Degradable lacrimal canaliculus insert and preparation method therefor

Abstract

The present invention relates to a degradable lacrimal canaliculus insert and a preparation method therefor. Each bar of the degradable lacrimal canaliculus insert comprises 0.15-1.0 mg of a hydrogel matrix, 0.01-1.0 mg of a poorly soluble active pharmaceutical ingredient distributed in the hydrogel matrix, and 0-0.30 mg of a buffering salt. The prepared degradable lacrimal canaliculus insert has a prolonged degradation period of about 3 months, improving xerophthalmia patients' compliance during use. In addition, the exploration of the preparation process for the lacrimal canaliculus insert enables the uniform distribution of the poorly soluble active ingredient in the lacrimal canaliculus insert, facilitating quality control in actual production. Moreover, the preparation process is stable, enabling continuous industrial batch production.

Description

Degradable lacrimal canaliculus insert and preparation method TECHNICAL FIELD

[0001] The present application belongs to the technical field of lacrimal canaliculus inserts, and particularly relates to a degradable lacrimal canaliculus insert and a preparation method. BACKGROUND

[0002] Dry eye syndrome is a syndrome of foreign body sensation, burning sensation or irritation of the eye, etc. caused by increased tear film loss usually due to reduced tear production or increased tear evaporation. The existing treatment method for dry eye syndrome is mainly to compensate for insufficient tears by dropping artificial tears or to control inflammation by dropping anti-inflammatory drugs. However, the effect of the above eye drops is temporary, and needs to be used multiple times a day, which greatly reduces the compliance of patients.

[0003] An ocular lacrimal canaliculus insert refers to a drug and a matrix mixed to form a preparation, which is inserted into the lacrimal canaliculus of the eyelid non-invasively, so that the active ingredient is slowly and continuously released. Compared with traditional eye drops, the ocular insert has the advantage of increasing the residence time in the eye, thereby prolonging the action time of the active ingredient. According to the differences in delivery matrix and implementation means, the sustained-release time can be achieved from several days to up to several months. In terms of action time, it has obvious advantages over eye suspensions and eye gels.

[0004] CN109077993B discloses loading drugs for treating eye diseases (such as glaucoma, dry eye syndrome, conjunctivitis, etc.) in a lacrimal canaliculus insert. However, the product has a degradation time of only about one month. This is too short for eye diseases that need long-term treatment or continuous treatment (such as dry eye syndrome), at which time the release of the drug may not bring the expected therapeutic effect. After the lacrimal canaliculus insert degrades and falls off, a new insert needs to be inserted in the hospital to maintain the drug effect. However, this is still a relatively frequent insertion operation for patients, which greatly reduces the compliance of patients. Therefore, it is more reasonable to formulate the degradation time of the insert according to the drug loaded in the insert and the treatment cycle of the corresponding disease.

[0005] Compared with general suspensions, the national standard has strict requirements for the composition of lacrimal canaliculus inserts. The First Supplement to the 2020 Chinese Pharmacopoeia also clearly stipulates that "ophthalmic inserts shall not add bacteriostatic agents or antioxidants or inappropriate additives." Generally, the preparation of suspensions requires the addition of suspending agents or cosolvents, wetting agents, and other additives to help the uniform distribution of drug particles. However, it is not appropriate to add these substances to lacrimal canaliculus inserts to control the uniform distribution of drugs in the liquid. Especially after the matrix is dried, there is a risk that the amount of additives exceeds the safe percentage of the amount of excipients. However, many drugs have low solubility in water. When they are loaded into lacrimal canaliculus inserts made of hydrogel, without the addition of suspending agents or cosolvents, wetting agents, and other additives to help the uniform distribution of drug particles, the drug may not be uniformly dispersed and may produce bubbles, resulting in unevenness on the surface of the lacrimal canaliculus insert or the adhesion of drug particles, thereby making the surface of the lacrimal canaliculus insert uneven, with burrs or cracks, which may cause poor patient compliance when the lacrimal canaliculus insert is applied. In addition, the uneven distribution of drugs in the lacrimal canaliculus insert also causes inconsistent drug release rates in different parts of the lacrimal canaliculus insert, with some parts releasing too fast and others releasing too slow, thereby affecting the consistency and predictability of the therapeutic effect and failing to provide stable therapeutic effect.

[0006] In addition, the quality and stability of the drug directly affect the therapeutic effect and safety. For an ocular drug delivery system such as a lacrimal canaliculus insert, uniformity is particularly important because even a small difference can affect the drug release rate and therapeutic effect. Therefore, consistency between batches needs to be ensured during production.

[0007] Therefore, there is a need to develop a lacrimal canaliculus insert with long degradation time, uniform drug content, and stable process. SUMMARY

[0008] To solve the above problems, through repeated experiments, the inventors found that by combining two specific hydrogel precursors and their amounts, the degradation time of the prepared lacrimal canaliculus insert can be extended to about 3 months, improving the compliance of dry eye patients during use. In addition, through the exploration of the preparation process of the lacrimal canaliculus insert, the inventors achieved uniform distribution of poorly soluble active ingredients in the lacrimal canaliculus insert, which is helpful for quality control in actual production, and the preparation process is stable and can be industrialized for continuous batch production. On this basis, the present application is completed.

[0009] In one aspect, the present application provides a degradable lacrimal canaliculus insert, wherein each insert comprises:

[0010] (1) 0.15-1.0 mg of a hydrogel matrix,

[0011] (2) 0.01-1.0 mg of a poorly soluble pharmaceutically active ingredient distributed in the hydrogel matrix; and

[0012] (3) 0-0.30 mg of a buffer salt,

[0013] wherein the hydrogel matrix is formed by reacting a multi-arm polyethylene glycol derivative 1 of Formula I and multi-arm-PEG-NH2:

[0014] Multi-arm PEG-A (I)

[0015] wherein A represents a functional group attached at the end of the multi-arm PEG, each independently selected from:

[0016] a succinimidyl succinate group (SS):

[0017] a succinimidyl glutarate group (SG):

[0018] a succinimidyl glutaric amide group (SGA):

[0019] a succinimidyl carboxymethyl ester group (SCM):

[0020] a succinimidyl adipate group (SAP):

[0021] a succinimidyl carbonate group (SC):

[0022] a succinimidyl propionate group (SPA):

[0023] In some embodiments, each of the degradable canaliculus inserts comprises 0.4-0.95 mg, such as 0.5-0.9 mg, such as 0.55, 0.6, 0.65, 0.70, 0.75, 0.80, 0.85 mg of the hydrogel matrix, but is not limited thereto.

[0024] In some embodiments, the multi-arm PEG derivative 1 can be selected from one or more of Multi-arm-PEG-SS, Multi-arm-PEG-SG, Multi-arm-PEG-SGA, Multi-arm-PEG-SCM, Multi-arm-PEG-SAP, Multi-arm-PEG-SC, Multi-arm-PEG-SPA.

[0025] In some embodiments, the multi-arm PEG derivative 1 and the multi-arm PEG amine, the multi-arm is selected from 2-10 arms, such as bi-arm, tri-arm, tetra-arm, hexa-arm, octa-arm, deca-arm, etc. In particular, the multi-arm is 4-arm or 8-arm.

[0026] In some embodiments, the molecular weight of the polyethylene glycol segment in the multi-arm PEG derivative 1 and the multi-arm PEG amine can be 5000-25000D, such as 6000, 7000, 8000, 9000, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000, 20000, 21000, 22000, 23000, 24000D, etc. Preferably, the molecular weight is 8000-20000D, such as 10000-15000D.

[0027] Unless otherwise specified, the "molecular weight" in the present application refers to the weight average molecular weight.

