Punctal plug comprising shape memory polymer and manufacturing method thereof

Abstract

The present invention relates to: a punctal plug comprising a shape memory polymer; and a manufacturing method thereof. More specifically, the present invention relates to: a punctal plug made of a shape memory polymer, which includes a copolymer of lactone and glycidyl methacrylate, and located in a punctal opening of a lacrimal duct to prevent lacrimal fluid from flowing in the lacrimal duct; and a manufacturing method thereof. The punctal plug according to the present invention is made of a material having biocompatibility and shape memory properties, and thus has the advantages of being easy to insert and simple to fix, and being easy to remove by a head formed at the top of an insert. In addition, the copolymer of lactone and glycidyl methacrylate is appropriately blended, and thus the punctal plug can be applied to the lacrimal duct without causing a foreign body sensation. Moreover, the punctal plug can block the punctum without becoming dislodged even under everyday pressure generated by sneezing and the like, and thus can be effectively used in punctal occlusion procedures.

Description

A puncture plug comprising a shape memory polymer and a method for manufacturing the same

[0001] The present invention relates to a punctal plug comprising a shape memory polymer and a method for manufacturing the same, and more particularly, to a punctal plug comprising a copolymer of caprolactone and glycidyl methacrylate positioned within a punctal opening of a lacrimal duct to prevent lacrimal fluid from flowing into the lacrimal duct, and a method for manufacturing the same.

[0002]

[0003] Dry eye is an eye disease that occurs when the ocular surface is damaged due to insufficient tears or excessive evaporation of tears, which causes an imbalance in the composition of the tears, causing irritation symptoms such as eye stinging, irritation, foreign body sensation, and dryness. It is caused by aging, diseases such as rheumatoid arthritis and diabetes, chronic conjunctivitis, thyroid disease, decreased female hormones, medication, dry environment, and irritation from smoke or dust. If dry eye worsens, it can cause post-nasal drip, sinusitis, allergies, headaches, and snoring.

[0004] Treatments for dry eye include artificial tear drops, eyelid cleansing, and punctal occlusion. Among these, surgical punctal occlusion, also known as plug insertion, involves inserting a punctal plug, a device designed to prevent tear outflow, into the punctal opening.

[0005] Punctal occlusion is a simple procedure, so it can be easily performed when dry eye persists for a long time or symptoms are severe. However, in patients with short tear ducts, the punctal plug may not be properly seated within the tear duct, causing it to dislodge through the punctal opening or causing a foreign body sensation.

[0006] To secure a punctal plug within the tear duct, prior art such as US 2012-0245539 A1 and US 6629533 B1 propose designs for fixation such as wedges or anchoring arms in the shape of the punctal plug, and prior art such as US 2009-0264861 A1 and US 2006-0074370 A1 propose methods of using a material such as hydrogel, a hydrophilic material that swells in tears, in the body.

[0007] However, since the punctum and tear duct are different for each individual undergoing punctal occlusion surgery, it is difficult to insert and fix the punctal plug, and in the case of swelling materials, there is a problem that the swelling of the material in the tear duct causes it to become constricted with the tissues inside the body, making it difficult to remove.

[0008] Accordingly, the inventors of the present invention have developed a shape memory polymer punctal plug that is easy to insert, fix, and remove by taking note of the problems of the prior art, and have confirmed that the punctal plug is comfortably placed in the tear duct without deformation during the procedure due to its shape memory characteristics, and that the punctal plug does not come off even under high pressure in the nasal and oral cavities, such as when sneezing, and blocks the punctum, thereby allowing tears to remain in the eye for a long time, thereby completing the present invention.

[0009]

[0010] The purpose of the present invention is to provide a novel punctal plug manufactured from a polymer compound having biocompatibility and shape memory properties, and a method for manufacturing the same.

[0011] To achieve the above object, the present invention provides a puncture plug comprising a shape memory polymer comprising a copolymer of a lactone monomer and glycidyl methacrylate.

[0012] In the present invention, the copolymer may have a linear or multi-arm structure.

[0013] In the present invention, the copolymer is

[0014] A compound represented by the following chemical formula (1):

[0015] Chemical formula (1)

[0016]

[0017] In the above chemical formula (1),

[0018] R1, R2 and R3 are each independently hydrogen (H) or an alkyl group having 1 to 6 carbon atoms,

[0019] m and n are integers from 1 to 20, independently of each other,

[0020] A, B1 and B2 are independently oxygen (O) or sulfur (S),

[0021] x and y represent the mole % of repeating units,

[0022] x+y is 100, and x is between 80 and 95;

[0023] A compound represented by the following chemical formula (2):

[0024] Chemical formula (2)

[0025]

[0026] In the above chemical formula (2),

[0027] x is an integer from 1 to 20,

[0028] m and n represent the mole % of repeating units,

[0029] m+n is 100, and m is between 80 and 96; or

[0030] A compound represented by the following chemical formula (3):

[0031] Chemical formula (3)

[0032]

[0033] In the above chemical formula (3),

[0034] x and y are integers from 1 to 20, independently of each other,

[0035] m and n represent the mole % of repeating units,

[0036] m+n is 100, and m is between 70 and 99;

[0037] In the present invention, the shape memory polymer may be a copolymer of chemical formula (1); a copolymer of chemical formula (2) or a copolymer of chemical formula (3); and a crosslinked polycaprolactone.

[0038] In the present invention, the shape memory polymer may be a crosslinked copolymer of chemical formula (1): a copolymer of chemical formula (2) or a copolymer of chemical formula (3): polycaprolactone mixed in a weight ratio of 10:6 to 8:0.5 to 1.

[0039] In the present invention, the shape memory polymer may be a crosslinked copolymer of chemical formula (1): a copolymer of chemical formula (2) or a copolymer of chemical formula (3): polycaprolactone mixed in a weight ratio of 57:38:5.

[0040] In the present invention, the shape memory polymer may be a copolymer of chemical formula (1); a copolymer of chemical formula (2) or a copolymer of chemical formula (3); and a polycaprolactone that is thermally crosslinked or photocrosslinked.

