Lacrimal duct plug for sustained-release levofloxacin and preparation method thereof

Abstract

The present invention discloses a sustained-release levofloxacin punctal plug and a preparation method thereof. The sustained-release levofloxacin punctal plug prepared by cross-linking levofloxacin, polyglycolide, chitosan, and polylysine and then plasma-treating the plug can reduce the frequency of antibiotic use or eliminate the need for antibiotics. The plug has good patient compliance, comfort, biocompatibility, short-term degradation, minimal side effects, good water swelling properties, and is not easily dislodged.

Description

Technical Field

[0001] The present invention relates to the field of medical materials, and in particular to a lacrimal duct plug for sustained-release levofloxacin and a preparation method thereof. Background Art

[0002] Dry eye syndrome refers to a broad range of conditions characterized by abnormal tear quality, quantity, or dynamics, resulting from any cause, leading to decreased tear film stability, accompanied by ocular discomfort and ocular surface pathology. Common symptoms include dry eyes, fatigue, itching, a foreign body sensation, pain and burning, thick discharge, fear of wind and light, and sensitivity to external stimuli. Currently, a significant number of patients suffer from combined acute and chronic dacryocystitis, punctitis, and dacryoductitis.

[0003] In recent years, the use of punctal plugs or tear duct plugs has become increasingly common in clinical practice. By blocking the tear ducts, tear discharge is reduced, the balance of tears on the ocular surface is reestablished, and the ocular surface environment is improved, thereby alleviating the symptoms and signs of dry eye. However, currently, patients with dry eye combined with acute and chronic dacryocystitis, dry eye combined with acute and chronic punctitis, and dry eye combined with acute and chronic dacryoductitis require multiple additional doses of antibiotics. There is an urgent need to develop punctal plugs that can effectively treat dry eye combined with acute and chronic dacryocystitis, dry eye combined with acute and chronic punctitis, and dry eye combined with acute and chronic dacryoductitis. Summary of the Invention

[0004] In response to the deficiencies in the prior art, the present invention aims to provide a sustained-release levofloxacin punctal plug and a preparation method thereof. The sustained-release levofloxacin punctal plug prepared by the present 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 performance, is not easy to fall off, and can treat dry eye while providing anti-inflammatory effects.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

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

[0007] (1) dispersing levofloxacin, polyglycolide, chitosan, and polylysine in a solvent and mixing them uniformly, wherein the mass ratio of levofloxacin:polyglycolide:chitosan:polylysine is 0.5-3:15-40:12-50:0.2-3;

[0008] (2) performing a cross-linking reaction at 45-55° C. for 5-15 hours, cooling, and drying to obtain a mixture;

[0009] (3) The mixture obtained in step (2) is subjected to plasma treatment at a pressure less than 6 Pa for 30 seconds to 5 minutes, and then solidified to obtain a punctal plug for sustained-release levofloxacin.

[0010] Preferably, in step (1), the mass ratio of levofloxacin:polyglycolide:chitosan:polylysine is 0.5-1.5:25-40:20-50:0.5-1.

[0011] Preferably, in step (1), the solvent is acetic acid.

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

[0013] Preferably, in step (2), the cross-linking reaction is carried out for 5-10 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 solidified and formed into a cylindrical shape, the diameter is 0.1-1 mm and the length is 0.5-10 mm.

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

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

[0018] In a second aspect, the present invention provides a punctal plug for sustained-release levofloxacin, which is prepared according to the above preparation method.

[0019] The beneficial effects of the present invention are:

[0020] The present invention uses levofloxacin, polyglycolide, chitosan, and polylysine as raw materials for a cross-linking reaction and adopts plasma treatment to prepare a sustained-release levofloxacin punctal plug. The levofloxacin can reduce the frequency of antibiotic use or eliminate the need for antibiotic use, and has good patient compliance, good comfort, good biocompatibility, short-term degradation, few side effects, and anti-inflammatory effects while treating dry eye. The inventors have also discovered that plasma treatment can impart excellent hydrophilicity and water-swellability to the sustained-release levofloxacin punctal plug. The plug rapidly swells in water and, after implantation, can rapidly expand in the lacrimal canaliculus within a few seconds, thereby being fixed in the lacrimal canaliculus and not easily falling off.

