后同时意料之外地发现,本发明制备的新型莫西沙星滴眼液在相同用药情况下眼表的浓度是市售同类第二代产品的2倍之高,这对临床青光眼、白内障内眼手术后或/和玻璃体注射后的预防性治疗,以及眼前段感染治疗提供了一次性解决方案和手段。本发明滴眼液技术提高了此类抗生素滴眼剂的生物利用度,在相同的用药剂量情况下可获得更高的体内抗菌浓度,提高抗菌效果,降低了诱导耐药性产生的风险。
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. In particular, it was unexpectedly found that 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.
具体的,本发明的滴眼液还具有如下优势:Specifically, the eye drops of the present invention also has the following advantages:
1、本发明的滴眼液(实施例12)1次滴入50μL(相当于0.27mg莫西沙星),0.5h时检测到玻璃体里药物浓度为0.27μg/mL;而动物玻璃体注射19mg(相当于本制剂给药量的80倍),0.5h后的浓度为0.43μg/mL(Bronner1et al.,2003)。由此可见,本发明的滴眼剂滴眼与玻璃体注射相比,不但避免了有创性注射给药,用药量大幅度减少,而药物在眼底的生物利用率提高了44倍,可减少潜在的眼细胞毒性。1, 50 μ L (equivalent to 0.27 mg moxifloxacin) of the eye drops of the present invention (embodiment 12) was instilled once, and the drug concentration in the vitreous was detected to be 0.27 μg/mL during 0.5 h; while the animal vitreous was injected with 19 mg (equivalent to 80 times the dosage of this preparation), the concentration after 0.5h is 0.43μg/mL (Bronner1 et al., 2003). It can be seen that compared with vitreous injection, the eye drop of the present invention not only avoids invasive injection administration, but also greatly reduces the dosage, and the bioavailability of the drug in the fundus has increased by 44 times, which can reduce potential ocular cytotoxicity.
据报道,莫西沙星对敏感金葡菌和表皮葡萄球菌的MIC
90均为0.06μg/mL,对大肠埃希菌、肺炎克雷伯菌和变形杆菌的MIC
90分别为0.06μg/mL、0.12μg/mL、0.025μg/mL(陈祖基,2011,P116,P630)。本发明滴眼液滴眼后,玻璃体里莫西沙星浓度为0.27μg/mL,高于眼内感染主要致病菌MIC
90的2-4倍,可杀灭眼内感染主要致病菌,有效治疗眼深部感染。
According to reports, the MIC 90 of moxifloxacin against sensitive Staphylococcus aureus and Staphylococcus epidermidis was 0.06 μg/mL, and the MIC 90 against Escherichia coli, Klebsiella pneumoniae and Proteus were 0.06 μg/mL and 0.12 respectively. μg/mL, 0.025 μg/mL (Chen Zuji, 2011, P116, P630). After the eye drops of the present invention are instilled, the concentration of moxifloxacin in the vitreous body is 0.27 μg/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.
2、本发明的滴眼液(实施例10、12和13)给兔滴眼后30分钟时泪液里药物含量分别为:29.6、34.1和46.1μg/mL,明显高于市售莫西沙星滴眼液(维莫思
)的浓度(4.3μg/mL)。莫西沙星的抑菌/或杀菌作用是浓度依赖型,浓度越高,杀菌作用越强,治疗结膜炎、角膜炎等眼前段感染性炎症更好。药物浓度高,可减少给药频次,提高依从性和治疗效果;
2. When the eye drops of the present invention (Examples 10, 12 and 13) were given to rabbits for 30 minutes, the drug contents in the tears were respectively: 29.6, 34.1 and 46.1 μg/mL, significantly higher than the commercially available moxifloxacin drops eye drops ) concentration (4.3μg/mL). The bacteriostatic and/or bactericidal effect of moxifloxacin is concentration-dependent. The higher the concentration, the stronger the bactericidal effect, and the better the treatment of conjunctivitis, keratitis and other anterior segment infectious inflammations. High drug concentration can reduce the frequency of administration, improve compliance and treatment effect;
3、本发明的滴眼液(实施例4)的体外抑菌实验结果显示出对一些耐药 菌株(包括肺炎克雷伯菌、大肠杆菌、鲍曼不动杆菌和金黄色葡萄球菌)仍有比较对照药更好的抗菌效果(见表1)。表明本发明的眼用制剂对这些菌株有强的渗透性,使莫西沙星发挥抑菌和杀菌作用。3. The in vitro antibacterial test results of the eye drops of the present invention (Example 4) 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.
本发明所述滴眼给药是:将药液滴入眼内的一种给药方法,属于眼表给药途径。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.
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。Apparently, according to the above content of the present invention, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.
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。The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.
图1为实施例4的样品的扫描电镜图片。Fig. 1 is the scanning electron microscope picture of the sample of embodiment 4.
图2为实施例4的样品体外抑菌实验结果(图中数字编号对应的药物及药物浓度如下:0号-空白对照(生理盐水);1号-市售对照品(商品名维莫思),盐酸莫西沙星浓度5.45mg/mL;2号-实施例4受试品1.2mg/mL;3号-实施例4受试品1.25mg/mL;4号-实施例4受试品2.5mg/mL;5号-实施例4受试品5mg/mL)。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).
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。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.
部分仪器设备如下:Part of the equipment is as follows:
ES225SM-DR(E)电子分析天平,Precisa公司(瑞士);ES225SM-DR (E) electronic analytical balance, Precisa company (Switzerland);
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);DF-101S collector type constant temperature heating magnetic stirrer, Gongyi Yingyu Gaoke Instrument Factory (Henan, China);
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);WH-2 Micro Vortex Mixer, Shanghai Huxi Analytical Instrument Factory Co., Ltd. (Shanghai, China);
分散机:T25easy clean digital,IKA公司(德国);Dispersing machine: T25easy clean digital, IKA company (Germany);
KQ-500型超声清洗仪,昆山市超声波仪器有限公司(昆山,中国);KQ-500 Ultrasonic Cleaner, Kunshan Ultrasonic Instrument Co., Ltd. (Kunshan, China);
JP-010T型超声清洗仪,深圳市洁盟清洗设备有限公司;JP-010T Ultrasonic Cleaner, Shenzhen Jiemeng Cleaning Equipment Co., Ltd.;
AH-NANO Plus高压均质机,安拓思纳米技术(苏州)有限公司(中国);AH-NANO Plus High Pressure Homogenizer, Antos Nano Technology (Suzhou) Co., Ltd. (China);
Mettler Toledo FE20pH meter,梅特勒-托利多公司(瑞士);Mettler Toledo FE20pH meter, Mettler-Toledo (Switzerland);
NS-90纳米粒度分析仪,珠海欧美克仪器有限公司(珠海,中国);NS-90 nanometer particle size analyzer, Zhuhai Euro-American Instrument Co., Ltd. (Zhuhai, China);
安捷伦1100HPLC高效液相色谱仪,安捷伦科技有限公司(美国);Agilent 1100HPLC high-performance liquid chromatograph, Agilent Technologies Co., Ltd. (USA);
API4000三重四极杆质谱仪(美国Applied Biosystems公司);API4000 triple quadrupole mass spectrometer (Applied Biosystems, USA);
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)。STY-1A Osmotic Pressure Meter, Tianjin Tianda Tianfa Technology Co., Ltd. (Tianjin, China).