[0041] In the present invention, a copolymer of the chemical formula (1); a copolymer of the chemical formula (2) or a copolymer of the chemical formula (3); And polycaprolactone may be crosslinked by at least one selected from the group consisting of potassium persulfate, ammonium persulfate, benzoyl peroxide, diauryl peroxide, dicumyl peroxide, hydrogen peroxide, azobisisobutuyronitrile, Irgacure, Darocure, LAP (lithium phenyl-2,4,6-trim ethylbenzoylphosphinate), TPO (diphenyl(2,4,6-trimethylbenzoyl)phosphine), TPO-L (ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate).

[0042] In the present invention, the shape memory polymer has biocompatibility and may have a shape restoring force of 50% or more at a temperature of 30 to 60°C.

[0043] In the present invention, the puncture plug may have a structure including an insert that is inserted into and fixed to the puncture and a head formed at the upper end of the insert with an outer diameter larger than the outer diameter of the insert.

[0044] In the present invention, the point plug may additionally include a groove formed into the head as a groove for tool connection.

[0045] The present invention also provides a method for manufacturing a puncture plug comprising the following steps:

[0046] (a) a step of adding a crosslinking agent to a copolymer of caprolactone and glycidyl methacrylate and then mixing them;

[0047] (b) A step of manufacturing a leak plug by injecting the mixture into a mold and then crosslinking it.

[0048] In the present invention, the step (a) may be a step of adding a crosslinking agent to the copolymer of the chemical formula (1); the copolymer of the chemical formula (2) or the copolymer of the chemical formula (3); and polycaprolactone and mixing them.

[0049] In the present invention, the copolymer of the chemical formula (1): the copolymer of the chemical formula (2) or the copolymer of the chemical formula (3): polycaprolactone may be mixed and crosslinked in a weight ratio of 10:6 to 8:0.5 to 1.

[0050] In the present invention, the copolymer of the chemical formula (1): the copolymer of the chemical formula (2) or the copolymer of the chemical formula (3): polycaprolactone may be mixed and crosslinked in a weight ratio of 57:38:5.

[0051] In the present invention, the crosslinking agent is Iragcure 2959, and may be added in an amount of 0.1 to 5 wt% relative to the copolymer.

[0052] In the present invention, the step (b) may be crosslinked by irradiating UV for 100 to 1000 seconds.

[0053] The punctal plug according to the present invention is manufactured from a material having biocompatibility and shape memory properties, so it is easy to insert and fix, and has the advantage of being easily removed by the head formed at the top of the insert. In addition, the copolymer of caprolactone and glycidyl methacrylate is appropriately mixed, so that the punctal plug can be applied to the tear duct without a foreign body sensation, and the punctal plug can block the punctum without detachment even under everyday pressure such as when sneezing, so that it can be effectively used in punctal occlusion procedures.

[0054]

[0055] FIG. 1a is a front design drawing showing the structure of a puncture plug having shape memory characteristics according to one aspect of the present invention, and FIG. 1b is a puncture plug manufactured according to the above design drawing.

[0056] Figure 2 is a result showing the shape restoring force according to the deformation ratio of a point plug having shape memory characteristics according to one aspect of the present invention.

[0057] FIG. 3 is a photograph showing the shape recovery ability within a microtube of a puncture plug having shape memory characteristics according to one embodiment of the present invention.

[0058] Figure 4 shows the results of analyzing the tear flow properties of a punctal plug having shape memory characteristics according to one embodiment of the present invention.

[0059]

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art.

[0061]

[0062] In the present invention, it should be understood that terms such as “include” or “have” are intended to specify the presence of a feature, number, step, operation, component, part or combination thereof described in the specification, but do not exclude in advance the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, parts or combinations thereof.

[0063]

[0064] In the numerical ranges described in this specification, “within” is used to mean including (above and below) both critical ranges, and when both critical ranges are not included, the numerical ranges are described as “exceeding” and “below.” The term “about” used in the numerical values ​​in the present invention is used to mean including a range that is expected to exhibit substantially the same effect as the numerical values ​​described by those of ordinary skill in the art, and may be, for example, ±20%, ±10%, ±5%, etc. of the described numerical value, but is not limited thereto.

[0065]

[0066] Copolymer of lactone and glycidyl methacrylate

[0067] The nasal prosthesis according to the present invention can be manufactured using a copolymer [PCL-co-PGMA)] in which a lactone monomer (e.g., ε-caprolactone) and a glycidyl methacrylate monomer are polymerized.

[0068] The arrangement order of the lactone monomer and the glycidyl methacrylate monomer in the above copolymer is not particularly limited, and may be arranged alternately, randomly, or in blocks.

[0069] Additionally, a hydroxyl group or the like may be bonded to the terminal of the copolymer. A copolymer having a hydroxyl group bonded to the terminal can be produced by polymerization using an initiator having a hydroxyl group bonded to the terminal.

[0070]

[0071] 1. 2 arm copolymer

[0072] In one embodiment, the copolymer comprising a lactone monomer and glycidyl methacrylate used in the present invention may be a 2-arm copolymer, and the 2-arm copolymer may be represented by the following chemical formula (1):

[0073] Chemical formula (1)

[0074]

[0075] In the above chemical formula (1),

[0076] R1, R2 and R3 are each independently hydrogen (H) or an alkyl group having 1 to 6 carbon atoms,

[0077] m and n are integers from 1 to 20, independently of each other,

[0078] A, B1 and B2 are independently oxygen (O) or sulfur (S),

[0079] x and y represent the mole % of repeating units,

[0080] x+y is 100, and x is between 80 and 95.

[0081] Specifically, the 2-arm copolymer has the chemical formula (1):

[0082] R1, R2 and R3 are each independently hydrogen (H) or a methyl group (CH3-),

[0083] m and n are integers from 3 to 12, independently of each other,

[0084] A, B1 and B2 are all oxygen (O),

[0085] x and y represent the mole % of repeating units,

[0086] x+y=100, and x can be between 88 and 94.