[0021] The sustained-release levofloxacin punctal plug prepared by the present invention has important clinical application value. It should be noted that the sustained-release levofloxacin punctal plug prepared by the present invention can effectively treat dry eye combined with acute and chronic dacryocystitis, dry eye combined with acute and chronic punctitis, and dry eye combined with acute and chronic dacryocystitis, dry eye combined with acute and chronic punctitis, and dry eye combined with acute and chronic dacryoductitis mentioned in the present invention are only diseases commonly treated by the sustained-release levofloxacin punctal plug prepared by the present invention. The present invention is not limited to application to these eye diseases. The sustained-release levofloxacin punctal plug of the present 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. DETAILED DESCRIPTION

[0023] In order to make the purpose, technical solutions and beneficial effects of the present invention clearer, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described in the following embodiments of the present invention are only exemplary descriptions of the specific embodiments of the present invention, and are intended to be used for explaining the present invention, but do not constitute a limitation of the present invention.

[0024] The endpoints and any values of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values, and the aforementioned values close to these ranges or values refer to values such as specific point values ± 10%. For numerical ranges, the endpoint values of each range, the endpoint values of each range and the individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article. In the description of this application, unless otherwise stated, the meaning of similar words such as "multiple / multiple" is two / kinds or more than two / kinds. In addition, the terms "include", "comprise" and any variations thereof are intended to cover non-exclusive inclusions.

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

[0026] (1) dispersing levofloxacin, polyglycolide, chitosan, and polylysine in a solvent and mixing them uniformly, wherein the mass ratio of levofloxacin:polyglycolide:chitosan:polylysine is 0.5-3:15-40:12-50:0.2-3;

[0027] (2) performing a cross-linking reaction at 45-55° C. for 5-15 hours, cooling, and drying to obtain a mixture;

[0028] (3) The mixture obtained in step (2) is subjected to plasma treatment at a pressure less than 6 Pa for 30 seconds to 5 minutes, and then solidified to obtain a punctal plug for sustained-release levofloxacin.

[0029] In the present invention, levofloxacin should be understood in a broad sense, including salts of levofloxacin, such as levofloxacin hydrochloride; levofloxacin has anti-inflammatory and anti-infective effects.

[0030] In the present invention, the molecular weight of the polyglycolide can be selected within a wide range. Preferably, the weight-average molecular weight of the polyglycolide is 10,000-50,000, so that the sustained-release levofloxacin punctal plug can further reduce the frequency of antibiotic use or eliminate the need for antibiotics, improve patient compliance, provide good comfort, have good biocompatibility, minimize side effects, degrade quickly, swell well in water, and resist shedding.

[0031] In the present invention, the type of chitosan can be selected within a wide range, such as carboxymethyl chitosan. The molecular weight of chitosan can also be selected within a wide range. Preferably, in order to enable the sustained-release levofloxacin tear duct plug to further reduce the number of times antibiotics are used or to eliminate the need for antibiotics, with good patient compliance, good comfort, good biocompatibility, few side effects, short-term degradation, good water swelling performance, and not easy to fall off, the weight-average molecular weight of the chitosan is 50,000-150,000.

[0032] It should be noted that although in a strict medical sense, the lacrimal canaliculus is part of the lacrimal duct structure, the medical professional meanings of "lacrimal canaliculus" and "tear duct" are not necessarily strictly standardized in actual application. Therefore, the "lacrimal canaliculus plug" in the present invention should be understood in a broad sense, that is, "lacrimal canaliculus plug" is equivalent to "tear duct". Therefore, the "lacrimal canaliculus plug" in the present invention is equivalent to "tear duct plug".

[0033] Punctal plugs with low mechanical strength are prone to falling off, while those with high mechanical strength are prone to a foreign body sensation and lack comfort, which not only hinders the effectiveness of the treatment but also easily leads to adverse reactions. In the present invention, the use of polyglycolide in combination with other raw materials such as chitosan not only ensures that the punctal plug has good mechanical strength and comfort, but also has good biocompatibility, water-swellability, and minimal side effects. Furthermore, the use of polyglycolide and chitosan as the main raw materials allows for good cross-linking and promotes the slow release of levofloxacin, resulting in a more stable release rate, which is beneficial to the effectiveness of the treatment, has anti-inflammatory effects, and simultaneously treats dry eye.