本发明制剂的性质检测方法如下:The property detection method of preparation of the present invention is as follows:
粒径检测方法:Particle size detection method:
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(主要粒径及占比%)和多分散指数(PdI,Polydispersity Index)表示。 Transfer 1 mL of the sample prepared in the example or comparative example to the sample cell, set the detection temperature to 40°C, put the sample cell into the NS-90 nanometer particle size analyzer, and start the detection. Each sample is repeatedly detected 3 times, and the average value of the 3 detection results is taken as the sample detection result as particle size (main particle size and proportion %) and polydispersity index (PdI, Polydispersity Index) representation.
渗透压检测方法:Osmotic pressure detection method:
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。如溶液未达到等渗,则添加适量渗透压调节剂,使其达到或接近等渗。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 μL distilled water into 3 sample tubes, and after the instrument is preheated, screw the sample tube containing 100 μL 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 μL 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.
pH值检测方法:pH detection method:
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。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.
检测得到的溶液若pH<5,或>9,则需要用酸或碱调节至pH6~8,常用的pH调节剂为NaOH和HCl,磷酸和磷酸盐(如磷酸二氢钠、磷酸氢二钠),柠檬酸和柠檬酸盐(如柠檬酸钠),硼酸和硼砂等。If the pH of the detected solution is <5, or >9, it needs to be adjusted to pH 6-8 with acid or alkali. Commonly used 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.
除另有说明外,递送药物到达眼后段的效果验证方法如下:Unless otherwise stated, the effectiveness of drug delivery to the posterior segment of the eye was verified as follows:
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)。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 5μM, 2.1X30mm (Fortis, UK).
大鼠眼部吸收实验:Rat eye absorption test:
选用健康成年Sprague Dawley(SD)大鼠,分为受试剂组和对照组,每组6只眼,受试剂组滴入本发明实施例制备的眼用制剂,对照组每只眼睛滴入供试品20μL。给药后于预定的时间点安乐死处理动物,迅速采集玻璃体,玻璃体样品匀浆处理后,于-80℃保存。取10μL玻璃体匀浆,加入90μL 95%乙醇,超声2分钟,涡旋混合1分钟,得玻璃体匀浆液;取50μL匀浆液,加入175μL甲醇,涡旋混合3min,4℃ 12000rpm离心10min,取上清液用0.45μm的针头式过滤器过滤,滤液用于LC/MS/MS(正离子模式,MRM SCAN)法检测API含量。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. Sample 20μL. After administration, the animals were euthanized at a predetermined time point, and the vitreous body was collected quickly, and the vitreous body sample was homogenized and stored at -80°C. Take 10 μL vitreous homogenate, add 90 μL 95% ethanol, sonicate for 2 minutes, and vortex mix for 1 minute to obtain vitreous homogenate; take 50 μL homogenate, add 175 μL 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 μm syringe filter, and the filtrate was used to detect the API content by LC/MS/MS (positive ion mode, MRM SCAN).
新西兰兔眼部吸收实验:New Zealand rabbit eye absorption test:
选用健康3~4月龄雄性新西兰兔,体重2.0~2.5kg,分为两组,每组4 只眼睛。抓取新西兰兔至操作台上,待动物安静后,1组动物眼(空白对照)滴生理盐水各30μL;另一组动物眼各滴受试物30μL,于设定的时间点安乐处死动物,迅速采集双眼房水及玻璃体,保存于-80℃。Healthy 3-4 month-old male New Zealand rabbits, weighing 2.0-2.5 kg, 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 μL of normal saline is instilled in the eyes of animals in one group (blank control); 30 μL 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.
取新西兰兔房水样品50μL,加入50μL 75%乙腈-水,内标(咪达唑仑20ng/ml乙腈溶液)150μL,涡旋混合10min,4℃10000rpm离心5min,取上清液用于LC-MS/MS分析。取新西兰兔玻璃体样品匀浆后,取100μl,加入100μL 75%乙腈-水,内标(咪达唑仑50ng/ml乙腈溶液)50μL,涡旋混合10min,4℃10000rpm离心5min,取上清液用于LC-MS/MS(正离子模式,MRM SCAN)法检测API的含量。Take 50 μL of New Zealand rabbit aqueous humor sample, add 50 μL of 75% acetonitrile-water, internal standard (midazolam 20ng/ml acetonitrile solution) 150 μL, vortex and mix for 10 min, centrifuge at 10000 rpm at 4°C for 5 min, and take the supernatant for LC- MS/MS analysis. After homogenizing the New Zealand rabbit vitreous body sample, take 100 μl, add 100 μL 75% acetonitrile-water, internal standard (midazolam 50ng/ml acetonitrile solution) 50 μL, vortex mix for 10 min, centrifuge at 10,000 rpm at 4°C for 5 min, and take the supernatant Used for LC-MS/MS (positive ion mode, MRM SCAN) method to detect the content of API.
新西兰兔泪液含量实验:New Zealand rabbit tear content test:
雄性新西兰兔1只,双眼滴眼给予不同受试制剂50μL,给药后0.5h用毛细管采集泪液5μL,保存于-80℃。取泪液样品2μL,加入48μL生理盐水,内标(咪达唑仑20ng/ml乙腈溶液)25μL,甲醇150μL,涡旋混合2min,4℃ 12000rpm离心10min,取上清液用上述LC-MS/MS法测定泪液中API的含量。One male New Zealand rabbit was given 50 μL of different test preparations in both eyes, and 5 μL of tear fluid was collected with a capillary tube 0.5 hours after administration, and stored at -80°C. Take 2 μL of tear fluid sample, add 48 μL of normal saline, 25 μL of internal standard (midazolam 20 ng/ml acetonitrile solution), 150 μL 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.
实施例1、本发明眼用制剂的制备 Embodiment 1, the preparation of ophthalmic preparation of the present invention
按照表1称取0.29g聚山梨酯-80(TW-80)加到含有15mL纯净水的玻璃三角瓶中,开启磁力搅拌0.5小时,得溶液1;分别称取72mg聚维酮K12(PVP K12)和72mg羧甲基纤维素钠(CMC-Na)加到含有10mL纯净水的玻璃三角瓶中,磁力搅拌60分钟,得溶液2;称取36mg莫西沙星盐酸盐投入50mL聚丙烯管中,加入溶液2,搅拌30分钟,加入溶液1,加水至30mL,搅拌30分钟,得混合液;将混合液用分散机在转速9500rpm分散3分钟,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3分钟,然后提高压力至>1300Bar均质15分钟,减压至300Bar均质2分钟后排出,得到均质液,检测pH值和滲透压,用0.1N HCl或0.1N NaOH调节至pH5.4;加氯化钠调节滲透压至:272mOsmol/kg。溶液经滤膜减压过滤,得产品为淡黄色澄明溶液。Take by weighing 0.29g polysorbate-80 (TW-80) according to Table 1 and add in the glass Erlenmeyer flask containing 15mL pure water, turn on magnetic stirring for 0.5 hour, obtain solution 1; Weigh 72mg povidone K12 (PVP K12 ) and 72mg of carboxymethylcellulose sodium (CMC-Na) were added to a glass Erlenmeyer flask containing 10mL of purified water, and magnetically stirred for 60 minutes to obtain solution 2; weigh 36mg of moxifloxacin hydrochloride and put it into a 50mL polypropylene tube , add solution 2, stir for 30 minutes, add solution 1, add water to 30mL, stir for 30 minutes to obtain a mixed solution; disperse the mixed solution with a disperser at a speed of 9500rpm for 3 minutes, stop the machine until the foam disappears, and transfer the dispersion to high pressure Homogenizer, control the temperature at 15±5°C, homogenize at a pressure of about 400Bar for 3 minutes, then increase the pressure to >1300Bar and homogenize for 15 minutes, depressurize to 300Bar and homogenize for 2 minutes, and then discharge to obtain a homogeneous liquid, test the pH value And osmotic pressure, adjust to pH5.4 with 0.1N HCl or 0.1N NaOH; add sodium chloride to adjust osmotic pressure to: 272mOsmol/kg. The solution was filtered through a filter membrane under reduced pressure to obtain a light yellow clear solution.