[0087] More specifically,

[0088] R1, R2 and R3 are independently hydrogen (H),

[0089] m and n are integers from 5 to 6, independently of each other,

[0090] A, B1 and B2 are independently oxygen (O),

[0091] x and y represent the mole % of repeating units,

[0092] x+y=100, and x is between 88 and 94.

[0093] The above chemical formula (1) can be represented by the following chemical formula (1'):

[0094] Chemical formula (1')

[0095]

[0096] In the above chemical formula (1')

[0097] m and n are integers from 1 to 20, independently of each other,

[0098] x and y represent the mole % of repeating units,

[0099] x+y is 100, and x is between 80 and 95.

[0100] In the above chemical formula (1) or (1'), x and y represent the mol% of repeating units, x+y is 100, and x may be 80 to 95, or 88 to 94.

[0101] As a specific example, the 2-arm copolymer according to the present invention may be a 2-arm PCL-PGMA copolymer of ε-caprolactone monomer and glycidyl methacrylate.

[0102] In the present invention, the 2-arm copolymer is described in detail in Korean Patent No. 10-1906472 and Korean Patent No. 10-2355542, which are incorporated herein by reference in their entirety.

[0103]

[0104] 2. 4 arm copolymer

[0105] In another embodiment, the copolymer comprising a lactone monomer and glycidyl methacrylate used in the present invention may be a 4-arm copolymer, and the 4-arm copolymer may be represented by the following chemical formula (2):

[0106] Chemical formula (2)

[0107]

[0108] In the above chemical formula (2),

[0109] x is an integer from 1 to 20,

[0110] m and n represent the mole % of repeating units,

[0111] m+n is 100, and m is between 80 and 96.

[0112] In the chemical formula (2) of the present invention, x may be an integer from 2 to 10. In another specific example, x may be an integer from 2 to 9, an integer from 2 to 8, an integer from 2 to 7, an integer from 2 to 6, an integer from 2 to 5, an integer from 3 to 10, an integer from 3 to 9, an integer from 3 to 8, an integer from 3 to 7, an integer from 3 to 6, an integer from 3 to 5, an integer from 4 to 10, an integer from 4 to 9, an integer from 4 to 8, an integer from 4 to 7, an integer from 4 to 6, an integer from 4 to 5, an integer from 5 to 10, an integer from 5 to 9, an integer from 5 to 8, an integer from 5 to 7, or an integer from 5 to 6. Most specifically, a compound in which x in the chemical formula (2) is 5 may be used, but is not limited thereto.

[0113] More specifically, in the chemical formula (2), m and n represent the molar % of repeating units, m+n is 100, and m can be 70 to 99, 85 to 96, 88 to 96, 90 to 96, 92 to 96, or 94 to 96.

[0114] Here, mol% refers to the ratio of repeating units of m and n, and specifically, may refer to the mole fraction. For example, in PCL-co-PGMA, it may refer to the mole fraction of repeating units of PCL and PGMA.

[0115] As a specific example, the 4-arm copolymer according to the present invention may be a 4-arm PCL-PGMA copolymer of a caprolactone monomer and glycidyl methacrylate. The 4-arm PCL-PGMA may include a central carbon having four carbon-carbon bonding arms.

[0116] In the present invention, the 4-arm copolymer is described in detail in Korean Patent Publication No. 10-2021-0158356, which is incorporated herein by reference in its entirety.

[0117]

[0118] 3. 6 arm copolymer

[0119] In another embodiment, the copolymer comprising a lactone monomer and glycidyl methacrylate used in the present invention may be a 6-arm copolymer, and the 6-arm copolymer may be represented by the following chemical formula (3):

[0120] Chemical formula (3)

[0121]

[0122] In the above chemical formula (3),

[0123] x and y are integers from 1 to 20, independently of each other,

[0124] m and n represent the mole % of repeating units,

[0125] m+n is 100, and m is between 70 and 99.

[0126] More specifically, in the chemical formula (3), m and n represent the molar % of repeating units, m+n is 100, and m can be 70 to 99, 85 to 96, 88 to 96, 90 to 96, 92 to 96, or 94 to 96.

[0127] Here, mol% refers to the ratio of repeating units of m and n, and specifically, may refer to the mole fraction. For example, in PCL-co-PGMA, it may refer to the mole fraction of repeating units of PCL and PGMA.

[0128] The compound of the above chemical formula (3) can control the shape restoration temperature, etc. according to the amount of ε-caprolactone monomer and glycidyl methacrylate monomer constituting it.

[0129] More specifically, in the above chemical formula (3), x and y are each independently an integer from 1 to 20, which can be controlled by the carbon number of the lactone series monomer and the initiator in the step of synthesizing the compound of chemical formula (3).

[0130] For example, when epsilon caprolactone (ε-caprolactone) is used, x can be 3, and when dipentaerythritol is used, y can be 1. In addition, the number of x can be controlled by using monomers such as α-acetolactone, β-propiolactone, γ-butyrolactone, and δ-valerolactone instead of epsilon caprolactone (ε-CL), and the number of y can be controlled by using an initiator such as 6arm PEG instead of dipentaerythritol. In the present invention, x and y can be easily controlled by a person skilled in the art.

[0131] The compound of the present invention's chemical formula (3) can be prepared by reacting an α-acetolactone, β-propiolactone, γ-butyrolactone, δ-valerolactone or ε-caprolactone monomer with an acrylic monomer containing a glycidyl group and an initiator.

[0132] For example, the compound of the present invention's chemical formula (3) can be prepared by ring-opening polymerization of dipentaerythritol, caprolactone, and glycidyl methacrylate.

[0133] In this case, the reactivity can be improved by adding a catalyst or by adding a polymerization inhibitor together with or simultaneously with the initiator during the initial reaction when the polymerization conversion is almost zero, thereby inhibiting the reaction between temperature-sensitive glycidyl methacrylate groups.

