WO2023051149A1 - Antibiotic ophthalmic preparation, preparation method therefor and use thereof - Google Patents

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

A kind of antibiotic ophthalmic preparation and its preparation method and application technical field

The invention belongs to the field of biomedicine, and in particular relates to an antibiotic ophthalmic preparation and its preparation method and application.

Background technique

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).

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.

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.

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).

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).

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.

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.

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).

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).

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.

Contents of the invention

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.

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.

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;

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.

Further, it contains the following raw and auxiliary materials in parts by weight:

Active ingredient: 1 part of antibiotic; the content of active ingredient in the ophthalmic preparation is 1.2 mg/mL;

Pharmaceutically acceptable auxiliary materials: 6-8 parts of surfactant, 1-4 parts of emulsion stabilizer, 2 parts of thickener, and the balance is solvent.

Further, above-mentioned antibiotic is moxifloxacin or its salt, ofloxacin or its salt, or ciprofloxacin or its salt, preferably moxifloxacin or its salt.

Further, the above-mentioned surfactant is polysorbate, spans, alkyl glucoside, vitamin E polyethylene glycol succinate, sucrose stearate or azone.

Furthermore, the above-mentioned surfactant is polysorbate.

Further, the above-mentioned emulsion stabilizer is poloxamer, polyvinyl alcohol, povidone or sodium alginate.

Furthermore, the above-mentioned emulsion stabilizer is poloxamer, polyvinyl alcohol or povidone.

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.

Furthermore, the above-mentioned thickener is hydroxypropylmethylcellulose or carboxymethylcellulose or a salt thereof.

Further, 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;

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.

Further, it contains the following raw and auxiliary materials in parts by weight:

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;

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.

Further, it contains the following raw and auxiliary materials in parts by weight:

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;

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.

Further, it contains the following raw and auxiliary materials in parts by weight:

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;

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.

Further, it contains the following raw and auxiliary materials in parts by weight:

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;

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.

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.

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;

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.

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.

Furthermore, the above-mentioned thickener is at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose.

Further, the above-mentioned solvent is a polar solvent, preferably water.

Further, 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.

Further, the pH value of the above preparation is 5-8, preferably 6.5-7.5.

Further, 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.

Further, the above-mentioned preparation method comprises the following steps:

(1) disperse the emulsion stabilizer and/or tackifier in the solvent;

(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) stirring and dispersing and/or homogeneously dispersing the primary suspension obtained in step (2), to obtain final product;

or include the following steps:

(a) adding medium degree of polymerization povidone and tackifier into solvent to prepare solution;

(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) Grinding and/or homogeneously dispersing the mixed solution obtained in step (b), to obtain.

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 .

The present invention provides the use of the above-mentioned ophthalmic preparation in the preparation of medicines for treating eye diseases.

Further, the above-mentioned medicine for treating eye diseases is a medicine for treating fundus diseases and/or treating diseases of the anterior segment.

Further, the above-mentioned medicine for treating eye diseases is a medicine for treating infectious inflammation of the eye.

Furthermore, the above-mentioned medicine for treating ocular infectious inflammation is a medicine for treating endophthalmitis, conjunctivitis and/or keratitis.

Further, the above-mentioned medicine for treating ocular infectious inflammation is a medicine against intraocular bacterial infection.

The beneficial effects of the present invention include:

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.

Specifically, the eye drops of the present invention also has the following advantages:

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.

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. 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. 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.

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.

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.

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.

Description of drawings

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).

Detailed ways

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.

Part of the equipment is as follows:

ES225SM-DR (E) electronic analytical balance, Precisa company (Switzerland);

DF-101S collector type constant temperature heating magnetic stirrer, Gongyi Yingyu Gaoke Instrument Factory (Henan, China);

WH-2 Micro Vortex Mixer, Shanghai Huxi Analytical Instrument Factory Co., Ltd. (Shanghai, China);

Dispersing machine: T25easy clean digital, IKA company (Germany);

KQ-500 Ultrasonic Cleaner, Kunshan Ultrasonic Instrument Co., Ltd. (Kunshan, China);

JP-010T Ultrasonic Cleaner, Shenzhen Jiemeng Cleaning Equipment Co., Ltd.;

AH-NANO Plus High Pressure Homogenizer, Antos Nano Technology (Suzhou) Co., Ltd. (China);

Mettler Toledo FE20pH meter, Mettler-Toledo (Switzerland);

NS-90 nanometer particle size analyzer, Zhuhai Euro-American Instrument Co., Ltd. (Zhuhai, China);

Agilent 1100HPLC high-performance liquid chromatograph, Agilent Technologies Co., Ltd. (USA);

API4000 triple quadrupole mass spectrometer (Applied Biosystems, USA);

STY-1A Osmotic Pressure Meter, Tianjin Tianda Tianfa Technology Co., Ltd. (Tianjin, China).

The property detection method of preparation of the present invention is as follows:

Particle size detection method:

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.

Osmotic pressure detection method:

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 detection method:

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.

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.

Unless otherwise stated, the effectiveness of drug delivery to the posterior segment of the eye was verified as follows:

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).

Rat eye absorption test:

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).

New Zealand rabbit eye absorption test:

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.

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.

New Zealand rabbit tear content test:

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.

Embodiment 1, the preparation of ophthalmic preparation of the present invention

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 detection: Agilent HPLC1100 system is equipped with DAD detection unit, chromatographic conditions: chromatographic column is Waters XBridge C18, 5μm, 4.6x250mm;

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.

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 μL 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

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;

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 μL 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

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;

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 μL 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

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.