[0028] In the present application, by combining the multi-arm PEG derivative 1 and the multi-arm PEG amine, a lacrimal canicular insert with controllable degradation time can be obtained. In some embodiments, the weight ratio of the multi-arm PEG derivative 1 and the multi-arm PEG amine can be 1:(0.5-1.5), such as 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, etc. Preferably, the weight ratio is 1:(0.8-1.4), more preferably, the weight ratio is 1:(0.85-1.3). Within the above weight ratio range, a lacrimal canicular insert with a degradation time of about 3 months can be obtained.

[0029] In some embodiments, the multi-armed polyethylene glycol derivative 1 can be 4-arm polyethylene glycol succinimidyl hexanoate (4arm-PEG-SAP); a combination of 4-arm polyethylene glycol succinimidyl hexanoate (4arm-PEG-SAP) and 4-arm polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), wherein the weight ratio of 4arm-PEG-SAP to 4arm-PEG-SG can be 2: 1 to 1:2, such as 2: 1, 1: 1, 1:2, etc.; or a combination of 4-arm polyethylene glycol succinimidyl hexanoate (4arm-PEG-SAP) and 4-arm polyethylene glycol succinimidyl carboxymethyl ester (4arm-PEG-SCM), wherein the weight ratio of 4arm-PEG-SAP to 4arm-PEG-SCM can be 5: 1 to 1:5, such as 4: 1, 3: 1, 2: 1, 1: 1, 1:2, 1:3, 1:4, etc.

[0030] For example, 4-arm polyethylene glycol succinimidyl hexanoate (4arm-PEG-SAP) can have a structure shown in Formula II, but is not limited thereto:

[0031] For example, 4-arm polyethylene glycol succinimidyl glutarate (4arm-PEG-SG) can have a structure shown in Formula III, but is not limited thereto:

[0032] For example, 4-arm polyethylene glycol succinimidyl carboxymethyl ester (4arm-PEG-SCM) can have a structure shown in Formula IV, but is not limited thereto:

[0033] In some embodiments, the multi-armed polyethylene glycol amine can be 4-arm polyethylene glycol amine (4arm-PEG-NH2).

[0034] For example, 4-arm polyethylene glycol amine (4arm-PEG-NH2) can have a structure shown in Formula V, but is not limited thereto:

[0035] In the above Formulas III to VI, X represents a tetravalent group derived from a central molecule.

[0036] In the present invention, multi-arm polyethylene glycol (Multi-Arm Polyethylene Glycol) refers to polyethylene glycol having multiple PEG branches in the structure. The multi-arm polyethylene glycol derivative 1 of formula I used in the present invention is a multi-arm polyethylene glycol derivative having a functional group A at the end, and the multi-arm polyethylene glycol amine is a multi-arm polyethylene glycol derivative having a functional group -NH2 at the end. The multi-arm polyethylene glycol derivative can be commercially available, or can be obtained by self-designed customization, or can be prepared by any available method. For example, the multi-arm polyethylene glycol can be initiated by polymerization of ethylene oxide with glycerol, polyglycerol, pentaerythritol, oligomeric pentaerythritol, sorbitol, etc. as the central molecule, but the present invention is not limited thereto.

[0037] In the present invention, when polyethylene glycol derivative 1 and polyethylene glycol amine are mixed, the functional group A of polyethylene glycol derivative 1 (the related structure is represented as ) and -NH2 (the related structure is represented as R2— NH2) can undergo the reaction shown in formula I to produce a cross-linked structure.

[0038] In the present invention, the poorly soluble pharmaceutically active ingredient refers to a pharmaceutically active ingredient that is difficult to dissolve or insoluble in water. In embodiments, the poorly soluble pharmaceutically active ingredient is a pharmaceutically active ingredient for treating dry eye, which can be selected from one or more of tacrolimus, cyclosporine, dexamethasone, lifitegrast, indometacin, or a pharmaceutically acceptable salt thereof, etc., but is not limited thereto.

[0039] Tacrolimus, the English name of tacrolimus, has the structure

[0040] Cyclosporine, the English name of cyclosporine, has the structure

[0041] Dexamethasone, the English name of dexamethasone, has the structure

[0042] Lifitegrast, the English name of lifitegrast, has the structure

[0043] Indometacin, the English name of indometacin, has the structure

[0044] In some embodiments, each of the degradable canaliculus inserts contains 0.05-0.9 mg, for example 0.10-0.8 mg, for example 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80 mg of the poorly soluble pharmaceutically active ingredient, but is not limited thereto.

[0045] In the present application, the inventors have found that the combination of the above-mentioned multi-arm polyethylene glycol derivative 1 and multi-arm polyethylene glycol amine can extend the degradation time of the lacrimal canaliculus insert to about 3 months, particularly 70 to 100 days, thereby improving the compliance of patients with dry eye syndrome. Without being bound by any theory, in the case of using the combination of the above-mentioned multi-arm polyethylene glycol derivative 1 and multi-arm polyethylene glycol amine, the hydrophobic region of the multi-arm polyethylene glycol derivative 1 and the multi-arm polyethylene glycol amine can bind to the poorly soluble pharmaceutically active ingredient, help the uniform distribution of the poorly soluble pharmaceutically active ingredient, and affect the release of the pharmaceutically active ingredient.

[0046] In some embodiments, in the degradable lacrimal canaliculus insert according to the present application, the average particle size D 90 is 20 μm or less, preferably 10 μm or less, particularly 5 μm or less, for example 1.0 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm, etc., for example 2.0 to 5.0 μm. In the above-mentioned particle size range, it is helpful for the uniform distribution of the pharmaceutically active ingredient in the lacrimal canaliculus insert. When the average particle size is greater than 20 μm, the active ingredient may

[0047] In the present application, a buffer salt is used to adjust the pH of the lacrimal canaliculus insert so as to be compatible with the pH of the tear fluid, reduce irritation, and improve patient compliance. In general, the pH of the tear fluid is 5.20 to 8.35. Therefore, it is preferred to use a buffer salt to adjust the pH of the lacrimal canaliculus insert to 5.20 to 8.35, more preferably 6.0 to 7.0, for example 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, etc., particularly preferably 6.5. Any buffer salt suitable for application to the eye can be used without particular limitation, as long as it can be adjusted to the appropriate pH. The selection of the buffer salt is within the scope of a person skilled in the art and can be selected according to the pH of the tear fluid or the pH range that can be tolerated by a normal human eye, and therefore will not be described in detail so as not to obscure the main inventive points of the present application.

[0048] For example, the buffer salt can be selected from phosphate buffer salts, citric acid buffer salts, acetic acid buffer salts, and particularly preferably phosphate buffer salts. Phosphate buffer salts refer to buffer salts composed of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, or disodium hydrogen phosphate, sodium dihydrogen phosphate. Citric acid buffer salts refer to buffer salts composed of sodium citrate, citric acid. Acetic acid buffer salts refer to buffer salts composed of acetic acid, sodium acetate. In the preparation of the lacrimal canaliculus insert according to the present application, the above-mentioned buffer salts are prepared as buffer solutions.

[0049] In some embodiments, each insert of the degradable canaliculus insert contains 0.01-0.25 mg, for example 0.02-0.20 mg, for example 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15 mg of the buffered salt, but not limited thereto.

[0050] In some embodiments, in the degradable canaliculus insert according to the present application, a trace amount of organic solvent used in the preparation process can be left. In some embodiments, the content of the organic solvent is greater than 0 and less than or equal to 1000 ppm, for example 5 ppm to 500 ppm, or 10 ppm to 200 ppm, or 20 ppm to 100 ppm.

[0051] In some embodiments, the organic solvent is not a solvent belonging to the first category (should be avoided) as specified in the Chinese Pharmacopoeia 2020 edition.