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;HPLC detection: Agilent HPLC1100 system is equipped with DAD detection unit, chromatographic conditions: chromatographic column is Waters XBridge C18, 5μm, 4.6x250mm;
流动相A:0.1%甲酸水溶液,流动相B:ACN。Temp.:35℃,检测波长:296nm,Flowrate:0.8mL/min;梯度洗脱程序:0-2’:95%A-5%B,15’:55%A-45%B,18-21’:35%A-65%B,23’:95%A-5%B。HPLC含量检测结果:1.18mg/mL。Mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: ACN. Temp.: 35℃, 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.
粒径检测结果:粒径11.9nm(100.0%),PdI:0.150;Particle size test results: particle size 11.9nm (100.0%), PdI: 0.150;
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:12.7nm(98.2%),PdI:0.190,HPLC含量检测结果:1.16mg/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: 12.7nm (98.2%), PdI: 0.190, and the HPLC content test result: 1.16mg/mL.
大鼠眼部吸收实验结果:给大鼠滴眼20μL,0.5hAPI在动物玻璃体的浓度=315±93ng/mL。Rat eye absorption test results: 20 μL of eye drop was given to rats, and the concentration of 0.5hAPI in the animal vitreous was 315±93ng/mL.
实施例2、本发明眼用制剂的制备 Embodiment 2, the preparation of ophthalmic preparation of the present invention
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,得到淡黄色澄清溶液;pH检测结果:6.8;滲透压:279mOsmol/kg;The materials and ratios used are shown in Table 1. The preparation process and content detection are the same as in Example 1 to obtain a light yellow clear solution; pH test result: 6.8; osmotic pressure: 279mOsmol/kg;
粒径检测结果:粒径13.4nm(89.4%),PdI:0.210;HPLC含量检测结果:1.22mg/mL。Particle size test result: particle size 13.4nm (89.4%), PdI: 0.210; HPLC content test result: 1.22mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:12.9nm(98.5%),PdI:0.159,HPLC含量检测结果:1.21mg/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.
大鼠眼部吸收实验结果:给大鼠滴眼20μL,0.5hAPI在大鼠玻璃体的浓度=538±175ng/mL。Rat eye absorption test results: 20 μL of eye drop was given to rats, and the concentration of 0.5hAPI in rat vitreous was 538±175ng/mL.
实施例3、本发明眼用制剂的制备 Embodiment 3, the preparation of ophthalmic preparation of the present invention
所用物料及比例如表1所示,制备过程(pH调节至6.8)与含量检测同实施例1,得到淡黄色澄清溶液;The materials and ratios used are shown in Table 1, the preparation process (pH adjusted to 6.8) and content detection are the same as in Example 1, and a light yellow clear solution is obtained;
粒径检测结果:粒径14.4nm(96.6%),PdI:0.199;HPLC检测结果含量:1.19mg/mL。Particle size test result: particle size 14.4nm (96.6%), PdI: 0.199; HPLC test result content: 1.19 mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:14.2nm(99.1%),PdI:0.156,HPLC含量检测结果:1.14mg/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;
大鼠玻璃体吸收实验结果:给大鼠滴眼20μL,0.5hAPI在大鼠玻璃体的浓度=401±167ng/mL。Rat vitreous body absorption test results: 20 μL of eyedrops were given to rats, and the concentration of 0.5hAPI in the rat vitreous body was 401±167 ng/mL.
实施例4、本发明眼用制剂的制备 Embodiment 4, the preparation of ophthalmic preparation of the present invention
按照表1称取2.00g聚维酮K30(PVP K30)加到含有20mL纯净水的玻璃三角瓶中,开启磁力搅拌0.5小时,得溶液1;分别称取500mg PVP K12和500mg羟丙甲纤维素(HPMC)加到含有20mL纯净水的玻璃三角瓶中,磁力搅拌60分钟,得溶液2;称取250mg莫西沙星盐酸盐投入100mL聚丙烯管中,加入溶液2,搅拌30分钟,加入溶液1,加水至50mL,搅拌30分钟,得混合液;将混合液用分散机在转速9500rpm分散3分钟,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3分钟,然后提高压力至>1300Bar均质15分钟,减压至300Bar均质2分钟后排出,得到均质液,加入防腐剂,搅拌10min后,检测pH值和滲透压,用0.1N HCl或0.1N NaOH调节至pH6.8;加氯化钠调节滲透压至:283mOsmol/kg。溶液经滤膜减压过滤,得产品为黄色澄明溶液。Weigh 2.00g of povidone K30 (PVP K30) according to Table 1 and add it to a glass Erlenmeyer flask containing 20mL of pure water, turn on magnetic stirring for 0.5 hours to obtain solution 1; weigh 500mg of PVP K12 and 500mg of hypromellose respectively (HPMC) was added to a glass Erlenmeyer flask containing 20mL of purified water, and magnetically stirred for 60 minutes to obtain solution 2; weighed 250mg of moxifloxacin hydrochloride and put it into a 100mL polypropylene tube, added solution 2, stirred for 30 minutes, and added solution 1. Add water to 50mL, stir for 30 minutes to obtain a mixed solution; use a disperser to disperse the mixed solution at a speed of 9500rpm for 3 minutes, stop the machine until the foam disappears, transfer the dispersion to a high-pressure homogenizer, control the temperature at 15±5°C, Homogenize at a pressure of about 400Bar for 3 minutes, then increase the pressure to >1300Bar and homogenize for 15 minutes, depressurize to 300Bar and homogenize for 2 minutes, then discharge to obtain a homogeneous solution, add preservatives, stir for 10 minutes, and test the pH value and osmotic pressure , adjust to pH 6.8 with 0.1N HCl or 0.1N NaOH; add sodium chloride to adjust osmotic pressure to: 283mOsmol/kg. The solution was filtered through a filter membrane under reduced pressure, and the product was obtained as a yellow clear solution.
粒径检测结果:粒径16.3nm(86.5%),PdI:0.475;HPLC含量检测结果:5.09mg/mL。Particle size test result: particle size 16.3nm (86.5%), PdI: 0.475; HPLC content test result: 5.09mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:12.6nm(77.3%),PdI:0.266,HPLC含量检测结果:5.05mg/mL;其扫描电镜图片如图1所示。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: 12.6nm (77.3%), PdI: 0.266, HPLC content test result: 5.05mg/mL; the scanning electron microscope picture is shown in Figure 1 shown.
