Tear Duct Plug for Sustained Release of Tafluprost and Preparation Method Thereof

Abstract

The present invention discloses a preparation method of a lacrimal canaliculus plug for sustained release of tafluprost, which comprises the following steps: (1) dispersing tafluprost, poly(trimethylene carbonate), chitosan, and tri-lysine in a solvent and mixing evenly, wherein the mass ratio of tafluprost: poly(trimethylene carbonate): chitosan: tri-lysine is 0.001-0.5: 15-35: 10-35: 0.5-2; (2) carrying out a cross-linking reaction at 40-50 °C for 8-20 h, 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 s-5 min, and then curing and molding to obtain a lacrimal canaliculus plug for sustained release of tafluprost. The present invention uses tafluprost, poly(trimethylene carbonate), chitosan, and tri-lysine as raw materials for cross-linking reaction, and then the lacrimal canaliculus plug for sustained release of tafluprost prepared by plasma treatment can reduce the frequency of using antibiotic drugs or eliminate the need to use antibiotic drugs, with good patient compliance, good comfort, good biocompatibility, short-term degradation, small side effects, good water-swellable performance, not easy to fall off, reducing intraocular pressure while treating dry eye, and low corneal toxicity.

Description

Technical Field

[0001] The present invention relates to the field of medical materials, and particularly to a lacrimal canal plug for sustained release of tafluprost and a preparation method thereof. Background Art

[0002] Dry eye is a general term for a variety of diseases caused by any reason resulting in abnormal quality or quantity of tears or abnormal kinetics, leading to a decrease in the stability of the tear film, accompanied by eye discomfort and characteristics of ocular surface tissue lesions. Common symptoms include dry eyes, easy fatigue, itchy eyes, foreign body sensation, burning pain, viscous secretions, fear of wind, photophobia, and high sensitivity to external stimuli. At present, it is found that a considerable number of patients suffer from dry eye combined with glaucoma or dry eye combined with ocular hypertension.

[0003] In recent years, more and more clinical applications have been made of lacrimal canal plugs or lacrimal duct plugs for treatment. By blocking the lacrimal duct, reducing the drainage of tears, re - establishing the balance of ocular surface tears, and improving the ocular surface environment, the symptoms and signs of dry eye can be alleviated. However, at present, for patients with dry eye combined with glaucoma or dry eye combined with ocular hypertension, it is necessary to administer antibiotic drugs multiple times separately. There is an urgent need to develop lacrimal canal plugs that can effectively treat dry eye combined with glaucoma, dry eye combined with ocular hypertension, etc. Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the present invention aims to provide a lacrimal canal plug for sustained release of tafluprost and a preparation method thereof. The lacrimal canal plug for sustained release of tafluprost prepared by the present invention can reduce the number of times of using antibiotic drugs or eliminate the need for using antibiotic drugs, with good patient compliance, good comfort, good biocompatibility, short - term degradation, small side effects, good water - swelling performance, not easy to fall off, reducing intraocular pressure while treating dry eye, and low corneal toxicity.

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

[0006] In the first aspect, the present invention provides a preparation method of a lacrimal canal plug for sustained release of tafluprost, comprising the following steps:

[0007] (1) Disperse tafluprost, poly(trimethylene carbonate), chitosan, and tri - lysine in a solvent and mix evenly, where the mass ratio of tafluprost∶poly(trimethylene carbonate)∶chitosan∶tri - lysine is 0.001 - 0.5∶15 - 35∶10 - 35∶0.5 - 2;

[0008] (2) Conduct a cross - linking reaction at 40 - 50 °C for 8 - 20 h, cool, and dry 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 and formed to obtain a lacrimal canaliculus plug for sustained release of tafluprost.

[0010] Preferably, in step (1), the mass ratio of tafluprost∶poly(trimethylene carbonate)∶chitosan∶trilysine is 0.001 - 0.02∶25 - 35∶20 - 35∶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 12 - 20 h.

[0014] Preferably, in step (3), the conditions of plasma treatment include a treatment pressure of 3 - 5 Pa, a treatment time of 30 s - 3 min, an Ar flow rate of 1 - 3 L / min, and a power of 50 - 90 W.

[0015] Preferably, in step (3), when solidified and formed into a cylinder, 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 cylinder, the diameter is 0.1 - 0.5 mm and the length is 0.5 - 3 mm.