[0052] In some embodiments, the organic solvent is an organic solvent that can be miscible with water and has a boiling point of 50-150°C.

[0053] In some embodiments, the organic solvent is one or more selected from the group consisting of methanol (boiling point 67.4°C), ethanol (boiling point 78.4°C), formic acid (boiling point 100.8°C), acetic acid (boiling point 118°C), isopropanol (boiling point 82°C), n-propanol (boiling point 95.8°C), acetone (boiling point 56°C), but not limited thereto. In particular, the organic solvent is ethanol, methanol, n-propanol, isopropanol.

[0054] By using the above-mentioned organic solvent in the preparation process, the solubility of the poorly soluble active pharmaceutical ingredient can be improved, and the uniform dispersion of the active ingredient can be facilitated. The specific solvent used in the present application has a relatively low boiling point and is volatile, and is basically volatilized during the drying process of the canaliculus insert, so that the residual amount of the organic solvent is low, thereby ensuring the safety of the finished canaliculus insert.

[0055] In addition, compared with general suspensions, the composition of the canaliculus insert is strictly required by the national standard, and it is also clearly specified in the 2020 Chinese Pharmacopoeia First Supplement that “antibacterial agents or antioxidants or inappropriate additives should not be added to eye inserts”. Generally, the preparation of suspensions requires the addition of suspending agents or potential solvents, wetting agents and other additives to help the stable and uniform distribution of drug particles. However, it is not appropriate to add these substances to the canaliculus insert to control the uniform distribution of the drug in the liquid. Especially after the matrix is dried, there is a risk that the amount of auxiliary additives exceeds the safe percentage of the auxiliary materials.

[0056] Therefore, in the degradable canaliculus insert according to the present application, no additional agent such as a suspending agent, a wetting agent, a flocculating agent, a solvent, etc. is included.

[0057] The degradable canaliculus insert according to the present application has a degradation time of 70 to 100 days. Further, the degradation time is 80 to 100 days.

[0058] In addition to the above features, the degradable canaliculus insert according to the present application can have features of a conventional canaliculus insert. For example, the diameter of the canaliculus insert can be 0.2 to 0.8 mm; the length can be 1 to 5 mm, and the diameter can be expanded to 0.81 to 2.1 mm upon contact with water, and the length can be shortened to 0.8 to 4.0 mm upon contact with water.

[0059] Another aspect of the present application provides a method of preparing the above-described degradable canaliculus insert, comprising the steps of:

[0060] (1) adding an organic solvent to a pH buffer to obtain an organic solvent-buffer 1;

[0061] (2) dissolving a multi-armed polyethylene glycol derivative 1 in the organic solvent-buffer 1 to obtain a mixture 1;

[0062] (3) adding a poorly soluble pharmaceutically active ingredient to the mixture 1 to obtain a mixture 2;

[0063] (4) dissolving a multi-armed polyethylene glycol amine in a pH buffer or the organic solvent-buffer 1 to obtain a mixture 3;

[0064] (5) mixing the mixture 2 and the mixture 3 to obtain a mixture 4;

[0065] (6) injecting the mixture 4 into a circular mold, allowing the mixture to stand to form a hydrogel, and then removing the hydrogel from the mold;

[0066] (7) stretching the removed hydrogel, and then drying and cutting the stretched hydrogel to obtain a finished canaliculus insert.

[0067] Each of the above steps will be described in detail below.

[0068] Step (1):

[0069] In step (1), first, an organic solvent is added to a pH buffer to obtain an organic solvent-buffer 1.

[0070] The organic solvent can be any organic solvent that helps to increase the solubility of the poorly soluble pharmaceutically active ingredient and help the uniform dispersion of the pharmaceutically active ingredient.

[0071] In some embodiments, the organic solvent is an organic solvent that is miscible with water and has a boiling point of 50-150°C.

[0072] In some embodiments, the organic solvent is not a solvent that is classified as the first type (should be avoided) according to the Chinese Pharmacopoeia 2020 edition.

[0073] In some embodiments, the organic solvent is one or more selected from the group consisting of methanol (boiling point 67.4°C), ethanol (boiling point 78.4°C), formic acid (boiling point 100.8°C), acetic acid (boiling point 118°C), isopropanol (boiling point 82°C), n-propanol (boiling point 95.8°C), acetone (boiling point 56°C), but not limited thereto.

[0074] The pH buffer is a solution formed by dissolving the aforementioned buffer salt in water, and has a pH of 5.20-8.35, preferably 6.0-7.0, and more preferably 6.5. The pH buffer can be commercially available or can be prepared according to the formula, and the present application does not limit this. The description of the buffer salt is the same as before and is not repeated here.

[0075] In the organic solvent-buffer 1, the volume concentration of the organic solvent in the pH buffer is 5-50% (v / v), preferably 5-30%, and more preferably 8-20%, for example 8%, 10%, 12%, 15%, 20%, etc. Within the above concentration range, it is beneficial to uniformly disperse the poorly soluble active ingredient, and at this concentration, the buffer salt in the buffer can be prevented from precipitating.

[0076] Step (2):

[0077] In step (2), the multi-arm polyethylene glycol derivative 1 is added to the organic solvent-buffer 1 to be dissolved to obtain a mixture 1. The description of the multi-arm polyethylene glycol derivative 1 is the same as before and is not repeated here.

[0078] The concentration of the multi-arm polyethylene glycol derivative 1 in the mixture 1 is not particularly limited, as long as it can be fully dissolved and suitable for subsequent mixing operations. Those skilled in the art can appropriately select the amount of the organic solvent-buffer 1 to fully dissolve the multi-arm polyethylene glycol derivative 1, and to have an appropriate concentration of the multi-arm polyethylene glycol derivative 1 in the final mixture 4 to form a hydrogel.

[0079] Step (3):

[0080] In step (3), the poorly soluble pharmaceutical active ingredient is added to the mixture 1 to obtain a mixture 2.

[0081] The description of the poorly soluble pharmaceutical active ingredient is the same as before and is not repeated here.

[0082] The drug active ingredient meeting the particle size requirement can be commercially available, or can be obtained by micronizing the active ingredient of large particle size to obtain the active ingredient product meeting the particle size requirement.

[0083] The method for micronizing is not particularly limited, and any suitable micronizing method in the related art can be used as long as the active ingredient meeting the particle size requirement can be obtained and the product is suitable for use in the canaliculus insert.

[0084] The micronizing can be performed before being added to the mixed solution 1, or can be performed simultaneously with the mixing. For example, a step of micronizing the drug active ingredient to obtain the active ingredient meeting the particle size requirement can be additionally added to step (3), or the drug active ingredient can be mixed with part or all of the mixed solution 1 and then micronized.

[0085] The method for mixing the drug active ingredient is not particularly limited, and can be performed by any suitable method (e.g., ultrasonic, stirring, shaking, homogenization, etc.). In some embodiments, the mixing can be performed by ultrasonic mixing.

[0086] Step (4):

[0087] In step (4), the multi-arm polyethylene glycol amine is dissolved in the pH buffer or the organic solvent-buffer 1 to obtain a mixed solution 3.

[0088] The concentration of the multi-arm polyethylene glycol amine in the mixed solution 3 is not particularly limited, and can be appropriately selected by a person skilled in the art to sufficiently dissolve the multi-arm polyethylene glycol amine and to obtain an appropriate concentration of the multi-arm polyethylene glycol amine in the final mixed solution 4 to form the hydrogel.

[0089] Step (4) can be performed simultaneously with steps (1)-(3), or can be performed before or after steps (1)-(3).

[0090] Step (5):

[0091] In step (5), the mixed solution 2 and the mixed solution 3 are mixed to obtain a mixed solution 4.