新西兰兔眼部吸收实验结果:给试验动物滴眼50μL/次,0.5hAPI在动物房水里的浓度=1798±896ng/mL,玻璃体的浓度=141±56ng/mL;New Zealand rabbit eye absorption test results: 50μL/time was given to the test animals, the concentration of 0.5hAPI in the animal's aqueous humor = 1798±896ng/mL, and the concentration in the vitreous = 141±56ng/mL;
在相同条件下,盐酸莫西沙星滴眼液(维莫思
,按莫西沙星游离碱计,规格为0.5%w/v,NOVARTIS,其中含盐酸莫西沙星5.45mg/mL)给动物滴眼50μL/次,0.5hAPI在兔房水里的浓度=1127±346ng/mL,玻璃体的浓度=142±49ng/mL。
Under the same conditions, moxifloxacin hydrochloride eye drops (Vamox , in terms of moxifloxacin free base, the specification is 0.5% w/v, NOVARTIS, which contains moxifloxacin hydrochloride 5.45mg/mL) eye drops 50μL/time for animals, the concentration of 0.5hAPI in rabbit aqueous humor=1127± 346 ng/mL, concentration in vitreous = 142±49 ng/mL.
实施例5、本发明眼用制剂的制备 Embodiment 5, the preparation of ophthalmic preparation of the present invention
所用物料及比例如表1所示,制备过程(pH调节至6.8)及检测同实施例4,得到淡黄色澄清溶液;The materials and ratios used are shown in Table 1, the preparation process (pH adjusted to 6.8) and detection are the same as in Example 4 to obtain a light yellow clear solution;
粒径检测结果:粒径16.05nm(79.5%),PdI:0.237;HPLC含量检测结果:1.18mg/mL。Particle size test result: particle size 16.05nm (79.5%), PdI: 0.237; HPLC content test result: 1.18mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:14.35nm(84.2%),PdI:0.274,HPLC含量检测结果:1.13mg/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: 14.35nm (84.2%), PdI: 0.274, and the HPLC content test result: 1.13mg/mL;
大鼠玻璃体吸收实验结果:给大鼠滴眼20μL,0.5hAPI在大鼠玻璃体的浓度=379±228ng/mL。Rat vitreous absorption test results: 20 μL of eyedrops was given to rats, and the concentration of 0.5hAPI in rat vitreous was 379±228ng/mL.
实施例6、本发明眼用制剂的制备Embodiment 6, the preparation of ophthalmic preparation of the present invention
所用物料及比例如表1所示,制备过程(pH调节至7.2)及检测同实施例4,得到淡黄色澄清溶液;The materials and ratios used are shown in Table 1, the preparation process (pH adjusted to 7.2) and detection are the same as in Example 4, and a light yellow clear solution is obtained;
粒径检测结果:粒径16.0nm(64.8%),PdI:0.378;HPLC含量检测结果:1.19mg/mL。Particle size test result: particle size 16.0nm (64.8%), PdI: 0.378; HPLC content test result: 1.19 mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:15.2nm(83.4%),PdI:0.327,HPLC含量检测结果:1.16mg/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: 15.2nm (83.4%), PdI: 0.327, and the HPLC content test result: 1.16mg/mL;
大鼠眼部吸收实验结果:给大鼠滴眼20μL,0.5hAPI在大鼠玻璃体的浓度=470±259ng/mL。Rat eye absorption test results: 20 μL of eye drop was given to rats, and the concentration of 0.5hAPI in rat vitreous was 470±259ng/mL.
实施例7、本发明眼用制剂的制备Embodiment 7, the preparation of ophthalmic preparation of the present invention
所用物料及比例如表1所示,制备过程(pH调节至6.9)及检测同实施例4,得到淡黄色澄清溶液,含量检测同实施例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;
粒径检测结果:粒径16.1nm(79.5%),PdI:0.237;HPLC含量:1.17mg/mL。Particle size test results: particle size 16.1nm (79.5%), PdI: 0.237; HPLC content: 1.17mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:15.1nm(78.0%),PdI:0.206,HPLC含量检测结果:1.14mg/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;
大鼠眼部吸收实验结果:给大鼠滴眼20μL,0.5hAPI在大鼠玻璃体的浓度=498±142ng/mL。Rat eye absorption test results: 20 μL of eye drop was given to rats, and the concentration of 0.5hAPI in rat vitreous was 498±142ng/mL.
实施例8、本发明眼用制剂的制备Embodiment 8, the preparation of ophthalmic preparation of the present invention
所用物料及比例如表1所示,制备过程(pH调节至6.8)及检测同实施例1,得到黄色澄清溶液;The materials and ratios used are shown in Table 1, the preparation process (pH adjusted to 6.8) and detection are the same as in Example 1, and a yellow clear solution is obtained;
粒径检测结果:粒径11.1nm(83.8%),PdI:0.286;HPLC含量:5.43mg/mL。Particle size test results: particle size 11.1nm (83.8%), PdI: 0.286; HPLC content: 5.43mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:13.1nm(90.4%),PdI:0.329,HPLC含量检测结果:5.21mg/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.
新西兰兔眼部吸收实验结果,滴眼给药50μL,0.5h取泪液检查API的浓度=18.4±9.8μg/mL。New Zealand rabbit eye absorption test results, eye drop administration 50μL, 0.5h to take tears to check the concentration of API=18.4±9.8μg/mL.
实施例9、本发明眼用制剂的制备Embodiment 9, the preparation of ophthalmic preparation of the present invention
所用物料及比例如表1所示,制备过程(pH调节至6.8)及检测同实施例1,得到黄色澄清溶液;The materials and ratios used are shown in Table 1, the preparation process (pH adjusted to 6.8) and detection are the same as in Example 1, and a yellow clear solution is obtained;
粒径检测结果:粒径11.6nm(81.8%),PdI:0.359;HPLC含量:5.45mg/mL。Particle size test results: particle size 11.6nm (81.8%), PdI: 0.359; HPLC content: 5.45mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:13.5nm(77.1%),PdI:0.284,HPLC含量检测结果:5.24mg/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.
新西兰兔眼部吸收实验结果,滴眼50μL,0.5h取泪液检查API的浓度=14.0±6.3μg/mL。New Zealand rabbit eye absorption test results, instill 50 μL in eyes, take tear fluid for 0.5h to check API concentration = 14.0±6.3 μg/mL.
实施例10、本发明眼用制剂的制备Embodiment 10, the preparation of ophthalmic preparation of the present invention
所用物料及比例如表1所示,制备过程(pH调节至6.8)及检测同实施例1,得到黄色澄清溶液;The materials and ratios used are shown in Table 1, the preparation process (pH adjusted to 6.8) and detection are the same as in Example 1, and a yellow clear solution is obtained;
粒径检测结果:粒径15.0nm(75.7%),PdI:0.236;HPLC含量:4.90mg/mL。Particle size test results: particle size 15.0nm (75.7%), PdI: 0.236; HPLC content: 4.90mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:15.1nm(75.3%),PdI:0.243,HPLC含量检测结果:4.88mg/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.