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

[0018] In a second aspect, the present invention provides a lacrimal canaliculus plug for sustained release of tafluprost, which is prepared according to the above preparation method.

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

[0020] The present invention uses tafluprost, poly(trimethylene carbonate), chitosan, and trilysine as raw materials for cross-linking reaction. The lacrimal canaliculus plug for sustained release of tafluprost prepared by plasma treatment can reduce the frequency of using antibiotic drugs or eliminate the need for using antibiotic drugs. The patient compliance is good, the comfort is good, the biocompatibility is good, it degrades in the short term, has small side effects, can reduce intraocular pressure while treating dry eye, and has low corneal toxicity. Moreover, the inventor found that through plasma treatment, the lacrimal canaliculus plug for sustained release of tafluprost can obtain very good hydrophilicity and water swelling property, quickly swells in water, and can quickly swell in the lacrimal canaliculus within a few seconds after implantation, and then is fixed in the lacrimal canaliculus and is not easy to fall off.

[0021] The lacrimal canaliculus plug of sustained-release tafluprost prepared by the present invention has important clinical application value. It should be noted that the lacrimal canaliculus plug of sustained-release tafluprost prepared by the present invention can effectively treat dry eye syndrome combined with glaucoma or dry eye syndrome combined with ocular hypertension. However, the dry eye syndrome combined with glaucoma or dry eye syndrome combined with ocular hypertension mentioned in the present invention are only the diseases commonly treated by using the lacrimal canaliculus plug of sustained-release tafluprost prepared by the present invention. The present invention is not limited to the application to these ocular diseases. The lacrimal canaliculus plug of sustained-release tafluprost of the present invention can be applied to any other suitable ocular diseases.

[0022] The features and advantages of the present invention will be described in detail in the following specific implementation section. Specific implementation mode

[0023] In order to make the purpose, technical solution and beneficial effects of the present invention clearer, the present invention will be further described in detail below in combination with specific implementation modes. It should be understood that the specific examples described in the following implementation modes of the present invention are only illustrative descriptions of the specific implementation modes of the present invention, aiming to explain the present invention and not to limit the present invention.

[0024] In the ranges disclosed herein, the endpoints and any values are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. The aforementioned values close to these ranges or values refer to values such as specific point values ±10%. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and a single point value, and between single point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein. In the description of the present application, unless otherwise specified, the meaning of similar terms such as "multiple / various" is two / kinds or more than two / kinds. In addition, the terms "include", "comprise" and any variations thereof are intended to cover non-exclusive inclusion.

[0025] In the first aspect, the present invention provides a preparation method of a lacrimal canaliculus plug of sustained-release tafluprost, comprising the following steps:

[0026] (1) Disperse tafluprost, polytrimethylene carbonate, chitosan, and tri-lysine in a solvent and mix evenly, wherein the mass ratio of tafluprost∶polytrimethylene carbonate∶chitosan∶tri-lysine is 0.001 - 0.5∶15 - 35∶10 - 35∶0.5 - 2;

[0027] (2) Carry out a cross-linking reaction at 40 - 50 °C for 8 - 20 h, cool, and dry 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 s - 5 min, and then cured and molded to obtain a lacrimal canaliculus plug for sustained release of tafluprost.

[0029] In the present invention, tafluprost should be understood in a broad sense and also includes its analogs or derivatives. Tafluprost mainly functions to reduce intraocular pressure.

[0030] Currently, tafluprost eye drops are mainly used for treatment. However, it has been found in existing studies that tafluprost eye drops contain preservatives to varying degrees, which has become the main cause of corneal toxicity in patients after long-term use (usually more than 1 year). The manifestations are superficial punctate corneal epithelial lesions, which are more severe in the nasal inferior part. With the prolongation of the medication time and the intensification of the toxicity degree, the punctate staining can be diffuse or patchy. In addition, tafluprost will also cause corneal toxicity to a certain extent. However, the lacrimal canaliculus plug of the present invention does not contain preservative components, so it can greatly reduce corneal toxicity and has low corneal toxicity.

[0031] In the present invention, the molecular weight of poly(trimethylene carbonate) can be selected within a wide range. Preferably, in order to enable the lacrimal canaliculus plug for sustained release of tafluprost to further reduce the number of times of using antibiotic drugs or eliminate the need for using antibiotic drugs, with good patient compliance, good comfort, good biocompatibility, small side effects, short-term degradation, good water-swellable performance, and not easy to fall off, the weight-average molecular weight of poly(trimethylene carbonate) is 10,000 - 100,000.