[0134] The compound of the present invention's chemical formula (3) can be prepared by including a step of reacting dipentaerythritol, caprolactone, and glycidyl methacrylate. The reaction can be characterized as a ring-opening polymerization reaction. The reaction can be characterized as reacting in the presence of a catalyst selected from the group consisting of 1,5,7-triazabicyclo(4.4.0)dec-5-ene, tin(II)(2-ethylhexanoate), trimethylopropane tris(3-mercaptopropionate), and zinc succinate, but is not limited thereto.

[0135] In particular, it is preferable to use 1,5,7-Triazabicyclo(4.4.0)dec-5-ene as a catalyst, which can shorten the synthesis time of the compound, as a substance for inducing simultaneous ring-opening polymerization of two monomers (CL, GMA).

[0136] In the present invention, the reaction between methacrylate groups can be inhibited by adding an initiator and / or a polymerization inhibitor during the initial reaction, i.e., before adding glycidyl methacrylate.

[0137] In addition, the polymerization inhibitor plays a role in suppressing the exothermic reaction that occurs locally in the latter half of polymerization and eliminating unreacted residual radicals to terminate the reaction.

[0138] In this way, when the initiator and polymerization inhibitor are reacted with the monomers caprolactone and glycidyl methacrylate at about 110°C for about 6 hours, the ring structure in the monomers is opened, and a polycaprolactone-polyglycidyl methacrylate (6arm PCL-PGMA) copolymer having six arms is synthesized.

[0139] The above initiator may be characterized as being dipentaerythritol, and specifically, the present invention may be characterized as synthesizing a polycaprolactone-polyglycidyl methacrylate (6-arm PCL-PGMA) copolymer having six arms by the initial addition of the above initiator.

[0140] The polymerization inhibitor may be at least one selected from the group consisting of hydroquinone, hydroquinone monomethyl ether, p-benzoquinone, and phenothiazine, but is not limited thereto. Preferably, the polymerization inhibitor may be hydroquinone.

[0141] The method for producing a compound of chemical formula (3) may be characterized by reacting dipentaerythritol, caprolactone, and glycidyl methacrylate at 80 to 140°C, preferably 100 to 130°C, for example, at about 110°C.

[0142] In this case, if the synthesis of the compound of the chemical formula (3) of the present invention proceeds at a temperature below 100°C, the catalytic reaction may not proceed, and if the synthesis of the compound of the present invention proceeds at a temperature exceeding 130°C, the problem of the catalytic reaction rate decreasing may occur.

[0143] In a preferred embodiment, the polymerization mechanism of the compound of chemical formula (3) can be expressed as follows.

[0144]

[0145] [Reaction Formula 1]

[0146]

[0147]

[0148] The above crosslinking reaction may be characterized as a photocrosslinking or thermal crosslinking reaction, but is not limited thereto.

[0149] The compound of chemical formula (3) may have a structure of a copolymer in which an ε-caprolactone monomer and an acrylic monomer containing a glycidyl group are polymerized. For example, the compound of chemical formula (3) may have a structure of a copolymer [PCL-co-PGMA)] in which a caprolactone monomer (CL; ε-caprolactone) and a glycidyl methacrylate (GMA) monomer are polymerized.

[0150] In the compound of chemical formula (3), the arrangement order of the ε-caprolactone monomer and the glycidyl methacrylate monomer is not particularly limited and may be arranged alternately, randomly, or in blocks.

[0151] Additionally, a hydroxyl group or the like may be bonded to the terminal of the copolymer. A copolymer having a hydroxyl group bonded to the terminal can be produced by polymerization using an initiator having a hydroxyl group bonded to the terminal.

[0152] Meanwhile, the glycidyl group included in the glycidyl methacrylate monomer may be a crosslinkable functional group, and may be a photocrosslinkable functional group or a thermally crosslinkable functional group. In addition, the copolymer may have shape memory properties due to crosslinking.

[0153] As a specific example, the 6-arm copolymer according to the present invention may be a 6-arm PCL-PGMA copolymer of ε-caprolactone monomer and glycidyl methacrylate.

[0154] In the present invention, the 6-arm copolymer is described in detail in Korean Patent No. 10-2516991, which is incorporated herein by reference in its entirety.

[0155]

[0156] shape memory polymers

[0157] In the present invention, a "shape memory polymer (SMP)" means a polymer that has the property of returning to its original shape when an object is made to have a certain shape under specific conditions and the shape is subsequently changed by an external impact, when the object is made to have the same initial conditions (temperature, light, pH, humidity, etc.).

[0158] The puncture plug according to the present invention can be manufactured using a shape memory polymer having shape memory properties manufactured by crosslinking a copolymer of the above lactone and glycidyl methacrylate.

[0159] In a preferred embodiment, the shape memory polymer may be a copolymer of the formula (1); a copolymer of the formula (2) or the formula (3); and a crosslinked polycaprolactone. For example, the shape memory polymer may be a crosslinked copolymer of the formula (1): a copolymer of the formula (2) or the formula (3): polycaprolactone mixed in a weight ratio of about 10: about 6 to about 8: about 0.5 to about 1. More preferably, the shape memory polymer may be a crosslinked copolymer of the formula (1): a copolymer of the formula (2) or the formula (3): polycaprolactone mixed in a weight ratio of about 57: about 38: about 5.

[0160] In the present invention, the shape memory polymer may be a copolymer of chemical formula (1); a copolymer of chemical formula (2) or chemical formula (3); and polycaprolactone that is thermally crosslinked or photocrosslinked, and preferably, a photocrosslinked polymer.

[0161] The glycidyl group included in the glycidyl methacrylate monomer of the present invention may be a crosslinkable functional group, and may be a photocrosslinkable functional group or a thermally crosslinkable functional group.