新西兰兔眼部吸收实验结果,滴眼50μL,0.5h取泪液检查API的浓度=29.6±18.9μg/mL。New Zealand rabbit eye absorption test results, eye drop 50μL, 0.5h to take tears to check the concentration of API=29.6±18.9μg/mL.
新西兰兔眼部吸收实验结果,滴眼50μL,0.5hAPI在兔房水的浓度=2.28±0.63μg/mL,玻璃体的浓度=243±139ng/mL。New Zealand rabbit eye absorption test results, eye drops 50μL, the concentration of 0.5hAPI in the rabbit aqueous humor = 2.28 ± 0.63μg/mL, the concentration of the vitreous = 243 ± 139ng/mL.
实施例11、本发明眼用制剂的制备Embodiment 11, the preparation of ophthalmic preparation of the present invention
所用物料及比例如表1所示,制备过程(pH调节至6.8)及检测同实施例1,得到黄色澄清溶液;The materials and ratios used are shown in Table 1, the preparation process (pH adjusted to 6.8) and detection are the same as in Example 1, and a yellow clear solution is obtained;
粒径检测结果:粒径17.1nm(67.8%),PdI:0.295;HPLC含量:4.92mg/mL。Particle size test results: particle size 17.1nm (67.8%), PdI: 0.295; HPLC content: 4.92mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:13.8nm(80.5%),PdI:0.321,HPLC含量检测结果:4.88mg/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.
新西兰兔眼部吸收实验结果,滴眼50μL,0.5h取泪液检查API的浓度=19.4±15.5μg/mL。New Zealand rabbit eye absorption test results, instill 50 μL, 0.5h to take tears to check the concentration of API=19.4±15.5μg/mL.
新西兰兔眼部吸收实验结果,滴眼50μL,0.5hAPI在兔房水的浓度=1.69±0.22μg/mL,玻璃体的浓度=273±10.6ng/mL。New Zealand rabbit eye absorption test results, eye drop 50μL, 0.5hAPI concentration in rabbit aqueous humor = 1.69 ± 0.22μg/mL, vitreous concentration = 273 ± 10.6ng/mL.
实施例12、本发明眼用制剂的制备Embodiment 12, the preparation of ophthalmic preparation of the present invention
所用物料及比例如表1所示,制备过程(pH调节至6.8)及检测同实施例4,得到黄色澄清溶液;The materials and ratios used are shown in Table 1, the preparation process (pH adjusted to 6.8) and detection are the same as in Example 4, and a yellow clear solution is obtained;
粒径检测结果:粒径15.5nm(82.3%),PdI:0.335;HPLC含量:4.93mg/mL。Particle size test results: particle size 15.5nm (82.3%), PdI: 0.335; HPLC content: 4.93mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:14.1nm(85.3%),PdI:0.220,HPLC含量检测结果:4.89mg/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.
新西兰兔眼部吸收实验结果,滴眼50μL,取0.5h泪液检查API的浓度=34.1±21.9μg/mL。New Zealand rabbit eye absorption test results, eye drop 50μL, take 0.5h tears to check API concentration = 34.1±21.9μg/mL.
新西兰兔眼部吸收实验结果,滴眼50μL,0.5hAPI在兔房水的浓度=2.50±1.12μg/mL,玻璃体的浓度=255±73.5ng/mL。New Zealand rabbit eye absorption test results, eye drop 50μL, 0.5hAPI concentration in rabbit aqueous humor = 2.50±1.12μg/mL, vitreous concentration=255±73.5ng/mL.
实施例13、本发明眼用制剂的制备Embodiment 13, the preparation of ophthalmic preparation of the present invention
所用物料及比例如表1所示,制备过程(pH调节至6.8)及检测同实施例4,得到黄色澄清溶液;The materials and ratios used are shown in Table 1, the preparation process (pH adjusted to 6.8) and detection are the same as in Example 4, and a yellow clear solution is obtained;
粒径检测结果:粒径14.8nm(73.1%),PdI:0.221;HPLC含量:4.85mg/mL。Particle size test results: particle size 14.8nm (73.1%), PdI: 0.221; HPLC content: 4.85mg/mL.
产品在40℃避光放置30天,外观及含量无明显变化,粒径检测结果:16.9nm(83.1%),PdI:0.326,HPLC含量检测结果:4.81mg/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: 16.9nm (83.1%), PdI: 0.326, and the HPLC content test result: 4.81mg/mL.
新西兰兔眼部吸收实验结果,滴眼50μL,0.5h取泪液检查API的浓度=46.1±46.5μg/mL。New Zealand rabbit eye absorption test results, eye drop 50μL, 0.5h to take tears to check the concentration of API=46.1±46.5μg/mL.
新西兰兔眼部吸收实验结果,滴眼50μL,0.5hAPI在兔房水的浓度=1.12±0.078μg/mL,玻璃体的浓度=229±11.3ng/mL。New Zealand rabbit eye absorption test results, eye drops 50μL, the concentration of 0.5hAPI in the rabbit aqueous humor = 1.12 ± 0.078μg/mL, the concentration of the vitreous = 229 ± 11.3ng/mL.
对比例1Comparative example 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,得到淡黄色澄清溶液;The materials used and their proportions are shown in Table 1, the preparation process and content detection are the same as in Example 1, and a light yellow clear solution is obtained;
室温放置静置过夜产生沉淀,说明稳定性较差。Precipitation occurred after standing overnight at room temperature, indicating poor stability.
对比例2Comparative example 2
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4,得到淡黄色澄清溶液;The materials and ratios used are shown in Table 1, the preparation process and content detection are the same as in Example 4, and a light yellow clear solution is obtained;
粒径检测结果:粒径2424nm(77.9%);PdI:1.000,HPLC含量:0.009mg/mL。Particle size test results: particle size 2424nm (77.9%); PdI: 1.000, HPLC content: 0.009mg/mL.
产品40℃避光放置30天,外观无明显变化,粒径检测结果:903.7nm(69.3%),PdI:0.930,HPLC含量检测结果:0.004mg/mL。The product was placed in the dark at 40°C for 30 days, and the appearance did not change significantly. The particle size test result: 903.7nm (69.3%), PdI: 0.930, HPLC content test result: 0.004mg/mL.
在40℃避光放置30天,HPLC检测API含量下降高达55.5%,说明稳定性较差,且该实施例活性成分的转化率较低。Stored in the dark at 40° C. for 30 days, 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.
表1Table 1
注:PVP:聚维酮,CMC-Na:羧甲基纤维素钠,PVA:聚乙烯醇,HPMC:羟丙基甲基纤维素,HPC:羟丙基纤维素,HEC:羟乙基纤维素。Note: PVP: povidone, CMC-Na: sodium carboxymethylcellulose, PVA: polyvinyl alcohol, HPMC: hydroxypropylmethylcellulose, HPC: hydroxypropylcellulose, HEC: hydroxyethylcellulose .
以下通过实验例证明本发明的有益效果。The beneficial effects of the present invention are demonstrated through experimental examples below.
实验例1、体外抑菌试验Experimental example 1, in vitro antibacterial test
1、实验方法1. Experimental method
将实施例4制备的样品采用纸片扩散法检测本制备样品的抑菌效果。The sample prepared in Example 4 was used to detect the antibacterial effect of the prepared sample by the disc diffusion method.