[0032] 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 lacrimal canaliculus plug for sustained release of tafluprost to further reduce the number of times of using antibiotic drugs or eliminate the need for using antibiotic drugs, with good patient compliance, good comfort, good biocompatibility, small side effects, short-term degradation, good water-swellable performance, and not easy to fall off, the weight-average molecular weight of chitosan is 50,000 - 150,000.

[0033] It should be noted that although strictly speaking in the medical professional sense, the lacrimal canaliculus is part of the lacrimal passage structure, in reality, when applied, the medical professional meanings of "lacrimal canaliculus" and "lacrimal passage" are not necessarily used strictly and normatively. Therefore, the "lacrimal canaliculus plug" in the present invention should be understood in a broad sense, that is, the "lacrimal canaliculus plug" is equivalent to the "lacrimal passage", so the "lacrimal canaliculus plug" in the present invention is equivalent to the "lacrimal passage plug".

[0034] The mechanical strength of the canalicular plug is small and it is easy to fall off. If the mechanical strength is large, there is an easy foreign body sensation and it is not comfortable enough. This not only is not conducive to the exertion of the curative effect, but also easily produces adverse reactions. In the present invention, the use of poly(trimethylene carbonate) in combination with other raw materials such as chitosan can not only enable the canalicular plug to have a suitable mechanical strength and good comfort; but also enable the canalicular plug to have good biocompatibility, water swelling property, and small side effects; moreover, using poly(trimethylene carbonate) and chitosan as the main raw materials can crosslink well and promote the slow release of tafluprost, the release rate is more stable, which is conducive to the exertion of the curative effect, and has an anti-inflammatory effect.

[0035] In the present invention, the type of solvent can be selected within a wide range, as long as it can dissolve tafluprost, poly(trimethylene carbonate), chitosan, and tri-lysine. Preferably, in order to make the solvent more easily disperse tafluprost, poly(trimethylene carbonate), chitosan, and tri-lysine, the solvent is acetic acid (should be understood in a broad sense, such as an aqueous acetic acid solution with a molar concentration of 3%-10%). In the present invention, the amount of the solvent can be selected within a wide range.

[0036] In the present invention, the method of dispersion and uniform mixing can be selected within a wide range. In some preferred embodiments, in order to make the canalicular plug for sustained release of tafluprost release tafluprost better and the sustained release more stable, ultrasonic dispersion is used, the ultrasonic dispersion time is 15-20 min, and the ultrasonic power is 300-350 W.

[0037] In the present invention, the crosslinking reaction can be carried out at 40-50 °C for 8-20 h to obtain a canalicular plug for sustained release of tafluprost with good patient compliance, good comfort, good biocompatibility, small side effects, and short-term degradation. In the present invention, tri-lysine plays a very good crosslinking role. In some preferred embodiments, in step (2), the crosslinking reaction is carried out at 45-50 °C. In some preferred embodiments, in step (2), the crosslinking reaction is carried out for 12-20 h.

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

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

[0040] In the present invention, the conditions for plasma treatment are to perform plasma treatment for 30 s to 5 min at a pressure less than 6 Pa. In some preferred embodiments, in order to enable the prepared lacrimal canal plug for sustained release of tafluprost to further reduce the frequency of using antibiotic drugs or eliminate the need for using antibiotic drugs, with good patient compliance, water swelling, good comfort, good biocompatibility, low side effects, and short-term degradation, in step (3), the conditions for plasma treatment include a treatment pressure of 3 - 5 Pa, a treatment time of 30 s to 3 min, an Ar flow rate of 1 - 3 L / min, and a power of 50 - 90 W.

[0041] In the present invention, the inventors unexpectedly found that after tafluprost, poly(trimethylene carbonate), chitosan, and tri-lysine are cross-linked to obtain a mixture, plasma treatment can endow the lacrimal canal plug for sustained release of tafluprost with very good hydrophilicity and water swelling property, rapidly swelling in water, and can rapidly swell in the lacrimal canal within seconds after implantation, and then be fixed in the lacrimal canal and not easily fall off. After implantation, the lacrimal canal plug can rapidly swell in the lacrimal canal, such as within 6 s, within 5 s, or within 4 s. When the lacrimal canal plug is cylindrical, the length or diameter of the lacrimal canal plug rapidly swells by at least 3 times, at least 4 times, at least 5 times, or at least 6 times after implantation.