[0162] In the present invention, the copolymer of the chemical formula (1), the copolymer of the chemical formula (2) or (3) and polycaprolactone are composed of potassium persulfate, ammonium persulfate, benzoyl peroxide, diauryl peroxide, dicumyl peroxide, hydrogen peroxide, azobisisobutuyronitrile, Irgacure, Darocure, LAP (lithium phenyl-2,4,6-trim ethylbenzoylphosphinate), TPO (diphenyl(2,4,6-trimethylbenzoyl)phosphine), TPO-L (ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate). It may be crosslinked by one or more selected from the group, and preferably, it may be crosslinked using Irgacure2959 as a crosslinking agent (curing agent).

[0163] In the present invention, the shape memory polymer has biocompatibility and has a shape restoring ability of 50% or more, preferably, at a temperature of 30 to 60°C, or at any range of temperatures within the temperature of 30 to 60°C, for example, at a temperature of 35 to 55°C, or at any temperature within the temperature of 30 to 60°C, for example, at about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, about 51°C, about 52°C, about 53°C, about 54°C, about 55°C, about 56°C, about 57°C, about 58°C, about 59°C, or about 60°C. It can be, but is not limited to, 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%.

[0164] In another aspect, the present invention provides a polymer composition for manufacturing a punctal plug comprising a copolymer of lactone and glycidyl methacrylate.

[0165] The above polymer composition may additionally include polycaprolactone.

[0166] In a specific embodiment, the polymer composition may be characterized by including a copolymer of chemical formula (1); a copolymer of chemical formula (2) or chemical formula (3); and polycaprolactone, and may be characterized by further including a crosslinking agent.

[0167] The above polymer composition may be characterized by being crosslinked and exhibiting shape memory properties.

[0168] From another aspect, the present invention relates to the use of the polymer composition or shape memory polymer for manufacturing a puncture plug.

[0169]

[0170] punctal plug

[0171] The present invention provides a puncture plug manufactured using the shape memory polymer.

[0172] Therefore, the present invention relates to a punctal plug comprising a shape memory polymer comprising a copolymer of caprolactone and glycidyl methacrylate in one aspect.

[0173] A punctal plug is a device used in punctal occlusion, a procedure that inserts a punctal plug into the tear duct through the punctum to prevent tear outflow and alleviate dry eye.

[0174] A puncture plug according to the present invention may have a structure including an insert that is inserted into and fixed to a puncture point and a head formed at the upper end of the insert with an outer diameter larger than the outer diameter of the insert.

[0175] When the insert of the above punctal plug is inserted into the punctal canal through the punctal puncture, the head can be caught on the top of the punctal puncture to prevent the insert from being inserted excessively.

[0176] The punctal plug according to the present invention has a shape memory characteristic, so that even if it is manufactured with a small diameter that is easy to insert into the punctal plug, its diameter can be expanded to fit the size of the punctal duct at temperatures equal to or higher than body temperature depending on its shape recovery ability.

[0177] The outer diameter of the insert may be 0.22 to 0.30 mm, preferably 0.24 to 0.28 mm, for example, about 0.26 mm, when inserted into the punctum, and after insertion, the outer diameter of the insert may be restored to its shape by body temperature, so that the outer diameter may be 0.38 to 0.44 mm, preferably 0.40 to 0.42 mm, for example, about 0.41 mm. The length of the insert may be 5 to 5.5 mm, preferably 5.14 to 5.20 mm, for example, about 5.17 mm.

[0178] Meanwhile, the outer diameter of the head may be 1.1 to 1.5 mm, preferably 1.27 to 1.33 mm, for example, about 1.30 mm, and the height of the head may be 0.4 to 0.5 mm, preferably 0.44 to 0.48 mm, for example, about 0.46 mm.

[0179] In the present invention, the point plug may additionally include a groove formed into the head as a groove for tool connection.

[0180] The outer diameter of the above groove may be 0.1 to 0.4 mm, preferably 0.12 to 0.3 mm, more preferably 0.16 to 0.22 mm, for example about 0.19 mm, but may be formed to have an outer diameter and length suitable for inserting a medical tool used for punctal occlusion to handle the fistula plug.

[0181] In the present invention, the punctal plug may be fixed to the puncture duct through a shape change due to an external stimulus.

[0182] In the present invention, the punctal plug has an excellent ability to be restored to its original shape by body temperature even if its shape is deformed by an external stimulus, and has the characteristic of being restored to a shape suitable for the size of the punctal plug after being inserted into the punctal plug through the punctal plug.

[0183] In addition, the punctal plug according to the present invention has the characteristic of suppressing biofilm formation, thereby improving side effects such as inflammatory reactions frequently occurring due to insertion of conventional punctal plugs.

[0184] That is, a biofilm is generally a film formed when various bacterial substances adhere to a solid substance, and it causes various inflammatory reactions. In particular, when a biofilm is formed on a punctal plug inserted into a tear duct through a punctum, bacteria may proliferate around it, causing dacryocystitis, dacryocystitis, blepharitis, etc., and dry eye may actually worsen. To prevent such side effects, some punctal plugs are coated with a separate antibacterial component. However, in the present invention, since the shape memory polymer itself exhibits a biofilm-inhibiting effect, there is no need to add a separate antibacterial component.

[0185] In the present invention, the punctal plug can be manufactured by mixing polycaprolactone, 2-arm 94%PCL-6%PGMA, and 4-arm 94%PCL-6%PGMA or 6-arm 94%PCL-6%PGMA and UV crosslinking to have the strength and elasticity most suitable for application to the punctal area.

[0186]

[0187] Method for manufacturing a leak plug

[0188] The present invention relates to a method for manufacturing a puncture plug from another aspect, comprising the following steps:

[0189] (a) a step of first mixing polycaprolactone into a copolymer of lactone and glycidyl methacrylate;

[0190] (b) a step of adding a cross-linking agent to the mixture of step (a) and then performing a second mixing;

[0191] (c) A step of manufacturing a leak plug by injecting the mixture into a mold and then crosslinking it.