常规培养各受试菌,取稀释菌液100uL于96孔板内,酶标仪测定OD600至0.120(0.10-0.13的中间值),即为麦氏0.5浓度,细菌含量达到1*10
8到2*10
8CFU/mL。将稀释的菌液吸取10uL,用涂布棒均匀涂布在板上;半小时待菌液完全被培养基吸收,在分区中放入灭菌后烘干的滤纸片;向每块滤纸上分别加入实验所需的受试样品10uL;按如下顺序加样:空白对照生理盐水,市售对照品(商品名维莫思
滴眼液)盐酸莫西沙星浓度5.45mg/mL,受试品1.2mg/mL,受试品1.25mg/mL,受试品2.5mg/mL,受试品5mg/mL,将平板放入37℃孵箱培养16-20h后取出平板,用游标卡尺从培养皿的背面测量完整抑菌圈的直径。结果见表2、图2。
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. Take 10uL of the diluted bacterial solution and spread it evenly on the plate with a coating rod; half an hour after the bacterial solution is completely absorbed by the culture medium, put the sterilized and dried filter paper in the partition; apply to each filter paper separately Add 10 uL of the test sample required for the experiment; add samples in the following order: blank control saline, commercially available reference substance (trade name Weimosi Eye drops) moxifloxacin hydrochloride concentration 5.45mg/mL, test article 1.2mg/mL, test article 1.25mg/mL, test article 2.5mg/mL, test article 5mg/mL, put the flat plate into 37 After culturing in an incubator at ℃ for 16-20 hours, take out the plate, and use a vernier caliper to measure the diameter of the complete inhibition zone from the back of the culture dish. The results are shown in Table 2 and Figure 2.
2、实验结果2. Experimental results
表2体外抑菌试验结果Table 2 In vitro antibacterial test results
*表格中的“敏”指药物敏感型肺炎克雷伯菌/大肠杆菌/铜绿假单胞菌/鲍曼不动杆菌/金黄色葡萄球菌;“耐”指部分耐药性肺炎克雷伯菌/大肠杆菌/铜绿假单胞菌/鲍曼不动杆菌/金黄色葡萄球菌。* "Sensitive" in the table refers to drug-sensitive Klebsiella pneumoniae/Escherichia coli/Pseudomonas aeruginosa/Acinetobacter baumannii/Staphylococcus aureus; "resistant" refers to partially drug-resistant Klebsiella pneumoniae / Escherichia coli / Pseudomonas aeruginosa / Acinetobacter baumannii / Staphylococcus aureus.
可见,本发明制备的滴眼液(实施例4)与市售品在相同浓度下(5mg/mL)的抑菌效果相当,而本发明制备的滴眼液对部分耐药性肺炎克雷伯菌、大肠杆菌、鲍曼不动杆菌比市售品仍有显著更明显的抑制作用。It can be seen that the eye drops prepared by the present invention (Example 4) 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.
综上,本发明提供了一种抗生素眼用制剂,克服了眼球的解剖学、生理学屏障系统,能够通过滴眼给药的方式将抗生素穿透眼前段进入玻璃体。本发明眼用制剂不仅能将抗生素递送到眼后段,在眼后段达到较高浓度,解决眼内炎难以通过滴眼给药方式治疗的难题,同时还能在眼表积累较高浓度,对部分耐药菌也表现出优异的抑制效果。本发明为临床青光眼、白内障术后或/和玻璃体注射后的眼内炎预防性治疗,以及眼前段感染治疗提供了一次性解决方案和手段。To sum up, 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.
Claims (35)
- 一种抗生素眼用制剂,其特征在于,它含有如下重量份的原辅料制成:An antibiotic ophthalmic preparation is characterized in that it contains the following raw and auxiliary materials in parts by weight:活性成分:抗生素0.5~1.5份;所述眼用制剂中活性成分的含量为1~10mg/mL;Active ingredient: 0.5-1.5 parts of antibiotics; the content of the active ingredient in the ophthalmic preparation is 1-10 mg/mL;药学上可接受的辅料:表面活性剂1~10份、乳化稳定剂0.5~5份、增粘剂1~3份,余量为溶剂。Pharmaceutically acceptable auxiliary materials: 1-10 parts of surfactant, 0.5-5 parts of emulsion stabilizer, 1-3 parts of thickener, and the balance is solvent.
- 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:The ophthalmic preparation as claimed in claim 1, is characterized in that, it contains the raw and auxiliary materials of following parts by weight to make:活性成分:抗生素1份;所述眼用制剂中活性成分的含量为1.2mg/mL;Active ingredient: 1 part of antibiotic; the content of active ingredient in the ophthalmic preparation is 1.2 mg/mL;药学上可接受的辅料:表面活性剂6~8份、乳化稳定剂1~4份、增粘剂2份,余量为溶剂。Pharmaceutically acceptable auxiliary materials: 6-8 parts of surfactant, 1-4 parts of emulsion stabilizer, 2 parts of thickener, and the balance is solvent.
- 如权利要求1或2所述的眼用制剂,其特征在于,所述抗生素为莫西沙星或其盐、氧氟沙星或其盐,或环丙沙星或其盐,优选为莫西沙星或其盐。The ophthalmic preparation according to claim 1 or 2, wherein the antibiotic is moxifloxacin or a salt thereof, ofloxacin or a salt thereof, or ciprofloxacin or a salt thereof, preferably moxifloxacin or its salt.
- 如权利要求1或2所述的眼用制剂,其特征在于,所述表面活性剂为聚山梨酯、司盘类、烷基葡萄糖苷、维生素E聚琥珀酸乙二醇酯、蔗糖硬脂酸酯或氮酮。The ophthalmic preparation according to claim 1 or 2, wherein the surfactant is polysorbate, spans, alkyl glucoside, vitamin E polyethylene glycol succinate, sucrose stearate Esters or Azone.
- 如权利要求4所述的眼用制剂,其特征在于,所述表面活性剂为聚山梨酯。The ophthalmic preparation according to claim 4, wherein the surfactant is polysorbate.
- 如权利要求1或2所述的眼用制剂,其特征在于,所述乳化稳定剂为泊洛沙姆、聚乙烯醇、聚维酮或海藻酸钠。The ophthalmic preparation according to claim 1 or 2, wherein the emulsion stabilizer is poloxamer, polyvinyl alcohol, povidone or sodium alginate.
- 如权利要求6所述的眼用制剂,其特征在于,所述乳化稳定剂为泊洛沙姆、聚乙烯醇或聚维酮。The ophthalmic preparation according to claim 6, wherein the emulsion stabilizer is poloxamer, polyvinyl alcohol or povidone.
- 如权利要求1或2所述的眼用制剂,其特征在于,所述增粘剂为羧甲基纤维素或其盐、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、聚乙二醇、卡波姆、甲基纤维素、黄原胶、聚氧乙烯脂肪醇类、透明质酸或其盐中的至少一种。The ophthalmic preparation according to claim 1 or 2, wherein the thickener is carboxymethyl cellulose or its salt, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose at least one of ketone, polyethylene glycol, carbomer, methylcellulose, xanthan gum, polyoxyethylene fatty alcohols, hyaluronic acid or a salt thereof.
