Sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs and their preparation method

Abstract

This invention discloses a method for preparing a sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug, comprising: (1) dispersing levofloxacin, polyglycolic acid, chitosan, and polylysine in a first solvent to form a first dispersion, dispersing fluorometholone and alginate in a second solvent to form a second dispersion, and then mixing the first and second dispersions evenly; (2) performing a crosslinking reaction at 45-55℃ for 3-10 hours, cooling, and drying to obtain a mixture; (3) subjecting the mixture obtained in step (2) to plasma treatment at less than 6 Pa for 30 seconds to 5 minutes, and then solidifying it. The lacrimal canaliculus plug of this invention can reduce the frequency of antibiotic use or eliminate the need for antibiotic use, has good patient compliance, good comfort, good biocompatibility, short-term degradation, few side effects, good water-swelling properties, and is not easy to fall off, and has a triple effect of anti-inflammatory, anti-infective, and dry eye treatment after corneal refractive surgery.

Description

Technical Field

[0001] This invention relates to the field of medical materials, specifically to a lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone, and its preparation method. Background Technology

[0002] Dry eye syndrome is a general term for a variety of diseases caused by abnormalities in the quality or quantity of tears or abnormal tear dynamics, leading to decreased tear film stability and accompanied by ocular discomfort and ocular surface lesions. Common symptoms include dry eyes, easy eye fatigue, itchy eyes, foreign body sensation, burning or stinging sensation, thick discharge, sensitivity to wind and light, and hypersensitivity to external stimuli. Currently, a significant number of patients have been found to experience dry eye symptoms, inflammation, and infection after corneal refractive surgery.

[0003] In recent years, lacrimal canaliculus plugs or lacrimal duct plugs have been increasingly used clinically to treat dry eye syndrome. By blocking the lacrimal ducts, they reduce tear drainage, re-establish the balance of tear fluid on the ocular surface, improve the ocular surface environment, and thus alleviate the symptoms and signs of dry eye. However, currently, patients who develop dry eye symptoms, inflammation, and infection after corneal refractive surgery require multiple administrations of antibiotics. Therefore, there is an urgent need to develop lacrimal canaliculus plugs that can effectively treat dry eye symptoms, inflammation, and infection after corneal refractive surgery. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention aims to provide a sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug and its preparation method. The sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug prepared by this invention can reduce the frequency of antibiotic use or eliminate the need for antibiotic use. It has good patient compliance, good comfort, good biocompatibility, short-term degradation, few side effects, good water-swelling properties, and is not easy to fall off. It has a triple effect of anti-inflammatory, anti-infective, and dry eye treatment after corneal refractive surgery.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] In a first aspect, the present invention provides a method for preparing a lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone, comprising the following steps:

[0007] (1) Levofloxacin, polyglycolic acid, chitosan, and polylysine are dispersed in a first solvent to form a first dispersion, and fluorometholone and alginate are dispersed in a second solvent to form a second dispersion. The first and second dispersions are then mixed evenly, wherein the mass ratio of levofloxacin:fluorometholone: ​​polyglycolic acid: chitosan: polylysine: alginate is 0.2-3:0.01-1:15-50:10-50:0.1-3:0.5-2.

[0008] (2) Crosslinking reaction at 45-55℃ for 3-10 h, followed by cooling and drying to obtain a mixture;

[0009] (3) The mixture obtained in step (2) is subjected to plasma treatment at less than 6 Pa for 30 s-5 min, and then solidified to obtain a lacrimal canaliculus plug containing sustained-release levofloxacin and fluocinolone.

[0010] Preferably, in step (1), the mass ratio of levofloxacin: fluorometholone: ​​polyglycolic acid: chitosan: polylysine: alginate is 0.2-1.5: 0.01-0.1: 20-50: 25-50: 0.1-1: 0.5-1.5.

[0011] Preferably, in step (1), the first solvent is acetic acid and the second solvent is an aqueous solution of ethyl acetate.

[0012] Preferably, in step (2), the crosslinking reaction is carried out at 45-50°C.

[0013] Preferably, in step (2), the crosslinking reaction is carried out for 4-8 hours.

[0014] Preferably, in step (3), the plasma treatment conditions include a treatment pressure of 3-5.5 Pa, a treatment time of 10 s-2 min, an Ar flow rate of 1-3 L / min, and a power of 70-100 W.

[0015] Preferably, in step (3), when the solidified shape is cylindrical, the diameter is 0.1-1 mm and the length is 0.5-10 mm.

[0016] Preferably, in step (3), when the solidified shape is cylindrical, the diameter is 0.1-0.5 mm and the length is 0.5-3 mm.