[0034] In the present invention, the type of solvent can be selected within a wide range, as long as it can dissolve levofloxacin, polyglycolide, chitosan and polylysine. Preferably, in order to make the solvent more easily disperse levofloxacin, polyglycolide, chitosan and polylysine, the solvent is acetic acid (which should be understood in a broad sense, such as an acetic acid aqueous solution with a molar concentration of 3%-10%). In the present invention, the amount of the solvent can be selected within a wide range.

[0035] In the present invention, the dispersion and uniform mixing methods can be selected within a wide range. In some preferred embodiments, in order to make the prepared sustained-release levofloxacin punctum plug release levofloxacin more effective and more stable, ultrasonic dispersion is adopted, and the ultrasonic dispersion time is 15-20 minutes and the ultrasonic power is 400-500W.

[0036] In the present invention, the cross-linking reaction can be carried out at 45-55°C for 5-15 hours to obtain a sustained-release levofloxacin tear plug with good patient compliance, good comfort, good biocompatibility, small side effects, and short-term degradation. In the present invention, polylysine plays a good cross-linking role. In some embodiments, the weight-average molecular weight of polylysine is 3000-5000. In some preferred embodiments, in step (2), the cross-linking reaction is carried out at 45-50°C. In some preferred embodiments, in step (2), the cross-linking reaction is carried out for 5-10 hours.

[0037] In the present invention, the cooling conditions can be selected within a wide range, such as natural cooling to room temperature.

[0038] In the present 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.

[0039] In the present invention, the plasma treatment conditions are to perform the plasma treatment at a pressure of less than 6 Pa for 30 seconds to 5 minutes. In some preferred embodiments, in order to enable the prepared sustained-release levofloxacin punctal plug to further reduce the number of times antibiotics are used or to eliminate the need for antibiotics, and to have good patient compliance, water swelling, good comfort, 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 seconds to 2 minutes, an Ar flow rate of 1-3 L / min, and a power of 70-100 W.

[0040] In the present invention, the inventor unexpectedly found that after levofloxacin, polyglycolide, chitosan, and polylysine were cross-linked to obtain a mixture, the tear duct plug of the sustained-release levofloxacin was obtained by plasma treatment, and it was found to have excellent hydrophilicity and water-swelling property, and it was found to expand rapidly in the tear duct after being implanted, and then it was fixed in the tear duct and was not easy to fall off. After implantation, the tear duct plug can expand rapidly in the tear duct such as within 6s, within 5s, or within 4s. When the tear duct plug was cylindrical, the length or diameter of the tear duct plug after implantation all expanded rapidly in the tear duct at least 2 times, at least 3 times, at least 4 times, or at least 5 times when it was found to expand rapidly in the tear duct.

[0041] In some preferred embodiments, in step (1), the mass ratio of levofloxacin:polyglycolide:chitosan:polylysine is 0.5-1.5:25-40:20-50:0.5-1.

[0042] In the present invention, preferably, in order to further make the sustained-release levofloxacin punctal plug more comfortable when implanted in the lacrimal duct and less likely to fall out, in step (3), when 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 solidified into a cylindrical shape, the diameter is 0.1-0.5 mm and the length is 0.5-3 mm.

[0043] In the present invention, preferably, in step (3), when solidified into a cylindrical shape, at least one tear drain hole is opened along the central axis direction, and the position of the tear drain hole can be centered on the central axis or around the central axis, and the diameter of the tear drain hole is 0.02mm-0.2mm, which is beneficial to reducing the loss of tears and moistening the eyeball, and can also make the tears circulate and discharge through the through hole, reducing the accumulation and retention of tears, so that the tear duct plug of the sustained-release levofloxacin can discharge excess tears in time, thereby reducing the related inflammation caused by the accumulation and retention of tears. In combination with the above-mentioned polyglycolide and chitosan as the main raw materials, it is not easy to produce inflammation, and the tear duct plug of the sustained-release levofloxacin of the present invention has a good anti-inflammatory effect. In the present invention, the tear drain hole can be opened after molding, and can also be obtained by mold or 3D printing during preparation.

