Degradable lacrimal ductule insertion agent and preparation method thereof

Abstract

The invention relates to a degradable lacrimal ductule insertion agent and a preparation method thereof. In the degradable lacrimal canaliculus insertion agent, each insertion agent contains 0.15 to 1.0 mg of hydrogel matrix, 0.01 to 1.0 mg of insoluble drug active ingredients distributed in the hydrogel matrix, and 0 to 0.30 mg of buffer salt. According to the degradable lacrimal canaliculi insertion agent, the degradation time of the prepared lacrimal canaliculi insertion agent can be prolonged to about 3 months, and the compliance of a patient with xerophthalmia during use is improved. Besides, the inventor explores the preparation process of the lacrimal canaliculi insertion agent, so that the indissolvable active ingredients are uniformly distributed in the lacrimal canaliculi insertion agent, quality control in actual production is facilitated, and the preparation process is stable and can be used for industrial continuous batch production.

Description

Technical Field

[0001] The invention belongs to the technical field of lacrimal canaliculus inserts, and particularly relates to a degradable lacrimal canaliculus insert and a preparation method thereof. Background Art

[0002] Dry eye syndrome is a syndrome characterized by symptoms such as foreign body sensation, burning, or irritation, typically caused by decreased tear production or increased tear film loss due to tear evaporation. Existing treatments for dry eye primarily involve the use of artificial tears to compensate for insufficient tear production or anti-inflammatory drugs to control inflammation. However, the effects of these eye drops are temporary and require multiple daily applications, significantly reducing patient compliance.

[0003] An ophthalmic canaliculus insert is a drug-based formulation that is non-invasively inserted into the canaliculus of the eyelid, resulting in a slow, sustained release of the active ingredient. Compared to traditional eye drops, ophthalmic inserts offer the advantage of increased ocular retention, thereby prolonging the duration of action of the active ingredient. Depending on the delivery matrix and delivery method, sustained release can last from several days to several months. In terms of duration of action, they offer significant advantages over ophthalmic suspensions and gels.

[0004] CN109077993B discloses loading a lacrimal canaliculus insert with drugs for treating eye diseases (such as glaucoma, dry eye, conjunctivitis, etc.), but the product only has a degradation time of about one month. This is too short for eye diseases that require long-term or continuous treatment (such as dry eye), and the release of the drug at this time may not bring the expected therapeutic effect. After the lacrimal canaliculus insert degrades and falls off, it is necessary to go to the hospital to insert a new insert to maintain the efficacy of the drug. However, this is still a relatively frequent insertion operation for patients, which will greatly reduce the patient's compliance. Therefore, it is more reasonable to formulate a corresponding insert degradation time based on the drug carried by the insert and its corresponding disease treatment cycle.

[0005] Compared to general suspensions, the national standard has stricter requirements for the composition of lacrimal inserts. The 2020 First Supplement to the Chinese Pharmacopoeia also clearly stipulates that "ophthalmic inserts must not contain antibacterial agents, antioxidants, or inappropriate additives." Generally speaking, the preparation of suspensions requires the addition of additives such as suspending agents, cosolvents, and wetting agents to stabilize and evenly distribute drug particles. However, lacrimal inserts are not suitable for the purpose of controlling the uniform distribution of the drug in the liquid. Especially after the matrix has dried, there is a risk that the excipient additives will exceed the safe dosage percentage. However, many drugs are not highly soluble in water. When loaded into hydrogel-based canaliculus inserts without the addition of additives such as suspending agents, cosolvents, and wetting agents to stabilize and evenly distribute the drug particles, uneven drug dispersion and the generation of bubbles can occur. This can lead to uneven surfaces or drug particle adhesion, resulting in uneven surfaces with burrs and cracks, leading to poor patient compliance. Furthermore, uneven drug dispersion within the canaliculus insert can lead to inconsistent drug release rates, with some sites releasing the drug at higher rates while others release it at lower rates. This can affect the consistency and predictability of therapeutic effects and prevent them from providing stable therapeutic effects.

[0006] Furthermore, drug quality and stability directly impact therapeutic efficacy and safety. For ocular drug delivery systems like punctal inserts, ensuring uniformity is particularly crucial, as even minor variations can affect drug release rate and therapeutic efficacy. Therefore, batch-to-batch consistency is crucial during the production process.

[0007] Therefore, there is a need to develop a lacrimal duct insert with a long degradation time, uniform drug content and stable process. Summary of the Invention

[0008] To address these issues, the inventors, through repeated experiments, discovered that by combining two specific hydrogel precursors and their dosages, the degradation time of the prepared canaliculus insert could be extended to approximately three months, improving the compliance of dry eye patients. Furthermore, by exploring the preparation process for the canaliculus insert, the inventors achieved uniform distribution of the poorly soluble active ingredient within the canaliculus insert, facilitating quality control in actual production. Furthermore, the preparation process is stable and amenable to industrialized continuous batch production. This led to the completion of the present invention.

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

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

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

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

[0013] The hydrogel matrix is formed by reacting a multi-arm polyethylene glycol derivative 1 of formula I with a multi-arm polyethylene glycol amine (Multi-arm-PEG-NH2):

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

[0015] Wherein, A represents the functional group connected to the end of the multi-arm PEG, each independently selected from:

[0016] Succinimidyl succinate (SS):

[0017] Succinimidyl glutarate (SG):

[0018] Succinimidylglutaramide (SGA):

[0019] Succinimidyl carboxymethyl ester (SCM):

[0020] Succinimidyl adipate (SAP):

[0021] Succinimidyl carbonate (SC):

[0022] Succinimidyl propionate (SPA):

[0023] In some embodiments, each degradable lacrimal duct insert 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, or 0.85 mg of the hydrogel matrix, but is not limited thereto.