[0017] Preferably, in step (3), when the solidified shape is cylindrical, at least one drainage hole is made along the central axis, and the diameter of the drainage hole is 0.02mm-0.2mm.

[0018] Secondly, the present invention provides a lacrimal canaliculus plug that releases levofloxacin and fluocinolone, which is prepared according to the above-described preparation method.

[0019] The beneficial effects of this invention are as follows:

[0020] This invention utilizes levofloxacin, fluorometholone, polyglycolic acid, chitosan, polylysine, and alginate as raw materials for cross-linking reactions. The resulting sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs, prepared through plasma treatment, reduce or eliminate the need for antibiotics. They exhibit good patient compliance, comfort, and biocompatibility, exhibit short-term degradation, and have minimal side effects. They possess a triple effect of anti-inflammatory, anti-infective, and dry eye treatment after corneal refractive surgery. Furthermore, the inventors discovered that plasma treatment imparts excellent hydrophilicity and water-swellable properties to the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs. Upon contact with water, they rapidly expand within seconds of implantation, securing themselves firmly in the lacrimal canaliculus and preventing dislodgement.

[0021] The sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs prepared by this invention have significant clinical application value. It should be noted that while the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs prepared by this invention can effectively treat dry eye symptoms, reduce inflammation, and fight infection after corneal refractive surgery, the treatment of dry eye symptoms, inflammation, and infection mentioned in this invention are only for diseases commonly treated with the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs prepared by this invention. This invention is not limited to these eye diseases; the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs of this invention can be applied to any other suitable eye disease.

[0022] The features and advantages of the present invention will be described in detail in the following detailed description section. Detailed Implementation

[0023] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described in the following description are merely illustrative examples of specific implementations of this invention and are intended to explain the invention, but do not constitute a limitation thereof.

[0024] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, but should be understood to include values ​​close to these ranges or values, such as values ​​such as ±10% of a specific point value. For numerical ranges, endpoint values ​​of various ranges, endpoint values ​​of various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein. In the description of this application, unless otherwise stated, terms such as "multiple / a plurality" mean two / a kind or more. Furthermore, the terms "comprising," "including," and any variations thereof are intended to cover non-exclusive inclusion.

[0025] In a first aspect, the present invention provides a method for preparing a lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone, comprising the following steps:

[0026] (1) Levofloxacin, polyglycolic acid, chitosan, and polylysine are dispersed in a first solvent to form a first dispersion, and fluorometholone and alginate are dispersed in a second solvent to form a second dispersion. The first and second dispersions are then mixed evenly, wherein the mass ratio of levofloxacin:fluorometholone: ​​polyglycolic acid: chitosan: polylysine: alginate is 0.2-3:0.01-1:15-50:10-50:0.1-3:0.5-2.

[0027] (2) Crosslinking reaction at 45-55℃ for 3-10 h, followed by cooling and drying to obtain a mixture;

[0028] (3) The mixture obtained in step (2) is subjected to plasma treatment at less than 6 Pa for 30 s-5 min, and then solidified to obtain a lacrimal canaliculus plug containing sustained-release levofloxacin and fluocinolone.

[0029] In this invention, levofloxacin should be interpreted broadly to include salts of levofloxacin, such as levofloxacin hydrochloride; levofloxacin has anti-inflammatory and anti-infective effects. In this invention, fluorometholone should be interpreted broadly to include derivatives of fluorometholone, such as fluorometholone acetate; fluorometholone primarily exerts anti-inflammatory effects. Currently, there are no studies in the prior art on the combined use of levofloxacin and fluorometholone for the treatment of dry eye symptoms after corneal refractive surgery, or for their anti-inflammatory and anti-infective effects. Furthermore, in this invention, levofloxacin and fluorometholone are used together as the active pharmaceutical ingredients of lacrimal canaliculus plugs.

[0030] In this invention, the molecular weight of polyethylene glycol (PEG) can be selected within a wide range. Preferably, in order to further reduce or eliminate the need for antibiotic use in the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs, improve patient compliance, provide good comfort, enhance biocompatibility, minimize side effects, reduce short-term degradation, ensure good water swelling properties, and prevent easy dislodgement, the weight-average molecular weight of PEG is 10,000-50,000.

[0031] In this invention, the type of chitosan can be selected from a wide range, such as carboxymethyl chitosan. The molecular weight of the chitosan can also be selected from a wide range. Preferably, in order to further reduce or eliminate the need for antibiotics in the sustained-release levofloxacin and fluocinolone lacrimal canaliculus plugs, improve patient compliance, provide good comfort, have good biocompatibility, few side effects, short-term degradation, good water-swelling properties, and prevent easy dislodgement, the weight-average molecular weight of the chitosan is 50,000-150,000.