[0044] In the present invention, "short-term degradation" generally refers to degradation within 60 days, such as degradation within 7 days, degradation within 15 days, degradation within 30 days, degradation within 45 days.

[0045] In the present invention, "patient" should be understood in a broad sense, including animals such as mice, rabbits, dogs, cows, monkeys, and humans.

[0046] In a second aspect, the present invention provides a punctal plug for sustained-release levofloxacin, which is prepared according to the above preparation method.

[0047] The present invention will be described in detail below through examples and comparative examples. In the following examples and comparative examples, the drugs and pharmaceuticals are all conventional commercial products.

[0048] Example 1: Preparation of the sustained-release levofloxacin punctal plug of the present invention

[0049] A lacrimal duct plug for sustained-release levofloxacin, the preparation method of which is as follows:

[0050] (1) 0.5 g of levofloxacin, 25 g of polyglycolide (weight-average molecular weight of 15,000-30,000), 25 g of chitosan (weight-average molecular weight of 50,000-100,000), and 0.6 g of polylysine (weight-average molecular weight of 3,000-5,000) were dispersed in 100 ml of acetic acid aqueous solution (molar concentration of 5%), and then ultrasonically dispersed for 15 min at an ultrasonic power of 410 W to mix uniformly;

[0051] (2) performing a cross-linking reaction at 45° C. for 6 h, cooling naturally to room temperature, and drying at room temperature and normal pressure for 1.5 h to obtain a mixture;

[0052] (3) The mixture obtained in step (2) was plasma treated at 5 Pa for 30 s, with an Ar flow rate of 0.5 L / min and a power of 50 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear duct was opened with a diameter of 0.1 mm to obtain a tear duct plug P1 for sustained release of levofloxacin.

[0053] The sustained-release levofloxacin tear duct plug P1 prepared in this example rapidly expands 5.5 times in diameter and 4.6 times in length within 4 seconds after contacting water. It has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0054] Example 2: Preparation of the sustained-release levofloxacin punctal plug of the present invention

[0055] A lacrimal duct plug for sustained-release levofloxacin, the preparation method of which is as follows:

[0056] (1) 1.5 g of levofloxacin, 40 g of polyglycolide (weight-average molecular weight of 15,000-30,000), 50 g of chitosan (weight-average molecular weight of 50,000-100,000), and 0.8 g of polylysine (molecular weight of 3,000-5,000) were dispersed in 100 ml of acetic acid aqueous solution (molar concentration of 5%), and then ultrasonically dispersed for 15 min at an ultrasonic power of 400 W to mix uniformly;

[0057] (2) performing a cross-linking reaction at 50° C. for 6 h, cooling naturally to room temperature, and drying at room temperature and normal pressure for 1 h to obtain a mixture;

[0058] (3) The mixture obtained in step (2) was plasma treated at 4.5 Pa for 1 min, with an Ar flow rate of 2 L / min and a power of 80 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear duct was opened with a diameter of 0.1 mm to obtain a tear duct plug P2 for sustained release of levofloxacin.

[0059] The sustained-release levofloxacin tear duct plug P2 prepared in this example rapidly expands 4.5 times in diameter and 4.1 times in length within 4 seconds after contacting water. It has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0060] Example 3: Preparation of the sustained-release levofloxacin punctal plug of the present invention

[0061] A lacrimal duct plug for sustained-release levofloxacin, the preparation method of which is as follows:

[0062] (1) 1.2 g of levofloxacin, 30 g of polyglycolide (weight-average molecular weight of 15,000-30,000), 40 g of chitosan (weight-average molecular weight of 50,000-100,000), and 0.5 g of polylysine (weight-average molecular weight of 3,000-5,000) were dispersed in 100 ml of acetic acid aqueous solution (molar concentration of 5%), and then ultrasonically dispersed for 15 min at an ultrasonic power of 450 W to mix uniformly;

[0063] (2) performing a cross-linking reaction at 45° C. for 10 h, cooling naturally to room temperature, and drying at room temperature and normal pressure for 1 h to obtain a mixture;

[0064] (3) The mixture obtained in step (2) was plasma treated at 3.5 Pa for 1.5 min, with an Ar flow rate of 1 L / min and a power of 90 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear duct was opened with a diameter of 0.1 mm to obtain a tear duct plug P3 for sustained release of levofloxacin.