[0192] In the present invention, the step (a) may be a step of mixing polycaprolactone into the copolymer of the chemical formula (1), the copolymer of the chemical formula (2), or the copolymer of the chemical formula (3).

[0193] In the present invention, the copolymer of the above chemical formula (1): the copolymer of the above chemical formula (2) or the copolymer of the above chemical formula (3): polycaprolactone may be mixed and crosslinked in a weight ratio of about 10: about 6 to about 8: about 0.5 to about 1, and preferably, the copolymer of the above chemical formula (1): the copolymer of the above chemical formula (2) or the copolymer of the above chemical formula (3): polycaprolactone may be mixed and crosslinked in a weight ratio of about 57: about 38: about 5.

[0194] In the present invention, the crosslinking agent may be at least one selected from the group consisting of potassium persulfate, ammonium persulfate, benzoyl peroxide, diauryl peroxide, dicumyl peroxide, hydrogen peroxide, azobisisobutuyronitrile, Irgacure, Darocure, LAP (lithium phenyl-2,4,6-trim ethylbenzoylphosphinate), TPO (diphenyl(2,4,6-trimethylbenzoyl)phosphine), and TPO-L (ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate).

[0195] Preferably, the crosslinking agent is Iragcure 2959, and can be added in an amount of 0.1 to 5 wt%, for example, 0.5 to 3 wt%, preferably about 1 wt%, relative to the copolymer.

[0196] In the present invention, step (c) is to pour the mixture into a mold and then irradiate it with UV (about 365 nm) at 100 to 500 mW / cm 2 century, preferably 200 to 300 mW / cm 2century, for example, about 265 mW / cm 2 By century, it can be crosslinked by irradiation for 100 to 1000 seconds, preferably 200 to 500 seconds, for example about 300 seconds.

[0197]

[0198] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples.

[0199]

[0200] Example 1. Manufacture of a punctal plug comprising polycaprolactone, a 2-arm 94% polycaprolactone-0.6% polyglycidyl methacrylate copolymer, and a 4-arm 94% polycaprolactone-0.6% polyglycidyl methacrylate copolymer.

[0201]

[0202] Manufacturing of 2 arm 94% polycaprolactone-06% polyglycidyl methacrylate 1,6-hexanediol(mmol)HQ(mmol)ε-CL(mmol)GMA(mmol)TBD(mmol)2 arm 94% PCL-6% PGMA0.519461

[0203]

[0204] A magnetic bar was placed in a 3-neck round bottom flask, and 1,6-hexanediol (initiator, 0.5 mmol, Sigma Aldrich) and hydroquinone (inhibitor, HQ, 1 mmol, Sigma Aldrich) were added. The flask inlet was blocked, vacuum was applied for 10 min, and then nitrogen was purged at a rate of 50 cc / min. Purified ε-caprolactone (94 mmol, Sigma Aldrich) was injected into the flask using a 20G syringe needle. The mixture was mixed at 110°C and 180 rpm for 10 min. Glycidyl methacrylate (monomer, GMA, 6 mmol, Sigma Aldrich) was injected using a 20G syringe needle. Ten minutes after the injection of glycidyl methacrylate, 1,5,7-Triazabicyclo(4.4.0)dec-5-ene (TBD, catalyst, 1 mmol, Sigma Aldrich) dissolved in 1 mL acetonitrile (ACN, Sigma Aldrich) was injected using a 20G syringe needle (1 mmolTBD / 1 mL ACN). The flask was then reacted at 110°C for 6 h. The final reaction product was dissolved in 15 mL of chloroform (Daejung chemicals & metals Co., LTD., Korea) and then precipitated in 400 mL of cold ethyl ether (Daejung chemicals & metals CO., LTD., Korea) at 4°C. The obtained precipitate was filtered and then vacuum-dried.

[0205] HD (1,6-hexanediol) was used as an initiator, TBD (1,5,7-Triazabicyclo(4.4.0)dec-5-ene) was used as a catalyst, HQ (hydroquinone) was used as an inhibitor, and ε-CL (ε-caprolactone) and GMA (glycidyl methacrylate) were used as monomers.

[0206]

[0207] Manufacturing of 4-arm 94% polycaprolactone-06% polyglycidyl methacrylate copolymer pentaerythritol(mmol)HQ(mmol)ε-CL(mmol)GMA(mmol)TBD(mmol)4 arm 94% PCL-6% PGMA0.52.5225252.5

[0208]

[0209] A magnetic bar was placed in a 3-neck round bottom flask, and pentaerythritol (initiator, 0.5 mmol, Sigma Aldrich) and hydroquinone (inhibitor, HQ, 2.5 mmol, Sigma Aldrich) were added. The flask inlet was blocked, vacuum was applied for 10 min, and then nitrogen was purged at a rate of 50 cc / min. Purified ε-caprolactone (225 mmol, Sigma Aldrich) was injected into the flask using a 20G syringe needle. The mixture was mixed at 110°C and 180 rpm for 10 min. Glycidyl methacrylate (monomer, GMA, 25 mmol, Sigma Aldrich) was injected using a 20G syringe needle. Ten minutes after the injection of glycidyl methacrylate, 1,5,7-Triazabicyclo(4.4.0)dec-5-ene (TBD, catalyst, 2.5 mmol, Sigma Aldrich) dissolved in 1 mL acetonitrile (ACN, Sigma Aldrich) was injected using a 20G syringe needle (2.5 mmol TBD / 1 mL ACN). The flask was then reacted at 110°C for 6 h. The final reaction product was dissolved in 15 mL of chloroform (Daejung chemicals & metals CO., LTD., Korea) and then precipitated in 400 mL of cold ethyl ether (Daejung chemicals & metals CO., LTD., Korea) at 4°C. The obtained precipitate was filtered and then vacuum-dried.