[0032] It should be noted that although lacrimal canaliculi are part of the lacrimal duct structure in a strict medical sense, the medical meanings of "lacrimal canaliculi" and "lacrimal duct" are not always strictly used in practice. Therefore, the term "lacrimal canaliculus plug" in this invention should be interpreted broadly, that is, "lacrimal canaliculus plug" is equivalent to "lacrimal duct". Thus, the term "lacrimal canaliculus plug" in this invention is equivalent to "lacrimal duct plug".

[0033] Lacrimal canaliculus plugs have low mechanical strength and are prone to dislodgement, while those with high mechanical strength tend to cause a foreign body sensation and are uncomfortable, which not only hinders the therapeutic effect but also easily leads to adverse reactions. In this invention, the use of polyglycolic acid and chitosan, along with other raw materials, not only gives the lacrimal canaliculus plug good mechanical strength and comfort but also good biocompatibility, water-swellable properties, and minimal side effects. Furthermore, using polyglycolic acid and chitosan as the main raw materials effectively cross-links and promotes the slow release of levofloxacin and fluorometholone, resulting in a more stable release rate, which is beneficial for the therapeutic effect, has anti-inflammatory properties, and simultaneously treats dry eye syndrome.

[0034] In this invention, the types of the first and second solvents can be selected from a wide range, as long as they can dissolve levofloxacin, polyglycolic acid, chitosan, polylysine, fluorometholone, and alginate. Preferably, to make the first solvent more easily disperse levofloxacin, polyglycolic acid, chitosan, and polylysine, the first solvent is acetic acid (this should be interpreted broadly, such as an aqueous solution of acetic acid with a molar concentration of 3%-10%), and to make the second solvent more easily disperse fluorometholone and alginate, the second solvent is an aqueous solution of ethyl acetate (such as an aqueous solution of ethyl acetate with a molar concentration of 10%-20%). In this invention, the amount of solvent used can be selected from a wide range.

[0035] In this invention, the alginate can be sodium alginate or calcium alginate, which makes the first dispersion and the second dispersion easier to mix and also allows the cross-linking reaction to occur faster.

[0036] In this invention, the dispersion and uniform mixing methods can be selected within a wide range. In some preferred embodiments, in order to improve the release of levofloxacin and fluorometholone from the prepared sustained-release lacrimal tubule plugs and to make the sustained release more stable, ultrasonic dispersion is used. The ultrasonic dispersion time is 10-20 min, and the ultrasonic power is 400-500 W.

[0037] In this invention, the cross-linking reaction can be carried out at 45-55°C for 3-10 hours to obtain a sustained-release levofloxacin and fluorometholone lacrimal tubule plug with good patient compliance, comfort, biocompatibility, few side effects, and short-term degradation. In this invention, polylysine and alginate play a good cross-linking role. In some embodiments, the weight-average molecular weight of polylysine is 3000-5000. In some preferred embodiments, the cross-linking reaction in step (2) is carried out at 45-50°C. In some preferred embodiments, the cross-linking reaction in step (2) is carried out for 4-8 hours.

[0038] In this invention, the cooling conditions can be selected within a wide range, such as natural cooling to room temperature.

[0039] In this invention, the drying conditions can be selected within a wide range, such as drying at room temperature and normal pressure for 0.5-3 hours.

[0040] In this invention, the plasma treatment conditions are plasma treatment at less than 6 Pa for 30 s to 5 min. In some preferred embodiments, in order to further reduce the number of times antibiotics are used or eliminate the need for antibiotics, improve patient compliance, expand upon contact with water, provide good comfort, have good biocompatibility, few side effects, and short-term degradation, in step (3), the plasma treatment conditions include a treatment pressure of 3-5.5 Pa, a treatment time of 10 s to 2 min, an Ar flow rate of 1-3 L / min, and a power of 70-100 W.

[0041] In this invention, the inventors unexpectedly discovered that a mixture obtained by crosslinking levofloxacin, fluorometholone, polyglycolic acid, chitosan, polylysine, and alginate, followed by plasma treatment, can impart excellent hydrophilicity and water-swellable properties to the lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone. It expands rapidly upon contact with water, and after implantation, it can rapidly expand within the lacrimal canaliculus within seconds, thus securing itself firmly and preventing dislodgement. The lacrimal canaliculus plug can expand rapidly within the lacrimal canaliculus within, for example, within 6 seconds, 5 seconds, or 4 seconds. When the lacrimal canaliculus plug is cylindrical, its length or diameter expands rapidly by at least 3, 4, or 5 times upon contact with water after implantation.