[0042] In some preferred embodiments, in step (1), the mass ratio of tafluprost∶poly(trimethylene carbonate)∶chitosan∶tri-lysine is 0.001 - 0.02∶25 - 35∶20 - 35∶0.5 - 1.

[0043] In the present invention, preferably, in order to further improve the comfort when the lacrimal canal plug for sustained release of tafluprost is implanted into the lacrimal passage and is not easily dislodged, 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. More 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.

[0044] In the present invention, preferably, in step (3), when the solidification and molding is in a cylindrical shape, at least one tear drainage hole is drilled along the central axis direction. The position of the tear drainage hole can be centered on the central axis or around the central axis. The diameter of the tear drainage hole is 0.02 mm - 0.2 mm. This is beneficial for reducing the loss of tears to keep the eyeball moist, and at the same time, the tears can flow out through the through hole, reducing the accumulation and retention of tears, so that the lacrimal duct plug for sustained release of tafluprost can timely drain the excess tears, thereby reducing the related inflammation caused by the accumulation and retention of tears. Combining the above, using polytrimethylene carbonate and chitosan as the main raw materials is not likely to cause inflammation, and the lacrimal duct plug for sustained release of tafluprost of the present invention has a good anti-inflammatory effect. In the present invention, the tear drainage hole can be drilled after molding, or can be obtained through a mold or 3D printing during preparation.

[0045] In the present invention, "short-term degradation" generally refers to degradation within 60 days, such as degradation within 7 days, 15 days, 30 days, or 45 days.

[0046] In the present invention, "patient" should be understood in a broad sense, including animals such as mice, rabbits, dogs, cows, monkeys, etc. and humans.

[0047] In the second aspect, the present invention provides a lacrimal duct plug for sustained release of tafluprost, which is prepared according to the above 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 drugs and medicaments are all conventional commercially available products.

[0049] Example 1: Preparation example of the lacrimal duct plug for sustained release of tafluprost of the present invention

[0050] A lacrimal duct plug for sustained release of tafluprost, and its preparation method is as follows:

[0051] (1) Disperse 0.001 g of tafluprost, 25 g of polytrimethylene carbonate (weight average molecular weight is 20,000 - 50,000), 35 g of chitosan (weight average molecular weight is 50,000 - 100,000), and 0.6 g of trilysine in 100 ml of acetic acid aqueous solution (molar concentration is 5%), and then perform ultrasonic dispersion for 15 min with an ultrasonic power of 300 W to mix evenly;

[0052] (2) Carry out cross-linking reaction at 45 °C for 12 h, naturally cool to room temperature, and dry for 2 h under room temperature and normal pressure conditions to obtain a mixture;

[0053] (3) The mixture obtained in step (2) is subjected to plasma treatment at 4 Pa for 30 s, with the flow rate of Ar being 1 L / min and the power being 60 W. Then it is solidified into a cylinder with a diameter of 0.4 mm and a length of 1 mm, and a tear drainage hole with a diameter of 0.1 mm is drilled to obtain the lacrimal canaliculus plug P1 for sustained release of tafluprost.

[0054] The lacrimal canaliculus plug P1 for sustained release of tafluprost prepared in this example rapidly expands 6.4 times in diameter and 5.9 times in length within 4 s after contacting water. It has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0055] Example 2: Preparation example of the lacrimal canaliculus plug for sustained release of tafluprost of the present invention

[0056] A lacrimal canaliculus plug for sustained release of tafluprost, and its preparation method is as follows:

[0057] (1) 0.004 g of tafluprost, 35 g of polytrimethylene carbonate (weight-average molecular weight is 20,000 - 50,000), 25 g of chitosan (weight-average molecular weight is 50,000 - 100,000), and 1 g of trilysine are dispersed in 100 ml of acetic acid aqueous solution (molar concentration is 8%), and then ultrasonic dispersion is carried out for 20 min with an ultrasonic power of 300 W to mix evenly;

[0058] (2) Crosslinking reaction is carried out at 50 °C for 12 h, and it is naturally cooled to room temperature and dried at room temperature and normal pressure for 1.5 h to obtain a mixture;

[0059] (3) The mixture obtained in step (2) is subjected to plasma treatment at 3 Pa for 1 min, with the flow rate of Ar being 2 L / min and the power being 50 W. Then it is solidified into a cylinder with a diameter of 0.4 mm and a length of 1 mm, and a tear drainage hole with a diameter of 0.1 mm is drilled to obtain the lacrimal canaliculus plug P2 for sustained release of tafluprost.