[0092] The mixing can be performed by any suitable mixing method (e.g., stirring, ultrasonic, homogenization, etc.).

[0093] Preferably, the mixing is performed by homogenization, for example, using a homogenizer at a pressure of 100-500 MPa.

[0094] The homogenization treatment under the above high pressure condition can further promote the dispersion of the mixed solution, and the high pressure and shearing force can decompose or remove the agglomerates of the active ingredient in the lacrimal canaliculus insert.

[0095] The pressure for the homogenization treatment can be 100-500 MPa, preferably 200-450 MPa, more preferably 250-400 MPa, for example, 280 MPa, 300 MPa, 350 MPa, 400 MPa, etc., but is not limited thereto. Under this condition, the agglomerates of the poorly soluble active ingredient can be decomposed and removed by the high pressure, which is beneficial to the uniform dispersion of the poorly soluble active ingredient. If the pressure is too high, the hydrogel precursor can be broken, which affects the gelation. If the pressure is too low, the agglomerates of the poorly soluble active ingredient can not be completely removed.

[0096] The rotation speed for the homogenization treatment can be 100-500 rpm, preferably 150-400 rpm, more preferably 200-400 rpm, for example, 240 rpm, 300 rpm, 320 rpm, 400 rpm, etc., but is not limited thereto. Under this condition, the agglomerates of the poorly soluble active ingredient can be decomposed by the high shearing force, which is beneficial to the uniform dispersion of the poorly soluble active ingredient. If the rotation speed is too high, the hydrogel precursor can be severely damaged by the high shearing force, which affects the gelation. If the rotation speed is too low, the agglomerates of the poorly soluble active ingredient can not be completely removed.

[0097] The temperature for the homogenization treatment is not particularly limited and can be performed at room temperature to 40°C.

[0098] In the mixed solution 4, the concentration of the multi-arm polyethylene glycol derivative 1 can be 1-20% (w / w), preferably 2-10%, for example, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, etc., but is not limited thereto.

[0099] In the mixed solution 4, the concentration of the multi-arm polyethylene glycol amine can be 1-20% (w / w), preferably 2-10%, for example, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, etc., but is not limited thereto.

[0100] Within the above concentration range, the swelling range of the prepared canaliculus implant can be ensured to be within the bearing range of the canaliculus tissue, and the degradation time can be ensured to be within the range of 70-100 days. If the concentrations of the multi-armed polyethylene glycol derivative 1 and the multi-armed polyethylene glycol amine are too high, the prepared canaliculus implant will swell too much, causing compression to the canaliculus tissue and reducing patient compliance; and if the concentrations are too low, the degradation time will be much lower than the desired degradation time, and the patient will need to frequently replace the canaliculus implant, reducing patient compliance.

[0101] Step (6):

[0102] In step (6), the mixed solution 4 is injected into a circular mold, and the hydrogel is formed by standing, and then the hydrogel is taken out of the mold.

[0103] The circular mold can be any mold suitable for forming a hydrogel into the shape of a canaliculus implant in the art, for example, a hose or a mold having a circular gap. In some embodiments, the circular mold can be selected from a silica gel tube having a diameter of 0.5-2 mm or a polytetrafluoroethylene tube having a diameter of 0.5-2 mm.

[0104] The standing condition is not particularly limited, and any suitable condition in the art can be used as long as a hydrogel is formed. For example, the standing can be performed at 10-50°C under 0.05-0.2 MPa for 5 minutes or more, for example, 10 minutes, but the present application is not limited thereto.

[0105] During the standing, the functional group A in the multi-armed polyethylene glycol derivative 1 (the relevant structure is represented as ) and the -NH2 in the multi-armed polyethylene glycol amine (the relevant structure is represented as R2— NH2) can undergo the reaction of the above Reaction Formula I to generate a crosslinked structure.

[0106] Step (7):

[0107] In step (7), the taken-out hydrogel is stretched along the axial direction to increase its length, and then dried and cut to obtain the finished canaliculus implant.

[0108] Step (7) can be performed by any suitable method in the art, which does not involve the inventive points of the present application, and therefore will not be described in detail to avoid obscuring the innovative points of the present application.

[0109] In some embodiments, the stretching multiple of the canaliculus implant is 1.1-10 times, for example, 1.5, 2., 3, 4, 5, 6, 7, 8, 9 times, etc. Here, the stretching multiple refers to the multiple of the change in the length of the hydrogel.

[0110] The drying can be performed one or more times until the organic solvent and water content in the lacrimal canaliculi insert meet the specification requirements.

[0111] In some embodiments, the drying is performed at 20-30°C, 20-40% RH for 2-24 hours, but the present application is not limited thereto.

[0112] In the present application, the word "comprise" or its variations, such as "comprises" and "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0113] 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 application belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. In case of conflict, the

[0114] "A, B, and C at least one of" has the same meaning as "at least one of A, B, or C", and includes the following combinations of A, B, and C: only A, only B, only C, a combination of A and B, a combination of A and C, a combination of B and C, and a combination of A, B, and C. "A and / or B" includes the following three combinations: only A, only B, and a combination of A and B.

[0115] In the present disclosure, unless otherwise stated, the meaning of "a plurality" is two or more.

[0116] Unless otherwise stated, in the present application, the numerical range listed includes all point values between the endpoints and the endpoints, and all sub-ranges consisting of the point values increasing or decreasing by the smallest unit of the endpoints and consisting of the point values.

[0117] Unless otherwise stated, numerical values ​​in this invention represent approximate measures or limitations on the range of embodiments including minute deviations from a given value and having approximately the mentioned value as well as having the mentioned precise value. Except in the detailed description of the final embodiments, all numerical values ​​of parameters (e.g., quantities or conditions) in this application (including the appended claims) should in all cases be understood to be modified by the term "approximately," regardless of whether "approximately" actually appears before the numerical value. "Approximately" indicates that the stated numerical value allows for slight inaccuracies (some close to precision at that value; approximately or reasonably close to the value; approximate). If the inaccuracy provided by "approximately" is not understood in this general sense in the art, then "approximately" as used herein at least indicates a variation that can be produced by common methods of measuring and using these parameters. For example, "approximately" can include variations less than or equal to 15%, less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, less than or equal to 0.1%, and in some respects, less than or equal to 0.01%.

[0118] The present invention has been described in detail above, but it is not limited to the above description. To keep the description of the embodiments of the present invention clear and concise, detailed descriptions of known functions and components have been omitted. Beneficial effects

[0119] The lacrimal canaliculus insert of the present invention has the following advantages in practical preparation and use:

[0120] 1. The mixture of matrix, buffer salts, and active pharmaceutical ingredients for treating dry eye is homogenized to ensure uniform distribution of active ingredients in the finished lacrimal canaliculus insert.

[0121] 2. The degradation time of the lacrimal canaliculus insert is related to the matrix composition ratio, and its degradation time can be as long as 70-100 days.

[0122] 3. The lacrimal canaliculus inserter has a stable process and can meet the requirements of mass production. Attached Figure Description

[0123] Figure 1: Pharmacokinetic data of the lacrimal canaliculus insert determined in Example 6. Detailed Implementation

[0124] The present application will be described in detail through specific embodiments. However, it should be understood that these embodiments are only illustrative, and are not intended to limit the present application and its use. In addition, the present application is not limited by any theory described in the foregoing prior art or summary or the following detailed description or examples. The described examples are part of the embodiments of the present application, but not all. Based on the described embodiments of the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application. The provided comparative examples are only to illustrate the technical effects of the present application, and are not considered in any way as prior art.

[0125] Unless otherwise specified, the raw materials used in the present application are commercially available pharmaceutical reagents meeting the requirements of ophthalmic drugs.