[0210]

[0211] Leakage plug manufacturing

[0212] 2 arm 94% polycaprolactone-06% polyglycidyl methacrylate copolymer, 4 arm 94% polycaprolactone-06% polyglycidyl methacrylate copolymer and polycaprolactone (Mw. 80,000, Sigma-Aldrich) were mixed in a weight ratio of 57:38:5, and then 1% of the total weight of Iragcure 2959, a UV crosslinking agent, was added. The manufactured material was injected into a puncture plug reverse mold made of PDMS for injection molding a shape as shown in Fig. 1a and cured at 265 mW / cm 2 A cured sample as shown in Fig. 1b was obtained by irradiating the sample with UV (365 nm) for 300 seconds.

[0213]

[0214] Example 2. Preparation of a punctal plug comprising polycaprolactone, a 2-arm 94% polycaprolactone-0.6% polyglycidyl methacrylate copolymer, and a 6-arm 94% polycaprolactone-0.6% polyglycidyl methacrylate copolymer.

[0215]

[0216] 2 arm 94% polycaprolactone-06% polyglycidyl methacrylate copolymer was prepared in the same manner as in Example 1.

[0217]

[0218] Manufacturing of 6 arm 94% polycaprolactone-06% polyglycidyl methacrylate copolymer Dipentaerythritol(mmol)HQ(mmol)ε-CL(mmol)GMA(mmol)TBD(mmol)6 arm 94% PCL-06% PGMA0.53.5315351

[0219]

[0220] Dipentaerythritol (initiator, Sigma Aldrich) and hydroquinone (HQ, inhibitor, Sigma Aldrich) were placed in a three-necked flask, vacuum dried for 10 minutes, and then nitrogen purged at a rate of 50 cc / min. Purified epsilon-caprolactone (ε-caprolactone, ε-CL, monomer, AVENTION) was additionally added and stirred at 110°C for 10 minutes. After adding glycidyl methacrylate (GMA, monomer, Sigma Aldrich) and stirring for 10 minutes, 1,5,7-Triazabicyclo(4.4.0)dec-5-ene (TBD, catalyst, TCI) dissolved in acetonitrile (ACN, Sigma Aldrich) was injected and reacted at 110°C for 6 hours. The final compound was dissolved in chloroform (Daejung chemicals & metals CO., LTD.), precipitated in ethyl ether (Daejung chemicals & metals CO., LTD.) at 4°C, filtered, and vacuum dried.

[0221]

[0222] Leakage plug manufacturing

[0223] 2 arm 94% polycaprolactone-06% polyglycidyl methacrylate copolymer, 6 arm 94% polycaprolactone-06% polyglycidyl methacrylate copolymer and polycaprolactone (Mw. 80,000, Sigma-Aldrich) were mixed in a weight ratio of 57:38:5, and then 1% of the total weight of Iragcure 2959, a UV crosslinking agent, was added. The manufactured material was injected into a PDMS-made leak plug inverse mold for injection molding a shape as shown in Fig. 1a and cured at 265 mW / cm 2A cured sample as shown in Fig. 1b was obtained by irradiating the sample with UV (365 nm) for 300 seconds.

[0224]

[0225] Comparative Example 1. Polycaprolactone punctal plug

[0226] Polycaprolactone (Mw: 80,000, Sigma Aldrich) was injected into a PDMS reverse mold and dried to obtain a sample.

[0227]

[0228] Experimental Example 1. Shape Restoration Ability (Shape Restoration Force)

[0229] The examples were stretched by 50%, 100%, and 150%, and the comparative examples were stretched by 100%, and the stretched punctum plug samples were exposed to a temperature of 40 to 45°C to determine the degree of change in the thickness of the punctum plug body portion, and the shape recovery ability (%) according to Equation (1) was confirmed.

[0230]

[0231] --------Formula (1)

[0232]

[0233] As a result, as shown in FIG. 2 and Table 4, the shape recovery ability was shown to be 70% or more at all tensile ratios tested in the examples, and the shape recovery ability of Example 1 was found to be superior. However, it was confirmed that the shape recovery ability decreased somewhat as the tensile ratio increased. On the other hand, the comparative example showed no shape recovery ability at all.

[0234]

[0235] ClassificationInitial deformation recoveryShape recovery ability(%)Body diameter(mm)Ratio(%)Body diameter(mm)Body diameter(mm)Example 10.39500.260.3487.180.391000.210.3282.050.391500.210.2974.36Example 20.39500.260.3384.610.391000.210.3179.480.391500.210.2871.79Comparative example 10.391000.210.210

[0236]

[0237] Experimental Example 2. Shape Restoration Ability in Microtubules

[0238] A microtube simulating a punctate shape was manufactured using PDMS, and each of Example 1, Example 2, and Comparative Example 1 was stretched by 50%. The stretched punctate plug sample was inserted into the microtube, and then exposed to a temperature of 40 to 45°C to check the degree of change in the diameter and length of the punctate plug body.

[0239] As a result, as shown in Fig. 3 and Table 5, in the case of the example, both the diameter and length showed a shape restoration ability of 80% or more, but it was confirmed that the comparative example could not restore the shape at all.

[0240]

[0241] Partial measurement Partial circular deformation recovery Shape recovery ability (%) Example 1 Diameter (mm) 0.410.300.3892.68 Length (mm) 5.177.636.0882.40 Example 2 Diameter (mm) 0.410.300.3790.24 Length (mm) 5.177.636.1181.82 Comparative example 1 Diameter (mm) 0.410.300.300 Length (mm) 5.177.637.630

[0242]

[0243] Experimental Example 3. Tear flow

[0244] In order to confirm the tear flowability of the punctal plug before the shape deformation according to Example 1, a pressure gauge and a syringe pump were installed in a silicone-based mold similar in size to the punctum and tear duct, and saline solution was injected at a constant rate to measure the pressure over time.

[0245] As a result, as shown in Fig. 4, it was confirmed that saline solution leaked out when the average pressure was 0.1 bar or higher, which was higher than the maximum value of oral and nasal pressure of 0.08 bar when sneezing, confirming that the punctal plug according to the present invention can effectively prevent tear leakage through the punctal even at high pressure.