[0042] In some preferred embodiments, in step (1), the mass ratio of levofloxacin:flumethoxylon:polyglycolic acid:chitosan:polylysine:alginate is 0.2-1.5:0.01-0.1:20-50:25-50:0.1-1:0.5-1.5.

[0043] In this invention, preferably, to further improve the comfort and reduce the likelihood of dislodgement when the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug is implanted into the lacrimal duct, in step (3), when it is solidified into a cylindrical shape, the diameter is 0.1-1 mm and the length is 0.5-10 mm. More preferably, in step (3), when it is solidified into a cylindrical shape, the diameter is 0.1-0.5 mm and the length is 0.5-3 mm.

[0044] In this invention, preferably, in step (3), when the solidified shape is cylindrical, at least one tear drainage hole is made along the central axis. The position of the tear drainage hole can be centered on or around the central axis, and the diameter of the tear drainage hole is 0.02mm-0.2mm. This not only helps to reduce tear loss and keep the eyeball moist, but also allows the tears to flow out through the hole, reducing tear accumulation and retention. This allows the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug to drain excess tears in time, thereby reducing related inflammation caused by tear accumulation and retention. Combined with the fact that polyglycolic acid and chitosan are the main raw materials and are not prone to causing inflammation, the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug of this invention has a good anti-inflammatory effect. In this invention, the tear drainage hole can be made after molding, or it can be obtained during preparation by mold or 3D printing.

[0045] In this invention, "short-term degradation" usually refers to degradation within 60 days, such as degradation within 7 days, degradation within 15 days, degradation within 30 days, and degradation within 45 days.

[0046] In this invention, "patient" should be interpreted broadly, including animals such as rats, rabbits, dogs, cows, and monkeys, as well as humans.

[0047] Secondly, the present invention provides a lacrimal canaliculus plug that releases levofloxacin and fluocinolone, which is prepared according to the above-described preparation method.

[0048] The present invention will be described in detail below through examples and comparative examples. In the following examples and comparative examples, the pharmaceuticals and reagents are all conventional commercially available products.

[0049] Example 1: Preparation of the lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone according to the present invention

[0050] A lacrimal canaliculus plug for sustained release of levofloxacin and fluorometholone, the preparation method of which is as follows:

[0051] (1) Disperse 0.2g of levofloxacin, 30g of polyglycolic acid (weight average molecular weight of 15,000-30,000), 35g of chitosan (weight average molecular weight of 50,000-100,000), and 0.7g of polylysine (weight average molecular weight of 3,000-5,000) in 100ml of acetic acid aqueous solution (molar concentration of 5%) to form a first dispersion. Then disperse 0.02g of fluorometholone and 0.8g of calcium alginate in 2ml of ethyl acetate aqueous solution (molar concentration of 12%) to form a second dispersion. Mix the first dispersion and the second dispersion, and then use ultrasonic dispersion for 10min at an ultrasonic power of 450W until the mixture is homogeneous.

[0052] (2) The cross-linking reaction was carried out at 45℃ for 4 hours, then naturally cooled to room temperature, and dried at room temperature and normal pressure for 2 hours to obtain a mixture;

[0053] (3) The mixture obtained in step (2) is subjected to plasma treatment at 3 Pa for 1 min, with an Ar flow rate of 1 L / min and a power of 70 W. Then it is solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear drainage hole is opened with a diameter of 0.1 mm to obtain a sustained-release levofloxacin and fluocinolone lacrimal plug P1.

[0054] The sustained-release levofloxacin and fluocinolone lacrimal canaliculus plug P1 prepared in this embodiment expands rapidly by 6.5 times in diameter and 5.4 times in length within 4 seconds after contact with water. It is comfortable, biocompatible, has few side effects, is not easy to fall off, and degrades within 15 days.

[0055] Example 2: Preparation of the lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone according to the present invention

[0056] A lacrimal canaliculus plug for sustained release of levofloxacin and fluorometholone, the preparation method of which is as follows:

[0057] (1) Disperse 0.4g of levofloxacin, 30g of polyglycolic acid (weight average molecular weight of 15,000-30,000), 45g of chitosan (weight average molecular weight of 50,000-100,000), and 1g of polylysine (weight average molecular weight of 3,000-5,000) in 100ml of acetic acid aqueous solution (molar concentration of 5%) to form a first dispersion. Then disperse 0.03g of fluorometholone and 1g of calcium alginate in 2ml of ethyl acetate aqueous solution (molar concentration of 10%) to form a second dispersion. Mix the first dispersion and the second dispersion, and then use ultrasonic dispersion for 15min at an ultrasonic power of 420W until the mixture is homogeneous.