[0126] Raw materials and instruments:

[0127] Tacrolimus raw material was purchased from Aladdin, with an average particle size of 60 μm.

[0128] Dexamethasone raw material was purchased from Aladdin, with an average particle size of 50 μm.

[0129] Ristocetin was purchased from Aladdin, with an average particle size of 53 μm.

[0130] Indomethacin was purchased from Aladdin, with an average particle size of 65 μm.

[0131] 10k, 4-arm-PEG-SAP was purchased from Beijing KeyGen Biotech Co., Ltd.

[0132] 10k, 4-arm-PEG-NH2 was purchased from Beijing KeyGen Biotech Co., Ltd.

[0133] 10k, 4-arm-PEG-SG was purchased from Beijing KeyGen Biotech Co., Ltd.

[0134] 10k, 4-arm-PEG-SCM was purchased from Beijing KeyGen Biotech Co., Ltd.

[0135] 10k represents the weight average molecular weight of the polyethylene glycol segment is 10000D.

[0136] Other reagents are commercially available pharmaceutical reagents.

[0137] Degradation time detection method:

[0138] The tear duct insert agent is inserted into the lower tear ducts of both eyes of rabbits in New Zealand, and at a specified time, it is detected whether the tear duct insert agent still exists in the tear ducts of the rabbits. If it exists, it indicates that the tear duct insert agent has not been completely degraded, and if it does not exist, it is considered that the tear duct insert agent has been completely degraded, and the time from the last detection day to the detection day is considered as the degradation time of the tear duct insert agent.

[0139] Example 1: Tear duct insert agent 1

[0140] Preparation of tear duct insert agent 1

[0141] The tacrolimus raw material is micronized to obtain an average particle size of 2.8 μm.

[0142] A phosphate buffer is prepared using sodium dihydrogen phosphate, disodium hydrogen phosphate, and water for injection, and the pH is 6.5.

[0143] Anhydrous ethanol is diluted using the above phosphate buffer to obtain an ethanol solution with a volume fraction of 8% of 0.54 ml.

[0144] 0.030 g of 10 k, 4 arm-PEG-SAP is weighed and dissolved using 0.30 ml of the above ethanol solution to obtain a mixture 1;

[0145] 0.040 g of tacrolimus is weighed and added to the mixture 1, and is fully dispersed and ultrasonicated to obtain a mixture 2;

[0146] 0.030 g of polyethylene glycol amine (PEG-NH2) is weighed and dissolved using 0.24 ml of the above ethanol solution to obtain a mixture 3;

[0147] The mixtures 2 and 3 are mixed, and high-pressure homogenization (300 MPa, 400 rpm) is performed to obtain a mixture 4;

[0148] The mixture 4 is injected into a silica gel tube with a diameter of 2.0 mm using a syringe, and is left to form a gel, and the formed hydrogel is peeled off the silica gel tube after about 10 minutes;

[0149] The peeled hydrogel is placed on a stretching machine and is stretched 3 times along the axial direction of the hydrogel to increase its length;

[0150] The stretched hydrogel is placed in an environment of 25°C and 30% RH for continuous drying for 12 h to obtain a long rod-shaped tear duct insert agent with a diameter of 0.50 mm, and after cutting, a plurality of finished tear duct insert agents 1 with a diameter of about 0.50 mm and a length of 3.0 mm are obtained.

[0151] In vivo degradation observation of tear duct insert agent 1

[0152] The New Zealand rabbits were divided into 6 groups, 3 rabbits in each group, and each rabbit's lower tear ducts of both eyes were inserted with the tear duct insert 1.

[0153] The time for killing and performing eye dissection of each group of New Zealand rabbits was 40, 60, 70, 80, 90, and 100 days.

[0154] After dissection, it was observed that the tear duct insert was still present in the rabbits' tear ducts at 40, 60, 70, 80, and 90 days, but in 5 / 6 of the rabbits' tear ducts, the tear duct insert was not present at 100 days. The results are shown in Table 1.

[0155] Table 1: In vivo degradation of the tear duct insert 1

[0156] Wherein: "L" is the lower tear duct of the left eye, "R" is the lower tear duct of the right eye; "+" means that the tear duct insert is present in the tear duct; "-" means that the tear duct insert is not present in the tear duct.

[0157] Therefore, the degradation time of the tear duct insert 1 is 90-100 days.

[0158] Example 2: Tear duct insert 2

[0159] Preparation of the tear duct insert 2

[0160] The dexamethasone raw material was micronized to obtain an average particle size of 3.5 μm.

[0161] A phosphate buffer was prepared using sodium dihydrogen phosphate, disodium hydrogen phosphate, and water for injection, and the pH was 6.5.

[0162] The n-propyl alcohol was diluted using the above phosphate buffer to obtain a 0.56 ml n-propyl alcohol solution with a volume fraction of 12%.

[0163] 0.020 g of 10k, 4arm-PEG-SAP and 0.010 g of 10k, 4arm-PEG-SG were weighed and dissolved using 0.30 ml of the above n-propyl alcohol solution to obtain a mixture 1;

[0164] 0.030 g of dexamethasone was weighed and added to the mixture 1, and a mixture 2 was obtained by thoroughly dispersing and ultrasonicating;

[0165] 0.030 g of 10k, 4arm-PEG-NH2 was weighed and dissolved using 0.26 ml of the above n-propyl alcohol solution to obtain a mixture 3;

[0166] The mixtures 2 and 3 were mixed, and a mixture 4 was obtained by high-pressure homogenization (400 MPa, 300 rpm) treatment;

[0167] The mixed solution 4 was injected into a silica gel tube with a diameter of 2.0 mm using a syringe, and was left to form a gel. The formed hydrogel was peeled off the silica gel tube after about 10 minutes;

[0168] The peeled hydrogel was placed on a stretching machine and stretched 3 times along the axial direction of the hydrogel, so that the length was increased.

[0169] The stretched hydrogel was dried at 25°C and 30% RH for 12 hours, obtaining a long rod-shaped lacrimal canaliculus insert with a diameter of 0.50 mm. After cutting, a plurality of finished lacrimal canaliculus inserts 2 with a diameter of about 0.50 mm and a length of 3.0 mm were obtained.

[0170] In vivo degradation observation of the lacrimal canaliculus insert 2

[0171] New Zealand rabbits were divided into 6 groups, 3 rabbits in each group, and the lower lacrimal canaliculus of both eyes of each rabbit was inserted with the lacrimal canaliculus insert 2.

[0172] The New Zealand rabbits in each group were sacrificed and subjected to eye dissection at 40, 60, 70, 80, 90, and 100 days.

[0173] After dissection, it was observed that the lacrimal canaliculus insert was still present in the lacrimal canaliculus of the rabbits at 40, 60, 70, and 80 days; at 90 days, there was no lacrimal canaliculus insert in the lower lacrimal canaliculus of only one eye of a rabbit; and at 100 days, there was no lacrimal canaliculus insert in the lacrimal canaliculus of all rabbits. The results are shown in Table 2.

[0174] Table 2: In vivo degradation of the lacrimal canaliculus insert 2

[0175] Wherein: "L" is the lower lacrimal canaliculus of the left eye, "R" is the lower lacrimal canaliculus of the right eye; "+" means that the lacrimal canaliculus insert is present in the lacrimal canaliculus; "-" means that the lacrimal canaliculus insert is not present in the lacrimal canaliculus.

[0176] Therefore, the degradation time of the lacrimal canaliculus insert 2 is 90-100 days.

[0177] Example 3: Lacrimal canaliculus insert 3

[0178] Preparation of the lacrimal canaliculus insert 3

[0179] The lidamast raw material was micronized to obtain an average particle size of 3.5 μm.