- 如权利要求8所述的眼用制剂,其特征在于,所述增粘剂为羟丙基甲基纤维素或羧甲基纤维素或其盐。The ophthalmic preparation according to claim 8, wherein the thickener is hydroxypropylmethylcellulose or carboxymethylcellulose or a salt thereof.
- 如权利要求1或2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。The ophthalmic preparation according to claim 1 or 2, wherein the solvent is a polar solvent, preferably water.
- 一种抗生素眼用制剂,其特征在于,它含有如下重量份的原辅料制成:An antibiotic ophthalmic preparation is characterized in that it contains the following raw and auxiliary materials in parts by weight:活性成分:抗生素0.5~1.5份;所述眼用制剂中活性成分的含量为1~10mg/mL;Active ingredient: 0.5-1.5 parts of antibiotics; the content of the active ingredient in the ophthalmic preparation is 1-10 mg/mL;药学上可接受的辅料:中聚合度聚维酮1~10份、低聚合度聚维酮0~5份、高聚合度聚维酮0~5份、增粘剂0.5~3份,余量为溶剂。Pharmaceutically acceptable excipients: 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.
- 如权利要求11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:The ophthalmic preparation as claimed in claim 11, is characterized in that, it contains the raw and auxiliary materials of following parts by weight to make:活性成分:抗生素1份;所述眼用制剂中活性成分的含量为1~6mg/mL;Active ingredient: 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL;药学上可接受的辅料:中聚合度聚维酮3~8.3份、低聚合度聚维酮0~2份、高聚合度聚维酮0~2份、增粘剂1~2份,余量为溶剂。Pharmaceutically acceptable excipients: 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.
- 如权利要求12所述的眼用制剂,其特征在于,所述眼用制剂中活性成分的含量为1.2~5.45mg/mL。The ophthalmic preparation according to claim 12, characterized in that the content of the active ingredient in the ophthalmic preparation is 1.2-5.45 mg/mL.
- 如权利要求11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:The ophthalmic preparation as claimed in claim 11, is characterized in that, it contains the raw and auxiliary materials of following parts by weight to make:活性成分:抗生素1份;所述眼用制剂中活性成分的含量为1~6mg/mL;Active ingredient: 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL;药学上可接受的辅料:中聚合度聚维酮3~8.3份、低聚合度聚维酮1~2份、增粘剂1~2份,余量为溶剂。Pharmaceutically acceptable 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.
- 如权利要求14所述的眼用制剂,其特征在于,所述眼用制剂中活性成分的含量为1.2~5.45mg/mL。The ophthalmic preparation according to claim 14, characterized in that the content of the active ingredient in the ophthalmic preparation is 1.2-5.45 mg/mL.
- 如权利要求11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:The ophthalmic preparation as claimed in claim 11, is characterized in that, it contains the raw and auxiliary materials of following parts by weight to make:活性成分:抗生素1份;所述眼用制剂中活性成分的含量为1~6mg/mL;Active ingredient: 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL;药学上可接受的辅料:中聚合度聚维酮3~8.3份、增粘剂1.5~2份,余量为溶剂。Pharmaceutically acceptable excipients: 3-8.3 parts of povidone with medium degree of polymerization, 1.5-2 parts of tackifier, and the balance is solvent.
- 如权利要求16所述的眼用制剂,其特征在于,所述眼用制剂中活性成分的含量为1.2~5.45mg/mL,优选为5.45mg/mL。The ophthalmic preparation according to claim 16, wherein the content of the active ingredient in the ophthalmic preparation is 1.2-5.45 mg/mL, preferably 5.45 mg/mL.
- 如权利要求11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:The ophthalmic preparation as claimed in claim 11, is characterized in that, it contains the raw and auxiliary materials of following parts by weight to make:活性成分:抗生素1份;所述眼用制剂中活性成分的含量为1~6mg/mL;Active ingredient: 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL;药学上可接受的辅料:中聚合度聚维酮3份、高聚合度聚维酮2份、增粘剂1份,余量为溶剂。Pharmaceutically acceptable excipients: 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.
- 如权利要求18所述的眼用制剂,其特征在于,所述眼用制剂中活性成分的含量为1.2~5.45mg/mL,优选为5.45mg/mL。The ophthalmic preparation according to claim 18, wherein the content of the active ingredient in the ophthalmic preparation is 1.2-5.45 mg/mL, preferably 5.45 mg/mL.
- 如权利要求11~19任一项所述的眼用制剂,其特征在于,所述抗生素为莫西沙星或其盐、氧氟沙星或其盐,或环丙沙星或其盐,优选为莫西沙星或其盐。The ophthalmic preparation according to any one of claims 11 to 19, wherein the antibiotic is moxifloxacin or a salt thereof, ofloxacin or a salt thereof, or ciprofloxacin or a salt thereof, preferably Moxifloxacin or its salts.
- 如权利要求11~19任一项所述的眼用制剂,其特征在于,所述高聚合度聚维酮为重均分子量大于100000Dalton的聚维酮,优选为PVP K60或PVP K90;The ophthalmic preparation according to any one of claims 11 to 19, wherein the high degree of polymerization povidone is povidone with a weight average molecular weight greater than 100,000 Dalton, preferably PVP K60 or PVP K90;所述中聚合度聚维酮为重均分子量为35000~50000Dalton的聚维酮,优选为PVP K30;The polyvidone of described degree of polymerization is the polyvidone of weight-average molecular weight 35000~50000Dalton, is preferably PVP K30;所述低聚合度聚维酮为重均分子量为3500~15000Dalton的聚维酮,优选为PVP K12、PVP K15或PVP K17。The low degree of polymerization povidone is povidone with weight average molecular weight of 3500~15000Dalton, preferably PVP K12, PVP K15 or PVP K17.
- 如权利要求11~19任一项所述的眼用制剂,其特征在于,所述增粘剂为羧甲基纤维素或其盐、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、聚乙二醇、卡波姆、甲基纤维素、黄原胶、聚氧乙烯脂肪醇类、透明质酸或其盐中的至少一种。The ophthalmic preparation according to any one of claims 11 to 19, wherein the thickener is carboxymethyl cellulose or its salt, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl At least one of methylcellulose, polyethylene glycol, carbomer, methylcellulose, xanthan gum, polyoxyethylene fatty alcohols, hyaluronic acid or a salt thereof.
- 如权利要求22所述的眼用制剂,其特征在于,所述增粘剂为羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素中的至少一种。The ophthalmic preparation according to claim 22, wherein the thickener is at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose.
- 如权利要求11~19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。The ophthalmic preparation according to any one of claims 11-19, characterized in that the solvent is a polar solvent, preferably water.
- 如权利要求1~24任一项所述的眼用制剂,其特征在于,所述制剂中药学上可接受的辅料还包括渗透压调节剂、pH调节剂、防腐剂中的任意一种或多种;The ophthalmic preparation according to any one of claims 1 to 24, wherein the pharmaceutically acceptable adjuvant in the preparation also includes any one or more of an osmotic pressure regulator, a pH regulator, and a preservative. kind;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;The osmotic pressure regulator is any one or more of glucose, sodium chloride, potassium chloride, mannitol, sorbitol, sodium citrate, potassium citrate and glycerol;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;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;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(包括苯扎氯铵、苯扎溴铵、聚季銨盐-1、溴化十六烷基三甲铵)、羟苯酯类(包括羟苯甲酯、羟苯乙酯、羟苯丙酯)、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。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.