[0058] (2) Crosslinking reaction was carried out at 50℃ for 4 hours, then naturally cooled to room temperature, and dried at room temperature and normal pressure for 1 hour to obtain a mixture;

[0059] (3) The mixture obtained in step (2) was subjected to plasma treatment at 4 Pa ​​for 30 s, the flow rate of Ar was 1.5 L / min, the power was 90 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm. The tear drainage hole was opened with a diameter of 0.1 mm to obtain a sustained-release levofloxacin and fluocinolone lacrimal plug P2.

[0060] The sustained-release levofloxacin and fluocinolone lacrimal canaliculus plug P2 prepared in this embodiment expands rapidly by 5.9 times in diameter and 5.1 times in length within 5 seconds after contact with water. It is comfortable, biocompatible, has few side effects, is not easy to fall off, and degrades within 15 days.

[0061] Example 3: Preparation of the lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone according to the present invention

[0062] A lacrimal canaliculus plug for sustained release of levofloxacin and fluorometholone, the preparation method of which is as follows:

[0063] (1) Disperse 0.5g of levofloxacin, 40g of polyglycolic acid (weight average molecular weight of 15,000-30,000), 45g of chitosan (weight average molecular weight of 50,000-100,000), and 0.6g of polylysine (weight average molecular weight of 3,000-5,000) in 100ml of acetic acid aqueous solution (molar concentration of 5%) to form a first dispersion. Then disperse 0.04g of fluorometholone and 0.7g of calcium alginate in 2ml of ethyl acetate aqueous solution (molar concentration of 10%) to form a second dispersion. Mix the first dispersion and the second dispersion, and then use ultrasonic dispersion for 18min at an ultrasonic power of 400W until the mixture is homogeneous.

[0064] (2) The cross-linking reaction was carried out at 45℃ for 6 hours, then naturally cooled to room temperature, and dried at room temperature and normal pressure for 2 hours to obtain a mixture;

[0065] (3) The mixture obtained in step (2) is subjected to plasma treatment at 3 Pa for 1 min, with an Ar flow rate of 2 L / min and a power of 80 W. Then it is solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear drainage hole is opened with a diameter of 0.1 mm to obtain a sustained-release levofloxacin and fluocinolone lacrimal plug P3.

[0066] The sustained-release levofloxacin and fluocinolone lacrimal canaliculus plug P3 prepared in this embodiment expands rapidly by 6.2 times in diameter and 5.6 times in length within 5 seconds after contact with water. It is comfortable, biocompatible, has few side effects, is not easy to fall off, and degrades within 15 days.

[0067] Example 4: Preparation of the lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone according to the present invention

[0068] A lacrimal canaliculus plug for sustained release of levofloxacin and fluorometholone, the preparation method of which is as follows:

[0069] (1) Disperse 0.6g of levofloxacin, 50g of polyglycolic acid (weight average molecular weight of 15000-30000), 50g of chitosan (weight average molecular weight of 50000-100000), and 0.9g of polylysine (weight average molecular weight of 3000-5000) in 100ml of acetic acid aqueous solution (molar concentration of 6%) to form a first dispersion. Then disperse 0.05g of fluorometholone and 0.9g of calcium alginate in 2ml of ethyl acetate aqueous solution (molar concentration of 10%) to form a second dispersion. Mix the first dispersion and the second dispersion, and then use ultrasonic dispersion for 20min at an ultrasonic power of 450W until the mixture is homogeneous.

[0070] (2) The cross-linking reaction was carried out at 45℃ for 7 hours, then naturally cooled to room temperature, and dried at room temperature and normal pressure for 2 hours to obtain a mixture;

[0071] (3) The mixture obtained in step (2) is subjected to plasma treatment at 3 Pa for 2 min, with an Ar flow rate of 3 L / min and a power of 100 W. Then it is solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear drainage hole is opened with a diameter of 0.1 mm to obtain a sustained-release levofloxacin and fluocinolone acetonide lacrimal plug P4, which is not easy to fall off.

[0072] The sustained-release levofloxacin and fluocinolone lacrimal canaliculus plug P4 prepared in this embodiment expands rapidly by 6.3 times in diameter and 5.7 times in length within 5 seconds after contact with water. It is comfortable, biocompatible, has few side effects, is not easy to fall off, and degrades within 15 days.

[0073] Example 5: Preparation of the lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone according to the present invention

[0074] A lacrimal canaliculus plug for sustained release of levofloxacin and fluorometholone, the preparation method of which is as follows:

[0075] (1) Disperse 0.7g of levofloxacin, 48g of polyglycolic acid (weight average molecular weight of 15000-30000), 42g of chitosan (weight average molecular weight of 50000-100000), and 1g of polylysine (weight average molecular weight of 3000-5000) in 100ml of acetic acid aqueous solution (molar concentration of 8%) to form a first dispersion. Then disperse 0.06g of fluorometholone and 1.5g of calcium alginate in 2ml of ethyl acetate aqueous solution (molar concentration of 10%) to form a second dispersion. Mix the first dispersion and the second dispersion, and then use ultrasonic dispersion for 20min at an ultrasonic power of 420W until the mixture is homogeneous.