[0180] A phosphate buffer was prepared using sodium dihydrogen phosphate, disodium hydrogen phosphate, and water for injection, with a pH of 6.5.

[0181] The above phosphate buffer was used to dilute methanol to obtain a 0.54 ml methanol solution with a volume fraction of 8%.

[0182] Take 0.020 g of 10k, 4arm-PEG-SAP and 0.020 g of 10k, 4arm-PEG-SG, dissolve using 0.30 ml of the above methanol solution to obtain mixture 1;

[0183] Take 0.050 g of litaoxetine and add to mixture 1, disperse thoroughly and ultrasonic to obtain mixture 2;

[0184] Take 0.050 g of 10k, 4arm-PEG-NH2, dissolve using 0.24 ml of the above methanol solution to obtain mixture 3;

[0185] Mix mixture 2 and 3, and perform high pressure homogenization (300 MPa, 300 rpm) to obtain mixture 4;

[0186] Inject mixture 4 into a silica gel tube with a diameter of 2.0 mm using a syringe, and let it gel, then peel off the formed hydrogel from the silica gel tube after about 10 minutes;

[0187] Place the peeled hydrogel on a stretching machine and stretch it 3 times along the axial direction of the hydrogel to increase its length;

[0188] Place the stretched hydrogel in an environment of 25°C and 30% RH for continuous drying for 12 hours to obtain a long rod-shaped lacrimal canal insert with a diameter of 0.50 mm, and cut it to obtain multiple finished lacrimal canal inserts 3 with a diameter of about 0.50 mm and a length of 3.0 mm.

[0189] In vivo degradation observation of lacrimal canal insert 3

[0190] Divide New Zealand rabbits into 6 groups, 3 rabbits in each group, and insert lacrimal canal insert 3 into the lower lacrimal canals of both eyes of each rabbit.

[0191] The time for sacrificing the New Zealand rabbits in each group and performing eye dissection is 40, 60, 70, 80, 90, and 100 days.

[0192] After dissection, it is observed that the lacrimal canal insert still exists in the lacrimal canals of the rabbits at 40, 60, 70, and 80 days; at 90 days, the lacrimal canal insert does not exist in the lacrimal canals of only one eye of one rabbit; and at 100 days, the lacrimal canal insert does not exist in the lacrimal canals of all rabbits. The results are shown in Table 3.

[0193] Table 3: In vivo degradation of lacrimal canal insert 3

[0194] Wherein: "L" is the lower lacrimal canal of the left eye, "R" is the lower lacrimal canal of the right eye, "+" means that the lacrimal canal insert exists in the lacrimal canal, and "-" means that the lacrimal canal insert does not exist in the lacrimal canal.

[0195] Therefore, the degradation time of the lacrimal canaliculus insert 3 is 90-100 days.

[0196] Example 4: Lacrimal canaliculus insert 4

[0197] Preparation of lacrimal canaliculus insert 4

[0198] The indomethacin raw material was micronized to obtain an average particle size of 4.3 μm.

[0199] A phosphate buffer was prepared using sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection, and the pH was 6.5.

[0200] The anhydrous ethanol was diluted using the above phosphate buffer to obtain an ethanol solution with a volume fraction of 8% and a volume of 0.54 ml.

[0201] 0.025 g of 10k, 4arm-PEG-SAP and 0.010 g of 10k, 4arm-PEG-SCM were weighed out and dissolved using 0.30 ml of the above ethanol solution to obtain a mixture 1;

[0202] 0.040 g of indomethacin was weighed out and added to the mixture 1, and was dispersed and ultrasonicated to obtain a mixture 2;

[0203] 0.030 g of 10k, 4arm-PEG-NH2 was weighed out and dissolved using 0.24 ml of the above ethanol solution to obtain a mixture 3;

[0204] The mixtures 2 and 3 were mixed, and high-pressure homogenization (200 MPa, 300 rpm) was performed to obtain a mixture 4;

[0205] The mixture 4 was injected into a silica gel tube with a diameter of 2.0 mm using a syringe, and was left to form a gel, and the formed hydrogel was peeled off the silica gel tube after about 10 minutes;

[0206] The peeled hydrogel was placed on a stretching machine and was stretched along the axial direction of the hydrogel by a factor of 3, so that the length was increased;

[0207] The stretched hydrogel was placed in an environment of 25°C and 30% RH and was continuously dried for 12 h to obtain a long rod-shaped lacrimal canaliculus insert with a diameter of 0.50 mm, and the finished lacrimal canaliculus insert 4 with a diameter of about 0.50 mm and a length of 3.0 mm was obtained after cutting.

[0208] In vivo degradation observation of lacrimal canaliculus insert 4

[0209] New Zealand rabbits were divided into 6 groups, with 3 rabbits in each group, and the lower lacrimal canaliculus of each rabbit was inserted with the lacrimal canaliculus insert 4.

[0210] The time for each group of New Zealand rabbits to be sacrificed and eye dissection was 40, 60, 70, 80, 90, 100 days.

[0211] After dissection, it was observed that the lacrimal canaliculus insert agent still existed in the lacrimal canaliculus of rabbits at 40 days, 60 days, and 70 days; at 80 days, the lacrimal canaliculus insert agent no longer existed in the right lower lacrimal canaliculus of one rabbit; at 90 days, the lacrimal canaliculus insert agent no longer existed in the lacrimal canaliculus of 5 / 6 rabbits. The results are shown in Table 4.

[0212] Table 4: In vivo degradation of lacrimal canaliculus insert agent 4

[0213] Wherein: "L" is the left lower lacrimal canaliculus, "R" is the right lower lacrimal canaliculus; "+" means that the lacrimal canaliculus insert agent exists in the lacrimal canaliculus; "-" means that the lacrimal canaliculus insert agent does not exist in the lacrimal canaliculus.

[0214] Therefore, the degradation time of the lacrimal canaliculus insert agent 4 is 80-90 days.

[0215] Example 5: Lacrimal canaliculus insert agent 5

[0216] Preparation of lacrimal canaliculus insert agent 5

[0217] The tacrolimus raw material was micronized to obtain an average particle size of 2.8 μm.

[0218] A phosphate buffer was prepared using sodium dihydrogen phosphate, disodium hydrogen phosphate, and water for injection, and the pH was 6.5.

[0219] The n-propyl alcohol was diluted using the above phosphate buffer to obtain a 0.56 ml n-propyl alcohol solution with a volume fraction of 12%.

[0220] 0.015 g of 10k, 4arm-PEG-SAP and 0.025 g of 10k, 4arm-PEG-SCM were weighed and dissolved using 0.30 ml of the above n-propyl alcohol solution to obtain a mixture 1;

[0221] 0.040 g of tacrolimus was weighed and added to the mixture 1, and was dispersed and ultrasonicated to obtain a mixture 2;

[0222] 0.040 g of 10k, 4arm-PEG-NH2 was weighed and dissolved using 0.26 ml of the above n-propyl alcohol solution to obtain a mixture 3;

[0223] The mixtures 2 and 3 were mixed and subjected to high-pressure homogenization (300 MPa, 300 rpm) to obtain a mixture 4;

[0224] The mixture 4 was injected into a silica gel tube with a diameter of 2.0 mm using a syringe, and was left to form a gel. The formed hydrogel was peeled off the silica gel tube after about 10 minutes.

[0225] The peeled hydrogel was placed on a stretching machine and stretched 3 times along the axis of the hydrogel to increase its length;

[0226] The stretched hydrogel was placed in an environment of 25°C and 30% RH for continuous drying for 12 hours to obtain long rod-shaped lacrimal canaliculus inserts with a diameter of 0.50 mm, which were cut to obtain multiple finished lacrimal canaliculus inserts 5 with a diameter of about 0.50 mm and a length of 3.0 mm.