[0060] The lacrimal canaliculus plug P2 for sustained release of tafluprost prepared in this example rapidly expands 6.5 times in diameter and 5.7 times in length within 5 s after contacting water. It has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0061] Example 3: Preparation example of the lacrimal canaliculus plug for sustained release of tafluprost of the present invention

[0062] A lacrimal canaliculus plug for sustained release of tafluprost, and its preparation method is as follows:

[0063] (1) Dissolve 0.002 g of tafluprost, 30 g of poly(trimethylene carbonate) (weight-average molecular weight of 20,000 - 50,000), 20 g of chitosan (weight-average molecular weight of 50,000 - 100,000), and 0.8 g of tri-lysine in 100 ml of acetic acid aqueous solution (molar concentration of 3%), then perform ultrasonic dispersion for 16 min with an ultrasonic power of 350 W, and mix evenly;

[0064] (2) Conduct a cross-linking reaction at 45 °C for 15 h, naturally cool to room temperature, and dry for 2 h under room temperature and normal pressure conditions to obtain a mixture;

[0065] (3) Perform plasma treatment on the mixture obtained in step (2) at 5 Pa for 50 s, with an Ar flow rate of 1.5 L / min and a power of 70 W, then cure it into a cylinder with a diameter of 0.5 mm and a length of 0.8 mm, and drill a tear drainage hole with a diameter of 0.1 mm to obtain the lacrimal canal plug P3 for sustained release of tafluprost.

[0066] The lacrimal canal plug P3 for sustained release of tafluprost prepared in this example rapidly expands 6.3 times in diameter and 5.5 times in length within 5 s after contacting water, has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0067] Example 4: Preparation example of the lacrimal canal plug for sustained release of tafluprost of the present invention

[0068] A lacrimal canal plug for sustained release of tafluprost, and its preparation method is as follows:

[0069] (1) Dissolve 0.006 g of tafluprost, 32 g of poly(trimethylene carbonate) (weight-average molecular weight of 20,000 - 50,000), 28 g of chitosan (weight-average molecular weight of 50,000 - 100,000), and 0.7 g of tri-lysine in 100 ml of acetic acid aqueous solution (molar concentration of 5%), then perform ultrasonic dispersion for 15 min with an ultrasonic power of 310 W, and mix evenly;

[0070] (2) Conduct a cross-linking reaction at 50 °C for 12 h, naturally cool to room temperature, and dry for 2.5 h under room temperature and normal pressure conditions to obtain a mixture;

[0071] (3) Perform plasma treatment on the mixture obtained in step (2) at 3.5 Pa for 1 min, with an Ar flow rate of 2 L / min and a power of 90 W, then cure it into a cylinder with a diameter of 0.4 mm and a length of 1 mm, and drill a tear drainage hole with a diameter of 0.1 mm to obtain the lacrimal canal plug P4 for sustained release of tafluprost, which is not easy to fall off.

[0072] The lacrimal canaliculus plug P4 of sustained-release tafluprost prepared in this example rapidly expands 5.9 times in diameter and 5.2 times in length within 5 s after contacting water, has good comfort, good biocompatibility, few side effects, is not easily detached, and degrades within 15 days.

[0073] Example 5: Preparation example of the lacrimal canaliculus plug of the sustained-release tafluprost of the present invention

[0074] A lacrimal canaliculus plug of sustained-release tafluprost, and its preparation method is as follows:

[0075] (1) Disperse 0.008 g of tafluprost, 31 g of polytrimethylene carbonate (weight-average molecular weight is 20,000 - 50,000), 29 g of chitosan (weight-average molecular weight is 50,000 - 100,000), and 0.6 g of trilysine in 100 ml of acetic acid aqueous solution (molar concentration is 5%), then perform ultrasonic dispersion for 18 min with an ultrasonic power of 350 W, and mix evenly;

[0076] (2) Carry out crosslinking reaction at 48 °C for 15 h, naturally cool to room temperature, and dry for 1 h under room temperature and normal pressure conditions to obtain a mixture;

[0077] (3) Perform plasma treatment on the mixture obtained in step (2) for 1 min at 5 Pa, with an Ar flow rate of 2.5 L / min and a power of 80 W, then solidify it into a cylinder with a diameter of 0.4 mm and a length of 1.2 mm, and drill a tear drainage hole with a diameter of 0.1 mm to obtain the lacrimal canaliculus plug P5 of sustained-release tafluprost.