[0065] The sustained-release levofloxacin tear duct plug P3 prepared in this example rapidly expands 5.1 times in diameter and 4.7 times in length within 5 seconds after contacting water. It has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0066] Example 4: Preparation of the sustained-release levofloxacin punctal plug of the present invention

[0067] A lacrimal duct plug for sustained-release levofloxacin, the preparation method of which is as follows:

[0068] (1) 1.6 g of levofloxacin, 29 g of polyglycolide (weight-average molecular weight of 15,000-30,000), 26 g of chitosan (weight-average molecular weight of 50,000-100,000), and 1 g of polylysine (weight-average molecular weight of 3,000-5,000) were dispersed in 100 ml of acetic acid aqueous solution (molar concentration of 6%), and then ultrasonically dispersed for 15 min at an ultrasonic power of 420 W to mix uniformly;

[0069] (2) performing a cross-linking reaction at 50° C. for 5 h, cooling naturally to room temperature, and drying at room temperature and normal pressure for 1 h to obtain a mixture;

[0070] (3) The mixture obtained in step (2) was subjected to plasma treatment at 4.5 Pa for 1 min, with an Ar flow rate of 2 L / min and a power of 70 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear duct was opened with a diameter of 0.1 mm to obtain a lacrimal plug P4 for sustained release of levofloxacin, which is not easy to fall off.

[0071] The sustained-release levofloxacin tear duct plug P4 prepared in this example rapidly expands 5.2 times in diameter and 4.5 times in length within 6 seconds after contacting water. It has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0072] Example 5: Preparation of the sustained-release levofloxacin punctal plug of the present invention

[0073] A lacrimal duct plug for sustained-release levofloxacin, the preparation method of which is as follows:

[0074] (1) 1.3 g of levofloxacin, 26 g of polyglycolide (weight-average molecular weight of 15,000-30,000), 34 g of chitosan (weight-average molecular weight of 50,000-100,000), and 0.7 g of polylysine (weight-average molecular weight of 3,000-5,000) were dispersed in 100 ml of acetic acid aqueous solution (molar concentration of 8%), and then ultrasonically dispersed for 15 min at an ultrasonic power of 400 W to mix uniformly;

[0075] (2) performing a cross-linking reaction at 48° C. for 7 h, cooling naturally to room temperature, and drying at room temperature and normal pressure for 2 h to obtain a mixture;

[0076] (3) The mixture obtained in step (2) was plasma treated at 5 Pa for 1 min, with an Ar flow rate of 2 L / min and a power of 100 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1.2 mm, and the tear duct was opened with a diameter of 0.1 mm to obtain a tear duct plug P5 for sustained release of levofloxacin.

[0077] The sustained-release levofloxacin punctal plug P5 prepared in this example rapidly expands 5.1 times in diameter and 4.8 times in length within 5 seconds after contacting water. It has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0078] Example 6: Preparation of the sustained-release levofloxacin punctal plug of the present invention

[0079] A lacrimal duct plug for sustained-release levofloxacin, the preparation method of which is as follows:

[0080] (1) 1.4 g of levofloxacin, 27 g of polyglycolide (weight-average molecular weight of 15,000-30,000), 43 g of chitosan (weight-average molecular weight of 50,000-100,000), and 0.6 g of polylysine (weight-average molecular weight of 3,000-5,000) were dispersed in 100 ml of acetic acid aqueous solution (molar concentration of 5%) and then ultrasonically dispersed for 15 min at an ultrasonic power of 400 W to mix uniformly;

[0081] (2) performing a cross-linking reaction at 45° C. for 10 h, cooling naturally to room temperature, and drying at room temperature and normal pressure for 2 h to obtain a mixture;

[0082] (3) The mixture obtained in step (2) was plasma treated at 3 Pa for 2 min, with an Ar flow rate of 1.5 L / min and a power of 80 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear duct plug P6 with a diameter of 0.1 mm was opened to obtain a sustained-release levofloxacin.