[0227] In vivo degradation observation of lacrimal canaliculus insert 5

[0228] New Zealand rabbits were divided into 6 groups, 3 rabbits in each group, and the lower lacrimal canaliculus of each rabbit was inserted with lacrimal canaliculus insert 5.

[0229] The time for the New Zealand rabbits in each group to be sacrificed and subjected to eye dissection was 40, 60, 70, 80, 90, and 100 days.

[0230] After dissection, it was observed that the lacrimal canaliculus insert was still present in the lacrimal canaliculus of the rabbits at 40, 60, 70, and 80 days; at 90 days, the lacrimal canaliculus insert was no longer present in 1 / 3 of the rabbits; and at 100 days, the lacrimal canaliculus insert was no longer present in 5 / 6 of the rabbits. The results are shown in Table 5.

[0231] Table 5: In vivo degradation of lacrimal canaliculus insert 5

[0232] Wherein: “L” refers to the lower lacrimal canaliculus of the left eye, “R” refers to the lower lacrimal canaliculus of the right eye, “+” indicates the presence of a lacrimal canaliculus insert in the lacrimal canaliculus, and “-” indicates the absence of a lacrimal canaliculus insert in the lacrimal canaliculus.

[0233] Therefore, the degradation time of lacrimal canaliculus insert 5 is 90-100 days.

[0234] Example 6: Pharmacokinetic performance of lacrimal canaliculus insert

[0235] The lacrimal canaliculus insert 5 loaded with tacrolimus prepared in Example 5 was used as a model to evaluate the pharmacokinetic performance of the lacrimal canaliculus insert.

[0236] The performance of lacrimal canaliculus insert 5 was evaluated in a rabbit eye model to determine the in vivo correlation of tacrolimus release.

[0237] The lacrimal canaliculus insert 5 was inserted into the lower lacrimal canaliculus of a rabbit, and tear samples were analyzed by liquid chromatography over a period of 100 days. The results are shown in FIG. 1.

[0238] The results show that the drug in the lacrimal canaliculus insert maintains sustained release before the lacrimal canaliculus insert is completely degraded.

[0239] Comparative Example 1: Lacrimal canaliculus insert 6

[0240] Preparation of lacrimal canaliculus insert 6

[0241] The ritanserin raw material was micronized to obtain an average particle size of 3.5 μm.

[0242] A phosphate buffer was prepared using sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection, and the pH was 6.5.

[0243] Methanol was diluted using the above phosphate buffer to obtain a 0.54 ml methanol solution with a volume fraction of 8%.

[0244] 0.030 g of 10k, 4arm-PEG-SAP and 0.030 g of 10k, 4arm-PEG-SG were weighed out and dissolved using 0.30 ml of the above methanol solution to obtain a mixture 1;

[0245] 0.030 g of dexamethasone was weighed out and added to the mixture 1, and the mixture was dispersed and ultrasonicated to obtain a mixture 2;

[0246] 0.020 g of 10k, 4arm-PEG-NH2 was weighed out and dissolved using 0.24 ml of the above methanol solution to obtain a mixture 3;

[0247] The mixture 2 and 3 were mixed and subjected to high pressure homogenization (300 MPa, 300 rpm) to obtain a mixture 4;

[0248] The mixture 4 was injected into a silica gel tube with a diameter of 2.0 mm using a syringe, and the mixture was left to gel, and the formed hydrogel was peeled off the silica gel tube after about 10 minutes;

[0249] The peeled hydrogel was placed on a stretching machine and stretched 3 times along the axial direction of the hydrogel to increase the length;

[0250] The stretched hydrogel was placed in an environment of 25°C and 30% RH and dried for 12 h to obtain a long rod-shaped lacrimal canaliculus insert with a diameter of 0.50 mm, and the lacrimal canaliculus insert was cut to obtain a plurality of finished lacrimal canaliculus inserts 6 with a diameter of about 0.50 mm and a length of 3.0 mm.

[0251] In vivo degradation observation of lacrimal canaliculus insert 6

[0252] New Zealand rabbits were divided into 6 groups, 3 rabbits in each group, and the lower lacrimal canaliculus of each rabbit was inserted with the lacrimal canaliculus insert 6.

[0253] The New Zealand rabbits in each group were sacrificed and subjected to eye dissection at 40, 60, 70, 80, 90 and 100 days.

[0254] It was observed that the lacrimal canaliculus inserts were still present in the lacrimal canaliculus of the rabbits at 40 days; 1 / 3 of the lacrimal canaliculus of the rabbits had no lacrimal canaliculus insert at 60 days; and 5 / 6 of the lacrimal canaliculus of the rabbits had no lacrimal canaliculus insert at 70 days. The results are shown in Table 6.

[0255] Table 6: In vivo degradation of lacrimal canaliculus insert 6

[0256] Wherein: "L" is the left lower lacrimal canaliculus, "R" is the right lower lacrimal canaliculus; "+" means that the lacrimal canaliculus insert is present in the lacrimal canaliculus; "-" means that the lacrimal canaliculus insert is not present in the lacrimal canaliculus.

[0257] Therefore, the degradation time of the lacrimal canaliculus insert 6 is 60-70 days.

[0258] Comparative Example 2: Lacrimal canaliculus insert 7

[0259] Preparation of lacrimal canaliculus insert 7

[0260] The indomethacin raw material was micronized to obtain an average particle size of 4.3 μm.

[0261] A phosphate buffer was prepared using sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection, and the pH was 6.5.

[0262] The above phosphate buffer was used to dilute absolute ethanol to obtain an ethanol solution with a volume fraction of 8% and a volume of 0.54 ml.

[0263] 0.015 g of 10k, 4arm-PEG-SAP and 0.015 g of 10k, 4arm-PEG-SG were weighed and dissolved using 0.30 ml of the above ethanol solution to obtain a mixture 1;

[0264] 0.040 g of indomethacin was weighed and added to the mixture 1, and was dispersed and ultrasonicated to obtain a mixture 2;

[0265] 0.050 g of 10k, 4arm-PEG-NH2 was weighed and dissolved using 0.24 ml of the above ethanol solution to obtain a mixture 3;

[0266] The mixtures 2 and 3 were mixed and subjected to high-pressure homogenization (300 MPa, 300 rpm) to obtain a mixture 4;

[0267] The mixture 4 was injected into a silica gel tube with a diameter of 2.0 mm using a syringe, and was left to form a gel, and the formed hydrogel was peeled off the silica gel tube after about 10 minutes;

[0268] The peeled hydrogel was placed on a stretching machine and was stretched along the axial direction of the hydrogel by 3 times to increase the length;

[0269] The stretched hydrogel was placed in a 25°C, 30% RH environment for continuous drying for 12 h to obtain a long rod-shaped lacrimal canaliculus insert with a diameter of 0.50 mm, and after cutting, a plurality of finished lacrimal canaliculus inserts 7 with a diameter of about 0.50 mm and a length of 3.0 mm were obtained.

[0270] In vivo degradation observation of the lacrimal canaliculus insert 7

[0271] The New Zealand rabbits were divided into 6 groups, 3 rabbits in each group, and the lower lacrimal canaliculus of each rabbit was inserted with the lacrimal canaliculus insert 7.

[0272] The New Zealand rabbits in each group were sacrificed and subjected to eye dissection at 40, 60, 70, 80, 90 and 100 days.

[0273] After dissection, it was observed that at 40 days, the lacrimal canaliculus insert was present in all rabbit lacrimal canaliculi; at 60 days, the lacrimal canaliculus insert was not present in 1 / 6 of the rabbit lacrimal canaliculi. The results are shown in Table 7.