- 如权利要求1~25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6.5~7.5。The ophthalmic preparation according to any one of claims 1-25, characterized in that the pH value of the preparation is 5-8, preferably 6.5-7.5.
- 如权利要求1~26任一项所述的眼用制剂,其特征在于,它是滴眼剂。The ophthalmic preparation according to any one of claims 1 to 26, which is an eye drop.
- 权利要求1~27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。The preparation method of the ophthalmic preparation according to any one of claims 1 to 27, characterized in that it is to mix and disperse the active ingredient and the pharmaceutically acceptable excipients uniformly, and then carry out stirring and/or homogeneous dispersing .
- 权利要求28所述眼用制剂的制备方法,其特征在于,包括如下步骤:The preparation method of the ophthalmic preparation described in claim 28, is characterized in that, comprises the steps:(1)将乳化稳定剂和/或增粘剂分散在溶剂中;(1) disperse the emulsion stabilizer and/or tackifier in the solvent;(2)将活性成分分散在步骤(1)得到的溶液中,再加入表面活性剂或其溶于溶剂中形成的溶液,分散混合得到初悬液;(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;(3)将步骤(2)得到的初悬液搅拌分散和/或均质分散,即得;(3) stirring and dispersing and/or homogeneously dispersing the primary suspension obtained in step (2), to obtain final product;或包括以下步骤:or include the following steps:(a)将中聚合度聚维酮、增粘剂加入溶剂中配制成溶液;(a) adding medium degree of polymerization povidone and tackifier into solvent to prepare solution;(b)将治疗眼病的活性成分分散在步骤(a)得到的溶液中,或再加入低聚合度聚维酮或其溶于溶剂中形成的溶液,或再加入高聚合度聚维酮或其溶于溶剂中形成的溶液分散混合得到初悬液;(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;(c)将步骤(b)得到的混合液研磨和/或均质分散,即得。(c) Grinding and/or homogeneously dispersing the mixed solution obtained in step (b), to obtain.
- 如权利要求29所述的制备方法,其特征在于,步骤(2)或步骤(b)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、均质分散、研磨分散、超声分散中的至少一种。The preparation method according to claim 29, wherein the dispersion in step (2) or step (b) is selected from mechanical stirring dispersion, magnetic stirring dispersion, vortex shaking dispersion, shear dispersion, homogeneous dispersion , at least one of grinding dispersion and ultrasonic dispersion.
- 权利要求1~27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。Use of the ophthalmic preparation described in any one of claims 1-27 in the preparation of a medicament for treating eye diseases.
- 如权利要求31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底疾病和/或治疗眼前段疾病的药物。The use according to claim 31, characterized in that the medicament for treating eye diseases is a medicament for treating fundus diseases and/or treating anterior segment diseases.
- 如权利要求31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部感染性炎症的药物。The use according to claim 31, characterized in that the medicament for treating ocular diseases is a medicament for treating infectious inflammation of the eye.
- 如权利要求33所述的用途,其特征在于,所述治疗眼部感染性炎症的药物是治疗眼内炎、结膜炎和/或角膜炎的药物。The use according to claim 33, characterized in that the medicament for treating ocular infectious inflammation is a medicament for treating endophthalmitis, conjunctivitis and/or keratitis.
- 如权利要求33所述的用途,其特征在于,所述治疗眼部感染性炎症的药物是的抗眼内细菌感染的药物。The use according to claim 33, characterized in that the medicament for treating ocular infectious inflammation is a medicament for resisting intraocular bacterial infection.
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002015878A1 (en) * | 2000-08-25 | 2002-02-28 | Senju Pharmaceutical Co., Ltd. | Aqueous suspension preparations |
CN1846787A (en) * | 2005-04-11 | 2006-10-18 | 信谊药厂 | Eye gel and its prepn process |
US20140378401A1 (en) * | 2013-06-21 | 2014-12-25 | Gnt, Llc | Ophthalmic Lipophilic and Hydrophilic Drug Delivery Vehicle Formulations |
CN107837275A (en) * | 2016-09-19 | 2018-03-27 | 刘力 | The pharmaceutical composition being locally administered |
CN107854469A (en) * | 2016-09-21 | 2018-03-30 | 刘力 | Topical ophthalmic or the husky star medicine of ear or nose use or external preparation for skin and combinations thereof |
CN107998399A (en) * | 2017-12-22 | 2018-05-08 | 北京诺康达医药科技有限公司 | A kind of cyclosporine compound eye drops and preparation method thereof |
CN110664757A (en) * | 2018-11-19 | 2020-01-10 | 成都瑞沐生物医药科技有限公司 | Nanocrystalline eye drop, preparation method and application thereof |
CN113797162A (en) * | 2020-06-17 | 2021-12-17 | 成都瑞沐生物医药科技有限公司 | Eye preparation for treating macular edema, optic neuritis and non-infectious endophthalmitis by eye drop administration |
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Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002015878A1 (en) * | 2000-08-25 | 2002-02-28 | Senju Pharmaceutical Co., Ltd. | Aqueous suspension preparations |
CN1846787A (en) * | 2005-04-11 | 2006-10-18 | 信谊药厂 | Eye gel and its prepn process |
US20140378401A1 (en) * | 2013-06-21 | 2014-12-25 | Gnt, Llc | Ophthalmic Lipophilic and Hydrophilic Drug Delivery Vehicle Formulations |
CN107837275A (en) * | 2016-09-19 | 2018-03-27 | 刘力 | The pharmaceutical composition being locally administered |
CN107854469A (en) * | 2016-09-21 | 2018-03-30 | 刘力 | Topical ophthalmic or the husky star medicine of ear or nose use or external preparation for skin and combinations thereof |
CN107998399A (en) * | 2017-12-22 | 2018-05-08 | 北京诺康达医药科技有限公司 | A kind of cyclosporine compound eye drops and preparation method thereof |
CN110664757A (en) * | 2018-11-19 | 2020-01-10 | 成都瑞沐生物医药科技有限公司 | Nanocrystalline eye drop, preparation method and application thereof |
CN113797162A (en) * | 2020-06-17 | 2021-12-17 | 成都瑞沐生物医药科技有限公司 | Eye preparation for treating macular edema, optic neuritis and non-infectious endophthalmitis by eye drop administration |
Non-Patent Citations (2)
Title |
---|
HONG, YUPING ET AL.: "(Non-official translation: Research Progress and Clinical Application of Quinolones for Topical Application (Review))", GUANGDONG PHARMACEUTICAL JOURNAL, vol. 11, no. 2, 31 December 2001 (2001-12-31), pages 5 - 7 * |
MAO SHIRUI, YANG HONGTU; CHEN JIANMING; BI DIANZHOU: "Uses of Povidone in Pharmaceutics", JOURNAL OF SHENYANG PHARMACEUTICAL UNIVERSITY, vol. 14, no. 3, 20 July 1997 (1997-07-20), pages 224 - 230, XP055952034 * |
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