[0083] The sustained-release levofloxacin punctal plug P6 prepared in this example rapidly expands 4.9 times in diameter and 4.3 times in length within 5 seconds after contacting water. It has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0084] Example 7: Preparation of the sustained-release levofloxacin punctal plug of the present invention

[0085] A lacrimal duct plug for sustained-release levofloxacin, the preparation method of which is as follows:

[0086] (1) 1.5 g of levofloxacin, 35 g of polyglycolide (weight-average molecular weight of 15,000-30,000), 43 g of chitosan (weight-average molecular weight of 50,000-100,000), and 0.7 g of polylysine (weight-average molecular weight of 3,000-5,000) were dispersed in 100 ml of acetic acid aqueous solution (molar concentration of 5%), and then ultrasonically dispersed for 15 min at an ultrasonic power of 400 W to mix uniformly;

[0087] (2) performing a cross-linking reaction at 45° C. for 8 h, cooling naturally to room temperature, and drying at room temperature and normal pressure for 2 h to obtain a mixture;

[0088] (3) The mixture obtained in step (2) was plasma treated at 4 Pa for 1 min, with an Ar flow rate of 2 L / min and a power of 90 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1.2 mm, and the tear duct plug P7 with a diameter of 0.1 mm was opened to obtain a sustained-release levofloxacin.

[0089] The sustained-release levofloxacin punctal plug P7 prepared in this example rapidly expands 4.8 times in diameter and 4.1 times in length within 5 seconds after contacting water. It has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0090] Example 8: Preparation of the sustained-release levofloxacin punctal plug of the present invention

[0091] A lacrimal duct plug for sustained-release levofloxacin, the preparation method of which is as follows:

[0092] (1) 1.8 g of levofloxacin, 40 g of polyglycolide (weight-average molecular weight of 15,000-30,000), 45 g of chitosan (weight-average molecular weight of 50,000-100,000), and 1 g of polylysine (weight-average molecular weight of 3,000-5,000) were dispersed in 100 ml of acetic acid aqueous solution (molar concentration of 10%) and then ultrasonically dispersed for 15 min at an ultrasonic power of 420 W to mix uniformly;

[0093] (2) performing a cross-linking reaction at 50° C. for 5 h, cooling naturally to room temperature, and drying at room temperature and normal pressure for 1 h to obtain a mixture;

[0094] (3) The mixture obtained in step (2) was plasma treated at 5 Pa for 1 min, with an Ar flow rate of 1 L / min and a power of 70 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and the tear duct plug P8 with a diameter of 0.1 mm was opened to obtain a sustained-release levofloxacin.

[0095] The sustained-release levofloxacin punctal plug P8 prepared in this example rapidly expands 4.8 times in diameter and 4.1 times in length within 5 seconds after contacting water. It has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0096] Comparative Example 1: Comparative Example of Example 1 of the present invention

[0097] The raw materials did not contain polyglycolide, and the other steps were the same as in Example 1 to obtain the punctal plug DP1 for sustained-release levofloxacin.

[0098] The sustained-release levofloxacin tear duct plug DP1 prepared in this comparative example has insufficient mechanical strength, is easily detached, and releases levofloxacin unstably.

[0099] Comparative Example 2: Comparative Example of Example 1 of the Present Invention

[0100] Without plasma treatment, the other steps were the same as those in Example 1 to obtain the levofloxacin sustained-release punctal plug DP2.

[0101] The sustained-release levofloxacin tear duct plug DP2 prepared in this comparative example swells slowly when exposed to water, with the diameter expanding by 3.7 times and the length expanding by 3.2 times within 10 hours.

[0102] Comparative Example 3: Comparative Example of Example 1 of the Present Invention

[0103] Without ultrasonic dispersion, the other steps were the same as in Example 1 to obtain the levofloxacin sustained-release punctal plug DP3.

[0104] The sustained-release levofloxacin punctum plug DP3 prepared in this comparative example is not stable enough in releasing levofloxacin.