[0076] (2) The cross-linking reaction was carried out at 46℃ for 5 hours, then naturally cooled to room temperature, and dried at room temperature and normal pressure for 1.5 hours to obtain a mixture;

[0077] (3) The mixture obtained in step (2) was subjected to plasma treatment at 4.5 Pa for 2 min, with an Ar flow rate of 1 L / min and a power of 90 W. Then it was solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1.2 mm, and the tear drainage hole was opened with a diameter of 0.1 mm to obtain a sustained-release levofloxacin and fluocinolone lacrimal plug P5.

[0078] The sustained-release levofloxacin and fluocinolone lacrimal canaliculus plug P5 prepared in this embodiment expands rapidly by 6.4 times in diameter and 5.6 times in length within 5 seconds after contact with water. It is comfortable, biocompatible, has few side effects, is not easy to fall off, and degrades within 15 days.

[0079] Example 6: Preparation of the Lacrimal Tube Plutant of Sustained-Release Levofloxacin and Fluoromethol of the Present Invention

[0080] A lacrimal canaliculus plug for sustained release of levofloxacin and fluorometholone, the preparation method of which is as follows:

[0081] (1) Disperse 1.2g of levofloxacin, 46g of polyglycolic acid (weight average molecular weight of 15,000-30,000), 39g of chitosan (weight average molecular weight of 50,000-100,000), and 0.8g of polylysine (weight average molecular weight of 3,000-5,000) in 100ml of acetic acid aqueous solution (molar concentration of 5%) to form a first dispersion. Then disperse 0.07g of fluorometholone and 1.2g of calcium alginate in 2ml of ethyl acetate aqueous solution (molar concentration of 10%) to form a second dispersion. Mix the first dispersion and the second dispersion, and then use ultrasonic dispersion for 15min at an ultrasonic power of 400W until the mixture is homogeneous.

[0082] (2) Crosslinking reaction was carried out at 50℃ for 4 hours, then naturally cooled to room temperature, and dried at room temperature and normal pressure for 1 hour to obtain a mixture;

[0083] (3) The mixture obtained in step (2) is subjected to plasma treatment at 4 Pa ​​for 1 min, with an Ar flow rate of 1 L / min and a power of 100 W. Then it is solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear drainage hole is opened with a diameter of 0.1 mm to obtain a sustained-release levofloxacin and fluocinolone lacrimal plug P6.

[0084] The sustained-release levofloxacin and fluocinolone lacrimal canaliculus plug P6 prepared in this embodiment expands rapidly by 6.2 times in diameter and 5.5 times in length within 5 seconds after contact with water. It is comfortable, biocompatible, has few side effects, is not easy to fall off, and degrades within 15 days.

[0085] Example 7: Preparation of the Lacrimal Tube Plutant of Sustained-Release Levofloxacin and Fluoromethol of the Present Invention

[0086] A lacrimal canaliculus plug for sustained release of levofloxacin and fluorometholone, the preparation method of which is as follows:

[0087] (1) Disperse 1.5g of levofloxacin, 45g of polyglycolic acid (weight average molecular weight of 15,000-30,000), 50g of chitosan (weight average molecular weight of 50,000-100,000), and 0.9g of polylysine (weight average molecular weight of 3,000-5,000) in 100ml of acetic acid aqueous solution (molar concentration of 5%) to form a first dispersion. Then disperse 0.08g of fluorometholone and 1.1g of calcium alginate in 2ml of ethyl acetate aqueous solution (molar concentration of 10%) to form a second dispersion. Mix the first dispersion and the second dispersion, and then use ultrasonic dispersion for 15min at an ultrasonic power of 420W until the mixture is homogeneous.

[0088] (2) The cross-linking reaction was carried out at 45℃ for 7 hours, then naturally cooled to room temperature, and dried at room temperature and normal pressure for 1 hour to obtain a mixture;

[0089] (3) The mixture obtained in step (2) was subjected to plasma treatment at 3 Pa for 2 min, with an Ar flow rate of 1 L / min and a power of 80 W. Then it was solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1.2 mm, and the tear drainage hole was opened with a diameter of 0.1 mm to obtain a sustained-release levofloxacin and fluocinolone lacrimal plug P7.