[0078] The lacrimal canaliculus plug P5 of sustained-release tafluprost prepared in this example rapidly expands 6.1 times in diameter and 5.7 times in length within 6 s after contacting water, has good comfort, good biocompatibility, few side effects, is not easily detached, and degrades within 15 days.

[0079] Example 6: Preparation example of the lacrimal canaliculus plug of the sustained-release tafluprost of the present invention

[0080] A lacrimal canaliculus plug of sustained-release tafluprost, and its preparation method is as follows:

[0081] (1) Disperse 0.007 g of tafluprost, 33 g of polytrimethylene carbonate (weight-average molecular weight is 20,000 - 50,000), 27 g of chitosan (weight-average molecular weight is 50,000 - 100,000), and 0.7 g of trilysine in 100 ml of acetic acid aqueous solution (molar concentration is 5%), then perform ultrasonic dispersion for 15 min with an ultrasonic power of 340 W, and mix evenly;

[0082] (2) Crosslinking reaction is carried out at 50 °C for 15 h, then naturally cooled to room temperature, and dried under room temperature and normal pressure conditions for 2 h to obtain a mixture;

[0083] (3) The mixture obtained in step (2) is subjected to plasma treatment at 4 Pa for 50 s, the flow rate of Ar is 1.6 L / min, and the power is 90 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and a tear drainage hole with a diameter of 0.1 mm is drilled to obtain the lacrimal duct plug P6 for sustained release of tafluprost.

[0084] The lacrimal duct plug P6 for sustained release of tafluprost prepared in this example rapidly expands 5.8 times in diameter and 5.5 times in length within 5 s after contacting water, has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0085] Example 7: Preparation example of the lacrimal duct plug for sustained release of tafluprost of the present invention

[0086] A lacrimal duct plug for sustained release of tafluprost, and its preparation method is as follows:

[0087] (1) 0.005 g of tafluprost, 31 g of polytrimethylene carbonate (weight average molecular weight is 20,000 - 50,000), 29 g of chitosan (weight average molecular weight is 50,000 - 100,000), and 1 g of trilysine are dispersed in 100 ml of acetic acid aqueous solution (molar concentration is 5%), and then ultrasonic dispersion is carried out for 15 min, the ultrasonic power is 300 W, and the mixture is mixed evenly;

[0088] (2) Crosslinking reaction is carried out at 45 °C for 20 h, then naturally cooled to room temperature, and dried under room temperature and normal pressure conditions for 2 h to obtain a mixture;

[0089] (3) The mixture obtained in step (2) is subjected to plasma treatment at 3 Pa for 2 min, the flow rate of Ar is 1 L / min, and the power is 60 W, and then solidified into a cylindrical shape with a diameter of 0.4 mm and a length of 1.2 mm, and a tear drainage hole with a diameter of 0.1 mm is drilled to obtain the lacrimal duct plug P7 for sustained release of tafluprost.

[0090] The lacrimal duct plug P7 for sustained release of tafluprost prepared in this example rapidly expands 6.6 times in diameter and 5.9 times in length within 5 s after contacting water, has good comfort, good biocompatibility, few side effects, is not easy to fall off, and degrades within 15 days.

[0091] Example 8: Preparation example of the lacrimal duct plug for sustained release of tafluprost of the present invention

[0092] A lacrimal duct plug for sustained release of tafluprost, and its preparation method is as follows:

[0093] (1) Dissolve 0.0016 g of tafluprost, 37 g of poly(trimethylene carbonate) (weight-average molecular weight of 20,000 - 50,000), 33 g of chitosan (weight-average molecular weight of 50,000 - 100,000), and 0.9 g of tri-lysine in 100 ml of acetic acid aqueous solution (molar concentration of 5%), then perform ultrasonic dispersion for 15 min with an ultrasonic power of 350 W and mix evenly;

[0094] (2) Conduct a cross-linking reaction at 50 °C for 15 h, naturally cool to room temperature, and dry for 1 h under room temperature and normal pressure conditions to obtain a mixture;

[0095] (3) Subject the mixture obtained in step (2) to plasma treatment at 3 Pa for 3 min, with an Ar flow rate of 1 L / min and a power of 90 W, then solidify it into a cylindrical shape with a diameter of 0.4 mm and a length of 1 mm, and drill a drainage hole with a diameter of 0.1 mm to obtain the lacrimal canal plug P8 for sustained release of tafluprost.