Particle size test result: particle size 16.3nm (86.5%), PdI: 0.475; HPLC content test result: 5.09mg/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: 12.6nm (77.3%), PdI: 0.266, HPLC content test result: 5.05mg/mL; the scanning electron microscope picture is shown in Figure 1 shown.

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;

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.

Embodiment 5, the preparation of ophthalmic preparation of the present invention

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;

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. The particle size test result: 14.35nm (84.2%), PdI: 0.274, and the HPLC content test result: 1.13mg/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.

Embodiment 6, the preparation of ophthalmic preparation of the present invention

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;

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. The particle size test result: 15.2nm (83.4%), PdI: 0.327, and the HPLC content test result: 1.16mg/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.

Embodiment 7, the preparation of ophthalmic preparation of the present invention

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 μL 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

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;

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.

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.

Embodiment 9, the preparation of ophthalmic preparation of the present invention

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;

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.

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.

Embodiment 10, the preparation of ophthalmic preparation of the present invention

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;

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.

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.

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.

Embodiment 11, the preparation of ophthalmic preparation of the present invention

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;

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.

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.

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.

Embodiment 12, the preparation of ophthalmic preparation of the present invention

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;

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.

New Zealand rabbit eye absorption test results, eye drop 50μL, take 0.5h tears to check API concentration = 34.1±21.9μg/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.

Embodiment 13, the preparation of ophthalmic preparation of the present invention

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;

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. The particle size test result: 16.9nm (83.1%), PdI: 0.326, and the HPLC content test result: 4.81mg/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.

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.

Comparative example 1

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;

Precipitation occurred after standing overnight at room temperature, indicating poor stability.

Comparative example 2

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;

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 particle size test result: 903.7nm (69.3%), PdI: 0.930, HPLC content test result: 0.004mg/mL.

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.

Table 1

Note: PVP: povidone, CMC-Na: sodium carboxymethylcellulose, PVA: polyvinyl alcohol, HPMC: hydroxypropylmethylcellulose, HPC: hydroxypropylcellulose, HEC: hydroxyethylcellulose .

The beneficial effects of the present invention are demonstrated through experimental examples below.

Experimental example 1, in vitro antibacterial test

1. Experimental method

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. 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. Experimental results

Table 2 In vitro antibacterial test results

* "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.

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.

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)

1. An antibiotic ophthalmic preparation is characterized in that it 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;

   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.
2. 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:

   Active ingredient: 1 part of antibiotic; the content of active ingredient in the ophthalmic preparation is 1.2 mg/mL;

   Pharmaceutically acceptable auxiliary materials: 6-8 parts of surfactant, 1-4 parts of emulsion stabilizer, 2 parts of thickener, and the balance is solvent.
3. 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.
4. 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.
5. The ophthalmic preparation according to claim 4, wherein the surfactant is polysorbate.
6. The ophthalmic preparation according to claim 1 or 2, wherein the emulsion stabilizer is poloxamer, polyvinyl alcohol, povidone or sodium alginate.
7. The ophthalmic preparation according to claim 6, wherein the emulsion stabilizer is poloxamer, polyvinyl alcohol or povidone.
8. 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.
9. The ophthalmic preparation according to claim 8, wherein the thickener is hydroxypropylmethylcellulose or carboxymethylcellulose or a salt thereof.
10. The ophthalmic preparation according to claim 1 or 2, wherein the solvent is a polar solvent, preferably water.
11. An antibiotic ophthalmic preparation is characterized in that it 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;

    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.
12. 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:

    Active ingredient: 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL;

    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.
13. 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.
14. 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:

    Active ingredient: 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL;

    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.
15. 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.
16. 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:

    Active ingredient: 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL;

    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.
17. 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.
18. 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:

    Active ingredient: 1 part of antibiotic; the content of the active ingredient in the ophthalmic preparation is 1-6 mg/mL;

    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.
19. 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.
20. 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.
21. 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;

    The polyvidone of described degree of polymerization is the polyvidone of weight-average molecular weight 35000～50000Dalton, is preferably PVP K30;

    The low degree of polymerization povidone is povidone with weight average molecular weight of 3500～15000Dalton, preferably PVP K12, PVP K15 or PVP K17.
22. 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.
23. The ophthalmic preparation according to claim 22, wherein the thickener is at least one of hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose.
24. The ophthalmic preparation according to any one of claims 11-19, characterized in that the solvent is a polar solvent, preferably water.
25. 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;

    The osmotic pressure regulator is any one or more of glucose, sodium chloride, potassium chloride, mannitol, sorbitol, sodium citrate, potassium citrate and glycerol;

    The pH regulator is hydrochloric acid, sodium hydroxide, acetic acid or its salt, citric acid or its salt, fumaric acid, succinic acid, sorbic acid, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, 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.
26. 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.
27. The ophthalmic preparation according to any one of claims 1 to 26, which is an eye drop.
28. 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 .
29. The preparation method of the ophthalmic preparation described in claim 28, is characterized in that, comprises the steps:

    (1) disperse the emulsion stabilizer and/or tackifier in the solvent;

    (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) stirring and dispersing and/or homogeneously dispersing the primary suspension obtained in step (2), to obtain final product;

    or include the following steps:

    (a) adding medium degree of polymerization povidone and tackifier into solvent to prepare solution;

    (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) Grinding and/or homogeneously dispersing the mixed solution obtained in step (b), to obtain.
30. 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.
31. Use of the ophthalmic preparation described in any one of claims 1-27 in the preparation of a medicament for treating eye diseases.
32. 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.
33. 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.
34. 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.
35. 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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