[0090] The sustained-release levofloxacin and fluocinolone acetonide lacrimal canaliculus plug P7 prepared in this embodiment expands rapidly by 5.9 times in diameter and 5.3 times in length within 5 seconds after contact with water. It is comfortable, biocompatible, has few side effects, is not easy to fall off, and degrades within 15 days.

[0091] Example 8: Preparation of the lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone according to the present invention

[0092] A lacrimal canaliculus plug for sustained release of levofloxacin and fluorometholone, the preparation method of which is as follows:

[0093] (1) 1.4g of levofloxacin, 50g of polyglycolic acid (weight average molecular weight of 15,000-30,000), 49g of chitosan (weight average molecular weight of 50,000-100,000), and 1g of polylysine (weight average molecular weight of 3,000-5,000) were dispersed in 100ml of acetic acid aqueous solution (molar concentration of 10%) to form a first dispersion. Then, 0.09g of fluorometholone and 1g of calcium alginate were dispersed in 2ml of ethyl acetate aqueous solution (molar concentration of 10%) to form a second dispersion. The first and second dispersions were mixed and then ultrasonically dispersed for 20min at an ultrasonic power of 400W until homogeneous.

[0094] (2) Crosslinking reaction was carried out at 50℃ for 4 hours, then naturally cooled to room temperature, and dried at room temperature and normal pressure for 2 hours to obtain a mixture;

[0095] (3) The mixture obtained in step (2) was subjected to plasma treatment at 4 Pa ​​for 1 min, with an Ar flow rate of 2 L / min and a power of 80 W. Then it was solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear drainage hole was opened with a diameter of 0.1 mm to obtain a sustained-release levofloxacin and fluocinolone lacrimal plug P8.

[0096] The sustained-release levofloxacin and fluocinolone acetonide lacrimal canaliculus plug P8 prepared in this embodiment expands rapidly by 6.4 times in diameter and 5.3 times in length within 5 seconds after contact with water. It is comfortable, biocompatible, has few side effects, is not easy to fall off, and degrades within 15 days.

[0097] Comparative Example 1: A comparative example of Embodiment 1 of the present invention

[0098] The raw materials do not contain polyglycolic acid, and the other steps are the same as in Example 1, to obtain a lacrimal canaliculus plug DP1 that releases levofloxacin and fluorometholone.

[0099] The lacrimal canaliculus plug DP1 prepared in this comparative example has insufficient mechanical strength, is prone to detachment, and the release of levofloxacin and fluorometholone is unstable.

[0100] Comparative Example 2: A comparative example of Embodiment 1 of the present invention

[0101] Without plasma treatment, the other steps are the same as in Example 1, to obtain the lacrimal canaliculus plug DP2 that releases levofloxacin and fluocinolone.

[0102] The lacrimal canaliculus plug DP2 prepared in this comparative example, which is a sustained-release levofloxacin and fluocinolone, expands slowly upon contact with water, with its diameter expanding 4.1 times and its length expanding rapidly by 3.6 times after 10 hours.

[0103] Comparative Example 3: A comparative example of Embodiment 1 of the present invention

[0104] Without ultrasonic dispersion, the other steps are the same as in Example 1, to obtain a lacrimal canaliculus plug DP3 containing sustained-release levofloxacin and fluocinolone.

[0105] The sustained-release levofloxacin and fluocinolone duct plug DP3 prepared in this comparative example was not stable enough.

[0106] Example 9: Release experiment of the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug of the present invention

[0107] Simulated tears were prepared based on the composition of human tears. The lacrimal canaliculus plugs prepared in Examples 1-8 and Comparative Examples 1-3 were immersed in 5 ml of simulated tears, respectively. The concentrations of levofloxacin and fluorometholone in the simulated tears were measured, and the cumulative release rates of levofloxacin and fluorometholone were calculated based on their concentrations. The cumulative release rates of levofloxacin are shown in Table 1, and the cumulative release rates of fluorometholone are shown in Table 2.

[0108] Table 1 Cumulative Release Rate of Levofloxacin

[0109]

[0110] Table 2 Cumulative Release Rate of Fluoromethyl Fibre

[0111]

[0112] As can be seen from Tables 1 and 2 above, the sustained-release levofloxacin and fluocinolone lacrimal canaliculus plugs prepared in the above embodiments of the present invention can effectively promote the slow release of levofloxacin and fluocinolone, and the release rate is more stable. In contrast, the release of levofloxacin and fluocinolone in DP1 of Comparative Example 1 was always unstable. In Comparative Example 2, the release of levofloxacin and fluocinolone in DP2 was small and unstable in the first few hours due to the slow expansion rate upon contact with water, and then tended to stabilize. The release of levofloxacin and fluocinolone in Comparative Example 3 was always unstable.