[0246]

[0247] While specific aspects of the present invention have been described in detail above, it will be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

[0248]

[0249] National Project Information

[0250] [Project ID] 1711200487

[0251] [Assignment Number] 00302125 (RS-2023-00302125)

[0252] [Ministry Name] Ministry of Science and ICT

[0253] [Name of Project Management (Specialist) Institution] National Research Foundation of Korea

[0254] [Research Project Name] Future Convergence Technology Development Project

[0255] [Research Project Title] Development of Source Technology for Energy-Responsive Self-Structured Medical Materials Applicable to Biosystems

[0256] [Name of the project performing organization] TMD Lab Co., Ltd.

[0257] Research Period: September 1, 2023 - December 31, 2027

[0258]

[0259] [Project ID] 1465040845

[0260] [Assignment Number] 00265566 (RS-2023-002655566)

[0261] [Ministry Name] Ministry of Health and Welfare

[0262] [Name of Project Management (Specialist) Agency] Korea Health Industry Development Institute

[0263] [Research Project Name] Innovative Medical Device Company Technology Commercialization Support Project (R&D)

[0264] [Research Project Name] Global Joint Research and Medical Device Development on the Biofilm Reduction Effect of Polycaprolactone-Based Materials

[0265] [Name of the project performing organization] TMD Lab Co., Ltd.

[0266] Research Period: July 1, 2023 - December 31, 2025

Claims

1. A punctal plug comprising a shape memory polymer comprising a copolymer of lactone and glycidyl methacrylate.

2. A point plug according to claim 1, wherein the copolymer has a linear or multi-arm structure.

3. In the second paragraph, the copolymer A compound represented by the following chemical formula (1): Chemical formula (1) In the above chemical formula (1), R1, R2 and R3 are each independently hydrogen (H) or an alkyl group having 1 to 6 carbon atoms, m and n are integers from 1 to 20, independently of each other, A, B1 and B2 are independently oxygen (O) or sulfur (S), x and y represent the mole % of repeating units, x+y is 100, and x is between 80 and 95; A compound represented by the following chemical formula (2): Chemical formula (2) In the above chemical formula (2), x is an integer from 1 to 20, m and n represent the mole % of repeating units, m+n is 100, and m is between 80 and 96; or A compound represented by the following chemical formula (3): Chemical formula (3) In the above chemical formula (3), x and y are integers from 1 to 20, independently of each other, m and n represent the mole % of repeating units, m+n is 100, and m is between 70 and 99; , punctum plug.

4. In the third paragraph, the shape memory polymer is a copolymer of chemical formula (1); a copolymer of chemical formula (2) or a copolymer of chemical formula (3); and a polycaprolactone crosslinked, a puncture plug.

5. In the fourth paragraph, the shape memory polymer is a crosslinked puncture plug in which a copolymer of chemical formula (1): a copolymer of chemical formula (2) or a copolymer of chemical formula (3): polycaprolactone are mixed in a weight ratio of 10:6-8:0.5-1.

6. In the fifth paragraph, the shape memory polymer is a crosslinked puncture plug in which a copolymer of chemical formula (1): a copolymer of chemical formula (2) or a copolymer of chemical formula (3): polycaprolactone are mixed in a weight ratio of 57:38:

5.

7. In the fourth paragraph, the shape memory polymer is a copolymer of chemical formula (1); a copolymer of chemical formula (2) or a copolymer of chemical formula (3); and a polycaprolactone, which is thermally crosslinked or photocrosslinked.

8. In paragraph 7, the copolymer of the chemical formula (1); the copolymer of the chemical formula (2) or the copolymer of the chemical formula (3); And polycaprolactone is crosslinked by at least one selected from the group consisting of potassium persulfate, ammonium persulfate, benzoyl peroxide, diauryl peroxide, dicumyl peroxide, hydrogen peroxide, azobisisobutuyronitrile, Irgacure, Darocure, LAP (lithium phenyl-2,4,6-trimethylbenzoylphosphinate), TPO (diphenyl(2,4,6-trimethylbenzoyl)phosphine), TPO-L (ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate).

9. A puncture plug according to claim 1, wherein the shape memory polymer has biocompatibility and has a shape restoring force of 50% or more at a temperature of 30 to 60°C.

10. In the first paragraph, the puncture plug comprises an insert that is inserted and fixed in correspondence with the puncture tube and a head formed at the upper end of the insert with an outer diameter larger than the outer diameter of the insert.

11. In paragraph 10, The above-mentioned leak plug is a leak plug that additionally includes a groove formed in the head as a groove for tool connection.

12. A method for manufacturing a leak plug according to claim 1, comprising the following steps: (a) a step of adding a crosslinking agent to a copolymer of lactone and glycidyl methacrylate and then mixing them; (b) A step of manufacturing a leak plug by injecting the mixture into a mold and then crosslinking it.

13. In paragraph 12, The step (a) above is a method for manufacturing a puncture plug, which comprises mixing a copolymer of the chemical formula (1) of the third paragraph; a copolymer of the chemical formula (2) or a copolymer of the chemical formula (3); and a crosslinking agent with polycaprolactone.

14. A method for manufacturing a leak plug in claim 13, wherein the copolymer of the chemical formula (1): the copolymer of the chemical formula (2) or the copolymer of the chemical formula (3): polycaprolactone are mixed and crosslinked in a weight ratio of 10:6 - 8:0.5 - 1.

15. A method for manufacturing a puncture plug in claim 14, wherein the copolymer of the chemical formula (1): the copolymer of the chemical formula (2) or the copolymer of the chemical formula (3): polycaprolactone are mixed in a weight ratio of 57:38:5 and crosslinked.

16. A method for manufacturing a puncture plug, wherein the crosslinking agent in paragraph 12 is Iragcure 2959, and is added in an amount of 0.1 to 5 wt% relative to the copolymer.

17. A method for manufacturing a puncture plug, wherein step (b) is crosslinked by irradiating UV for 100 to 1000 seconds in the 12th paragraph.

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