[0096] The lacrimal canal plug P8 for sustained release of tafluprost prepared in this example rapidly expands 6.2 times in diameter and 5.6 times in length within 5 s after contacting water, has good comfort, good biocompatibility, few side effects, is not easily detached, and degrades within 15 days.

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

[0098] The raw materials do not contain poly(trimethylene carbonate), and other steps are the same as in Example 1 to obtain the lacrimal canal plug DPI for sustained release of tafluprost.

[0099] The lacrimal canal plug DP1 for sustained release of tafluprost prepared in this comparative example is too soft in texture, which is not conducive to mechanical processing, is easily detached, and the release of tafluprost is unstable. It can be seen that adding poly(trimethylene carbonate) in the example can obtain suitable mechanical strength and good mechanical processing performance.

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

[0101] Do not perform plasma treatment, and other steps are the same as in Example 1 to obtain the lacrimal canal plug DP2 for sustained release of tafluprost.

[0102] The lacrimal canal plug DP2 for sustained release of tafluprost prepared in this comparative example has a slow swelling rate when contacting water. Its diameter expands 4.2 times and its length expands 3.6 times in 10 hours.

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

[0104] Do not perform ultrasonic dispersion, and other steps are the same as in Example 1 to obtain the lacrimal canal plug DP3 for sustained release of tafluprost.

[0105] The sustained-release of tafluprost in the lacrimal canaliculus plug DP3 prepared in this comparative example is not stable enough.

[0106] Example 9: Release experiment of the lacrimal canaliculus plug for sustained-release tafluprost of the present invention

[0107] Simulated tears were prepared according to the composition of human tears. The lacrimal canaliculus plugs prepared in Examples 1-8 and Comparative Examples 1-3 were respectively immersed in 5 ml of simulated tears, and the concentration of tafluprost in the simulated tears was measured. The cumulative release rate of tafluprost was calculated based on the concentration of tafluprost. The cumulative release rate of tafluprost is shown in Table 1.

[0108] Table 1 Cumulative release rate of tafluprost

[0109]

[0110] As can be seen from Table 1 above, the lacrimal canaliculus plugs for sustained-release tafluprost prepared in the above examples of the present invention can well promote the slow release of tafluprost, and the release rate is stable. However, the release of tafluprost in DP1 of Comparative Example 1 has been unstable. For DP2 in Comparative Example 2, due to the slow water swelling rate, the release amount of tafluprost in the first few hours is small and unstable, and then it tends to be stable. The release of tafluprost in Comparative Example 3 has been unstable.

[0111] Example 10: Efficacy of the present invention for dry eye combined with glaucoma

[0112] The efficacy evaluation criteria are as follows: symptom disappearance is 0 points, mild symptoms are 1 point, moderate symptoms are 2 points, and severe symptoms are 3 points. Marked effect: symptoms basically disappear, and the score reduction ≥ 80%; Effective: symptoms are significantly improved, 80% < score reduction ≤ 30%; Ineffective: symptoms are not significantly improved. The total effective rate = (marked effect + effective) / total number of cases × 100%.

[0113] 100 patients (aged 18 - 59 years old) with dry eye combined with glaucoma were selected and implanted with the lacrimal canaliculus plug P1 for sustained-release tafluprost prepared in Example 1. The efficacy was evaluated on the 10th day after implantation, and the results are shown in Table 2.

[0114] The results show that: 10 days after implantation, the total effective rate of the lacrimal canaliculus plug for sustained-release tafluprost of the present invention for dry eye combined with glaucoma is 98%, and the efficacy is significant, with very significant statistical significance.

[0115] Example 11: Efficacy of the present invention for dry eye combined with ocular hypertension

[0116] The efficacy evaluation criteria are as follows: symptom disappearance is scored 0, mild symptoms are scored 1, moderate symptoms are scored 2, and severe symptoms are scored 3. Marked effect: symptoms basically disappear, and the score reduction is ≥80%; Effective: symptoms are significantly improved, and 80% < score reduction ≤ 30%; Ineffective: symptoms show no obvious improvement. The total effective rate = (marked effect + effective) / total number of cases × 100%.