[0113] Example 10: The efficacy of the present invention for dry eye symptoms, inflammation, and infection after corneal refractive surgery.

[0114] The efficacy evaluation criteria are as follows: 0 points for symptom disappearance, 1 point for mild symptoms, 2 points for moderate symptoms, and 3 points for severe symptoms. Marked effect: symptoms basically disappear, score reduction ≥80%; Effective: symptoms significantly improve, 80% < score reduction ≤30%; Ineffective: no significant improvement in symptoms. Total effective rate = (Marked effect + Effective) / Total number of cases × 100%.

[0115] One hundred patients (aged 18-59 years) who developed dry eye symptoms, inflammation, and infection after corneal refractive surgery were selected and implanted with lacrimal canaliculus plugs P1 containing sustained-release levofloxacin and fluorometholone prepared in Example 1. The efficacy was evaluated on day 10 after implantation, and the results are shown in Table 3.

[0116] The results showed that, 10 days after implantation, the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug of the present invention had a total effective rate of 99% for dry eye symptoms, inflammation and infection after corneal refractive surgery, with significant therapeutic effect and highly statistical significance.

[0117] Table 2. Results of therapeutic efficacy evaluation

[0118]

[0119] The above ineffective cases were effective after P1 implantation again because the patients had a longer disease course and required a longer treatment time.

[0120] The sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs prepared by this invention have significant clinical application value. It should be noted that while the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs prepared by this invention can effectively treat dry eye symptoms, reduce inflammation, and fight infection after corneal refractive surgery, the treatment of dry eye symptoms, inflammation, and infection mentioned in this invention are only for diseases commonly treated with the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs prepared by this invention. This invention is not limited to these eye diseases; the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plugs of this invention can be applied to any other suitable eye disease.

[0121] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and do not constitute a limitation on the content of the present invention. Although the present invention has been described in detail through the above embodiments, those skilled in the art can still make various changes in form and detail based on the technical content described in the Summary of the Invention and the Embodiments, without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

1. A method for preparing a lacrimal canaliculus plug containing sustained-release levofloxacin and fluorometholone, characterized in that, Includes the following steps: (1) Levofloxacin, polyglycolic acid, chitosan, and polylysine are dispersed in a first solvent to form a first dispersion, and fluorometholone and alginate are dispersed in a second solvent to form a second dispersion. The first and second dispersions are then mixed evenly, wherein the mass ratio of levofloxacin:fluorometholone: ​​polyglycolic acid: chitosan: polylysine: alginate is 0.2-3:0.01-1:15-50:10-50:0.1-3:0.5-2. (2) Crosslinking reaction at 45-55℃ for 3-10 h, followed by cooling and drying to obtain a mixture; (3) The mixture obtained in step (2) is subjected to plasma treatment at less than 6 Pa for 30 s-5 min, and then solidified to obtain a lacrimal canaliculus plug for sustained release of levofloxacin. In step (3), the conditions for plasma treatment include a treatment pressure of 3-5.5 Pa, a treatment time of 10 s-2 min, an Ar flow rate of 1-3 L / min, and a power of 70-100 W.

2. The method for preparing the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug according to claim 1, characterized in that, In step (1), the mass ratio of levofloxacin: fluorometholone: ​​polyglycolic acid: chitosan: polylysine: alginate is 0.2-1.5: 0.01-0.1: 20-50: 25-50: 0.1-1: 0.5-1.

5.

3. The method for preparing the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug according to claim 1, characterized in that, In step (1), the first solvent is acetic acid and the second solvent is an aqueous solution of ethyl acetate.

4. The method for preparing the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug according to claim 1, characterized in that, In step (2), a crosslinking reaction is carried out at 45-50°C.

5. The method for preparing the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug according to claim 1, characterized in that, In step (2), the crosslinking reaction is carried out for 4-8 hours.

6. The method for preparing the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug according to claim 1, characterized in that, In step (3), when the solidified shape is cylindrical, the diameter is 0.1-1 mm and the length is 0.5-10 mm.

7. The method for preparing the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug according to claim 6, characterized in that, In step (3), when the solidified shape is cylindrical, the diameter is 0.1-0.5 mm and the length is 0.5-3 mm.

8. The method for preparing the sustained-release levofloxacin and fluorometholone lacrimal canaliculus plug according to claim 6, characterized in that, In step (3), when the solidified and molded into a cylindrical shape, at least one drainage hole is made along the central axis direction, and the diameter of the drainage hole is 0.02mm-0.2mm.

9. A lacrimal canaliculus plug for sustained release of levofloxacin and fluorometholone, characterized in that, It is prepared by the method according to any one of claims 1-8.

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