[0105] Example 9: Release experiment of the lacrimal plug containing sustained-release levofloxacin of the present invention

[0106] Simulated tears were prepared based on the composition of human tears. The punctal plugs prepared in Examples 1-8 and Comparative Examples 1-3 were immersed in 5 ml of the simulated tears. The levofloxacin concentration in the simulated tears was measured, and the cumulative release rate of levofloxacin was calculated based on the levofloxacin concentration. The cumulative release rate of levofloxacin is shown in Table 1.

[0107] Table 1 Levofloxacin cumulative release rate

[0108]

[0109] As can be seen from Table 1 above, the sustained-release levofloxacin punctal plugs prepared in the above embodiments of the present invention can well promote the slow release of levofloxacin with a more stable release rate. However, the levofloxacin release of DP1 in Comparative Example 1 has been unstable. The levofloxacin release of DP2 in Comparative Example 2 is small and unstable in the first few hours due to its slow swelling rate when exposed to water, and then tends to be stable. The levofloxacin release of Comparative Example 3 has been unstable.

[0110] Example 10: Therapeutic effect of the present invention on dry eye combined with acute and chronic dacryocystitis

[0111] Efficacy evaluation criteria: 0 for symptom disappearance, 1 for mild symptoms, 2 for moderate symptoms, and 3 for severe symptoms. Marked efficacy: essentially eliminated symptoms, with a score reduction of ≥ 80%; effective: significantly improved symptoms, with a score reduction of < 80% or ≤ 30%; ineffective: no significant improvement. Total effective rate = (marked efficacy + effective) / total number of cases × 100%.

[0112] 100 patients (aged 18-59) with dry eye and acute dacryocystitis were selected and implanted with the sustained-release levofloxacin punctal plug P1 prepared in Example 1. The therapeutic efficacy was evaluated on the 10th day after implantation. The results are shown in Table 2.

[0113] 100 patients (aged 18-59) with dry eye and chronic dacryocystitis were selected and implanted with the sustained-release levofloxacin punctal plug P1 prepared in Example 1. The therapeutic efficacy was evaluated on the 10th day after implantation. The results are shown in Table 2.

[0114] The results showed that 10 days after implantation, the total effective rate of the sustained-release levofloxacin tear duct plug of the present invention for dry eye combined with acute dacryocystitis was 100%, and the total effective rate for dry eye combined with chronic dacryocystitis was 99%, with significant therapeutic effects and very significant statistical significance.

[0115] Example 11: Efficacy of the present invention for dry eye combined with acute and chronic punctitis

[0116] Efficacy evaluation criteria: 0 for symptom disappearance, 1 for mild symptoms, 2 for moderate symptoms, and 3 for severe symptoms. Marked efficacy: essentially eliminated symptoms, with a score reduction of ≥ 80%; effective: significantly improved symptoms, with a score reduction of < 80% or ≤ 30%; ineffective: no significant improvement. Total effective rate = (marked efficacy + effective) / total number of cases × 100%.

[0117] 100 patients (aged 18-59) with dry eye combined with acute punctum inflammation were selected and implanted with the sustained-release levofloxacin punctum plug P1 prepared in Example 1. The therapeutic efficacy was evaluated on the 10th day after implantation. The results are shown in Table 2.

[0118] 100 patients (aged 18-59) with dry eye and chronic punctum inflammation were selected and implanted with the sustained-release levofloxacin punctum plug P1 prepared in Example 1. The therapeutic efficacy was evaluated on the 10th day after implantation. The results are shown in Table 2.

[0119] The results showed that 10 days after implantation, the total effective rate of the sustained-release levofloxacin punctum plug of the present invention for dry eye combined with acute punctum inflammation was 100%, and the total effective rate for dry eye combined with chronic punctum inflammation was 98%, with significant therapeutic effects and very significant statistical significance.

[0120] Example 12: Efficacy of the present invention for dry eye combined with acute and chronic dacryoductitis

[0121] Efficacy evaluation criteria: 0 for symptom disappearance, 1 for mild symptoms, 2 for moderate symptoms, and 3 for severe symptoms. Marked efficacy: essentially eliminated symptoms, with a score reduction of ≥ 80%; effective: significantly improved symptoms, with a score reduction of < 80% or ≤ 30%; ineffective: no significant improvement. Total effective rate = (marked efficacy + effective) / total number of cases × 100%.