[0274] Table 7: In vivo degradation of the lacrimal canaliculus insert 7

[0275] Wherein: "L" is the lower lacrimal canaliculus of the left eye, "R" is the lower lacrimal canaliculus of the right eye; "+" means that the lacrimal canaliculus insert is present in the lacrimal canaliculus; "-" means that the lacrimal canaliculus insert is not present in the lacrimal canaliculus.

[0276] Therefore, the degradation time of the lacrimal canaliculus insert 7 is 40-60 days.

[0277] According to the description of the above examples, it can be seen that, using the specific prescription of the present application, especially by selecting specific hydrogel components and specific proportions, a lacrimal canaliculus insert with a degradation time of 80-100 days can be obtained. And during the degradation time, the drug in the insert is in a sustained release state.

[0278] According to Comparative Examples 1-2, it can be seen that if the proportion of the hydrogel components exceeds the above-mentioned proportion, the obtained lacrimal canaliculus insert will be unstable and prone to degradation.

Claims

1. A degradable canaliculus insert, wherein, Each insert comprises: (1) 0.15-1.0 mg of a hydrogel matrix, (2) 0.01-1.0 mg of a poorly soluble pharmaceutically active ingredient distributed in the hydrogel matrix; (3) 0-0.30 mg of a buffer salt, wherein the hydrogel matrix is formed by reacting a multi-armed polyethylene glycol derivative 1 of formula I and a multi-armed polyethylene glycol amine: Multi-armed PEG-A (I) wherein A represents a functional group attached to the end of the multi-armed PEG and is selected from:

2. The degradable canaliculus insert of claim 1, wherein, Each insert comprises (1) 0.4-0.95 mg, preferably 0.5-0.9 mg of a hydrogel matrix, (2) 0.05-0.9 mg, preferably 0.10-0.8 mg of a poorly soluble pharmaceutically active ingredient, (3) 0.01-0.25 mg, preferably 0.02-0.20 mg of a buffer salt.

3. The degradable canaliculus insert of claim 1 or 2, wherein, The multi-armed polyethylene glycol derivative 1 is selected from one or more of multi-armed polyethylene glycol succinimidyl succinate, multi-armed polyethylene glycol succinimidyl glutarate, multi-armed polyethylene glycol succinimidyl glutaramide, multi-armed polyethylene glycol succinimidyl carboxymethyl ester, multi-armed polyethylene glycol succinimidyl adipate, multi-armed polyethylene glycol succinimidyl carbonate, multi-armed polyethylene glycol succinimidyl propionate.

4. The degradable canaliculus insert of any one of claims 1-3, wherein, The multi-armed polyethylene glycol derivative 1 and the multi-armed polyethylene glycol amine comprise multi-arms selected from 2-10 arms, preferably 4 arms or 8 arms.

5. The degradable canaliculus insert of any one of claims 1-4, wherein, The polyethylene glycol segments of the multi-armed polyethylene glycol derivative 1 and the multi-armed polyethylene glycol amine have a molecular weight of 5000 to 25000 D, preferably 8000 to 20000 D, more preferably 10000 to 15000 D.

6. The degradable canaliculus insert of any one of claims 1-5, wherein, The multi-armed polyethylene glycol derivative 1 and the multi-armed polyethylene glycol amine have a weight ratio of 1 : (0.5-1.5), preferably 1 : (0.8-1.4), more preferably 1 : (0.85-1.3).

7. The degradable punctal insert of any one of claims 1-6, wherein The multi-armed polyethylene glycol derivative 1 is 4-armed polyethylene glycol succinimidyl adipate; a combination of 4-armed polyethylene glycol succinimidyl adipate and 4-armed polyethylene glycol succinimidyl glutarate, wherein the weight ratio of 4-armed polyethylene glycol succinimidyl adipate to 4-armed polyethylene glycol succinimidyl glutarate is 2:1 to 1:2; or a combination of 4-armed polyethylene glycol succinimidyl adipate and 4-armed polyethylene glycol succinimidyl carboxymethyl ester, wherein the weight ratio of 4-armed polyethylene glycol succinimidyl adipate to 4-armed polyethylene glycol succinimidyl carboxymethyl ester is 5:1 to 1:5; The multi-armed polyethylene glycol amine is 4-armed polyethylene glycol amine.

8. The degradable canaliculus insert of any one of claims 1-7, wherein, The poorly soluble pharmaceutically active ingredient is selected from one or more of tacrolimus, cyclosporin, dexamethasone, lifitegrast, indomethacin, or a pharmaceutically acceptable salt thereof.

9. The degradable canaliculus insert of any one of claims 1-8, wherein, Average particle size D of poorly soluble active pharmaceutical ingredient 90 The size is 20 μm or less, preferably 10 μm or less, and especially 5 μm or less, for example, 2.0-5.0 μm.

10. The degradable canaliculus insert of any one of claims 1-9, wherein, The buffer salt is selected from a phosphate buffer salt, a citrate buffer salt, an acetate buffer salt, particularly preferably a phosphate buffer salt.

11. The degradable punctal insert of any one of claims 1-10, comprising an organic solvent in an amount of greater than 0 and less than or equal to 1000 ppm, for example 5 ppm to 500 ppm, or 10 ppm to 200 ppm, or 20 ppm to 100 ppm. In particular, the organic solvent is not a solvent belonging to the first category as stipulated in the Chinese Pharmacopoeia 2020 edition; In particular, the organic solvent is an organic solvent that can be miscible with water and has a boiling point of 50-150℃. In particular, the organic solvent is one or more selected from methanol, ethanol, acetic acid, isopropanol, n-propanol, and acetone.

12. The degradable punctal plug of any one of claims 1-11, which does not comprise a suspending agent, a wetting agent, a flocculating agent, and a clathrating agent.

13. A method for preparing the degradable punctal plug of any one of claims 1-12, comprising the following steps: (1) adding an organic solvent to a pH buffer to obtain an organic solvent-buffer 1; (2) dissolving a multi-arm polyethylene glycol derivative 1 in the organic solvent-buffer 1 to obtain a mixture 1; (3) adding a poorly soluble pharmaceutically active ingredient to the mixture 1 to obtain a mixture 2; (4) dissolving a multi-arm polyethylene glycol amine in a pH buffer or the organic solvent-buffer 1 to obtain a mixture 3; (5) mixing the mixture 2 and the mixture 3 to obtain a mixture 4; (6) injecting the mixture 4 into a circular mold, allowing the mixture to form a hydrogel, and then taking the hydrogel out of the mold; (7) stretching the hydrogel, and then drying and cutting the hydrogel to obtain a finished punctal plug.

14. The method of claim 13, wherein, in the organic solvent-buffer 1, the volume concentration of the organic solvent in the pH buffer is 5-50%, preferably 5-30%, and more preferably 8-20%; in step (5), the mixing is completed by homogenization, for example, using a homogenizer at a pressure of 100-500 MPa; the rotation speed for homogenization is 100-500 rpm; and the homogenization is performed at room temperature to 40℃; in the mixture 4, the concentration of the multi-arm polyethylene glycol derivative 1 is 1-20 w / w%, preferably 2-10%; and the concentration of the multi-arm polyethylene glycol amine is 1-20 w / w%, preferably 2-10%; in step (6), the circular mold is selected from a silica gel tube with a diameter of 0.5 mm-2 mm or a polytetrafluoroethylene tube with a diameter of 0.5 mm-2 mm; the standing is performed at 10-50℃ under a pressure of 0.05-0.2 MPa for more than 5 minutes; in step (7), the stretching ratio of the punctal plug is 1.1-10 times.

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