[0117] 100 patients (aged 18 - 59 years old) with dry eye syndrome combined with ocular hypertension were selected and implanted with the lacrimal canaliculus plug P1 of sustained-release tafluprost prepared in Example 1. The efficacy was evaluated on the 10th day after implantation, and the results are shown in Table 2.

[0118] The results showed that: 10 days after implantation, the total effective rate of the lacrimal canaliculus plug of sustained-release tafluprost of the present invention for dry eye syndrome combined with ocular hypertension was 99%, with a significant efficacy and very significant statistical significance.

[0119] Table 2 Efficacy evaluation results

[0120]

[0121] The above ineffective cases became effective after being implanted with P1 for treatment again because the patient had a longer disease course and required a longer treatment time.

[0122] The lacrimal canaliculus plug of sustained-release tafluprost prepared in the present invention has important clinical application value. It should be noted that the tafluprost sustained-release lacrimal canaliculus prepared in the present invention can effectively treat dry eye syndrome combined with glaucoma and dry eye syndrome combined with ocular hypertension. However, the dry eye syndrome combined with glaucoma and dry eye syndrome combined with ocular hypertension mentioned in the present invention are only the diseases commonly treated. However, the present invention is not limited to the application to these eye diseases. The lacrimal canaliculus plug of sustained-release tafluprost of the present invention can be applied to any other suitable eye diseases.

[0123] 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 to 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 details according to the technical content described in the content part and the embodiment part without departing from the spirit and scope of the present invention defined by the appended claims.

Claims

1. A method for preparing a lacrimal canaliculus plug for sustained release of tafluprost, characterized in that, It includes the following steps: (1) Disperse tafluprost, poly(trimethylene carbonate), chitosan, and tri-lysine in a solvent and mix evenly, where the mass ratio of tafluprost: poly(trimethylene carbonate): chitosan: tri-lysine is 0.001 - 0.5: 15 - 35: 10 - 35: 0.5 - 2; (2) Conduct a cross-linking reaction at 40 - 50 °C for 8 - 20 h, cool, and dry to obtain a mixture; (3) Subject the mixture obtained in step (2) to plasma treatment for 30 s - 5 min under less than 6 Pa, and then cure and mold it to obtain a lacrimal canal plug for sustained release of tafluprost; In step (3), the conditions of the plasma treatment include a treatment pressure of 3 - 5 Pa, a treatment time of 30 s - 3 min, an Ar flow rate of 1 - 3 L / min, and a power of 50 - 90 W.

2. The preparation method of the lacrimal canaliculus plug for sustained release of tafluprost according to claim 1, wherein, In step (1), the mass ratio of tafluprost: poly(trimethylene carbonate): chitosan: tri-lysine is 0.001 - 0.02: 25 - 35: 20 - 35: 0.5 - 1.

3. The preparation method of the lacrimal canaliculus plug for sustained release of tafluprost according to claim 1, wherein, In step (1), the solvent is acetic acid.

4. The preparation method of the lacrimal canal plug for sustained release of tafluprost according to claim 1, characterized in that, In step (2), conduct the cross-linking reaction at 45 - 50 °C.

5. The preparation method of the lacrimal canaliculus plug for sustained release of tafluprost according to claim 1, wherein, In step (2), the cross-linking reaction is carried out for 12 - 20 h.

6. The preparation method of the lacrimal canaliculus plug for sustained release of tafluprost according to claim 1, characterized in that, In step (3), when cured and molded into a cylinder, the diameter is 0.1 - 1 mm and the length is 0.5 - 10 mm.

7. The preparation method of the lacrimal canaliculus plug for sustained release of tafluprost according to claim 6, characterized in that, In step (3), when cured and molded into a cylinder, the diameter is 0.1 - 0.5 mm and the length is 0.5 - 3 mm.

8. The preparation method of the lacrimal canaliculus plug for sustained release of tafluprost according to claim 6, characterized in that, In step (3), when cured and molded into a cylinder, at least one tear drainage hole is drilled along the central axis direction, and the diameter of the tear drainage hole is 0.02 mm - 0.2 mm.

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

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