[0122] 100 patients (aged 18-59) with dry eye and acute dacryoductitis were selected and implanted with the sustained-release levofloxacin punctal plug P1 prepared in Example 1. The therapeutic efficacy was evaluated on the 10th day after implantation. The results are shown in Table 2.

[0123] 100 patients (aged 18-59) with dry eye and chronic dacryoductitis were selected and implanted with the sustained-release levofloxacin punctal plug P1 prepared in Example 1. The therapeutic efficacy was evaluated on the 10th day after implantation. The results are shown in Table 2.

[0124] The results showed that 10 days after implantation, the total effective rate of the sustained-release levofloxacin tear duct plug of the present invention for dry eye combined with acute dacryoductitis was 100%, and the total effective rate for dry eye combined with chronic dacryoductitis was 96%, with significant therapeutic effects and very significant statistical significance.

[0125] Table 2 Efficacy evaluation results

[0126]

[0127] The above ineffective cases were effective after re-implantation of P1 treatment, but because the patient's disease course was longer, the treatment time required was longer.

[0128] The sustained-release levofloxacin punctal plug prepared by the present invention has important clinical application value. It should be noted that the sustained-release levofloxacin punctal plug prepared by the present invention can effectively treat dry eye combined with acute and chronic dacryocystitis, dry eye combined with acute and chronic punctitis, and dry eye combined with acute and chronic dacryocystitis. However, the dry eye combined with acute and chronic dacryocystitis, dry eye combined with acute and chronic punctitis, and dry eye combined with acute and chronic dacryoductitis mentioned in the present invention are only commonly used to treat diseases. The present invention is not limited to application to these eye diseases. The sustained-release levofloxacin punctal plug of the present invention can be applied to any other suitable eye disease.

[0129] Finally, it should be noted that the above embodiments are intended only to illustrate the technical solutions of the present invention and do not constitute a limitation of the present invention. Although the present invention has been described in detail through the above embodiments, those skilled in the art may still make various changes in form and details based on the technical contents described in the Summary of the Invention and Examples without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A method for preparing a lacrimal duct plug for sustained-release levofloxacin, characterized in that: The following steps are involved: (1) dispersing levofloxacin, polyglycolide, chitosan, and polylysine in a solvent and mixing them uniformly, wherein the mass ratio of levofloxacin:polyglycolide:chitosan:polylysine is 0.5-3:15-40:12-50:0.2-3; (2) performing a cross-linking reaction at 45-55° C. for 5-15 hours, cooling, and drying to obtain a mixture; (3) The mixture obtained in step (2) is subjected to plasma treatment at 3-5.5 Pa for 10 s-2 min, with an Ar flow rate of 1-3 L / min and a power of 70-100 W, and then solidified to obtain a punctal plug for sustained release of levofloxacin.

2. The method for preparing the sustained-release levofloxacin punctal plug according to claim 1, wherein: In step (1), the mass ratio of levofloxacin:polyglycolide:chitosan:polylysine is 0.5-1.5:25-40:20-50:0.5-1.

3. The method for preparing the sustained-release levofloxacin punctal plug according to claim 1, wherein: In step (1), the solvent is acetic acid.

4. The method for preparing the sustained-release levofloxacin punctal plug according to claim 1, wherein: In step (2), the cross-linking reaction is carried out at 45-50°C.

5. The method for preparing the sustained-release levofloxacin punctal plug according to claim 1, wherein: In step (2), the cross-linking reaction is carried out for 5-10 h.

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

7. The method for preparing the sustained-release levofloxacin punctal plug according to claim 6, characterized in that: In step (3), when solidified and formed into a cylindrical shape, 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 punctal plug according to claim 6, characterized in that: In step (3), when the solidified material is formed into a cylindrical shape, at least one tear hole is opened along the central axis, and the diameter of the tear hole is 0.02 mm to 0.2 mm.

9. A sustained-release levofloxacin punctal plug, characterized in that: It is prepared according to the preparation method according to any one of claims 1 to 8.

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