[0024] In some embodiments, the multi-arm polyethylene glycol derivative 1 can be selected from one or more of multi-arm polyethylene glycol succinimidyl succinate (Multi-arm-PEG-SS), multi-arm polyethylene glycol succinimidyl glutarate (Multi-arm-PEG-SG), multi-arm polyethylene glycol succinimidyl glutarate (Multi-arm-PEG-SGA), multi-arm polyethylene glycol succinimidyl carboxymethyl ester (Multi-arm-PEG-SCM), multi-arm polyethylene glycol succinimidyl adipate (Multi-arm-PEG-SAP), multi-arm polyethylene glycol succinimidyl carbonate (Multi-arm-PEG-SC), and multi-arm polyethylene glycol succinimidyl propionate (Multi-arm-PEG-SPA).

[0025] In some embodiments, in the multi-arm polyethylene glycol derivative 1 and the multi-arm polyethylene glycol amine, the multi-arm is selected from 2-10 arms, such as two arms, three arms, four arms, six arms, eight arms, ten arms, etc., in particular, the multi-arm is 4 arms or 8 arms.

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

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

[0028] In the present invention, a lacrimal canaliculus insert with a controllable degradation time can be obtained by combining a multi-arm polyethylene glycol derivative 1 and a multi-arm polyethylene glycol amine. In some embodiments, the weight ratio of the multi-arm polyethylene glycol derivative 1 to the multi-arm polyethylene glycol amine can be 1:(0.5-1.5), for example, 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 1:(0.8-1.4), and more preferably 1:(0.85-1.3). Within the above weight ratio range, a lacrimal canaliculus insert with a degradation time of approximately 3 months is advantageously obtained.

[0029] In some embodiments, the multi-arm polyethylene glycol derivative 1 can be 4-arm polyethylene glycol succinimidyl adipate (4arm-PEG-SAP); a combination of 4-arm polyethylene glycol succinimidyl adipate (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, for example, 2:1, 1:1, 1:2, etc.; or a combination of 4-arm polyethylene glycol succinimidyl adipate (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, for example, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, etc.

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

[0031]

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

[0033]

[0034] 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:

[0035]

[0036] In some embodiments, the multi-arm polyethylene glycol amine may be a 4-arm polyethylene glycol amine (4arm-PEG-NH2).

[0037] For example, 4-arm polyethylene glycol amine (4arm-PEG-NH2) can have a structure shown in Formula V, but is not limited thereto:

[0038]

[0039] In the above formulae III to VI, X represents a tetravalent group derived from the central molecule.

[0040] In the present invention, multi-arm polyethylene glycol (Multi-Arm Polyethylene Glycol) refers to a polyethylene glycol having multiple PEG branches in its 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-design and customization, or can be prepared by any available method. For example, multi-arm polyethylene glycol can be formed by initiating ethylene oxide polymerization with glycerol, polyglycerol, pentaerythritol, oligopentaerythritol, sorbitol, etc. as the central molecule, but the present invention is not limited thereto.

[0041] In the present invention, when the polyethylene glycol derivative 1 and the polyethylene glycol amine are mixed, the functional group A of the polyethylene glycol derivative 1 (the relevant structure is represented by ) and -NH2 (the related structure is represented by R2-NH2) can undergo the reaction shown in Reaction Formula I to produce a cross-linked structure.

[0042]

[0043] In the present invention, the poorly soluble active pharmaceutical ingredient refers to an active pharmaceutical ingredient that is poorly soluble or insoluble in water. In an embodiment, the poorly soluble active pharmaceutical ingredient is an active pharmaceutical ingredient for treating dry eye, and can be selected from one or more of tacrolimus, cyclosporine, dexamethasone, rifalast, indomethacin, or pharmaceutically acceptable salts thereof, but is not limited thereto.

[0044] The English name of tacrolimus is tacrolimus, and its structure is

[0045] Cyclosporine is an English name of Cyclosporine, and its structure is

[0046] Dexamethasone is called dexamethasone in English and its structure is

[0047] Lifitegrast is called lifitegrast in English and has a structure of

[0048] Indometacin is called Indometacin in English and its structure is

[0049] In some embodiments, each degradable lacrimal duct insert contains 0.05-0.9 mg, such as 0.10-0.8 mg, such as 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80 mg of the poorly soluble pharmaceutical active ingredient, but is not limited thereto.

[0050] In the present invention, the inventors, through repeated experiments, discovered that the combination of the multi-arm polyethylene glycol derivative 1 and the multi-arm polyethylene glycol amine can extend the degradation time of the lacrimal duct insert to approximately three months, specifically 70-100 days, thereby improving the compliance of dry eye patients. Without being limited by theory, when the specific multi-arm polyethylene glycol derivative 1 and the multi-arm polyethylene glycol amine are selected, the hydrophobic regions of the multi-arm polyethylene glycol derivative 1 and the multi-arm polyethylene glycol amine can bind to the poorly soluble active pharmaceutical ingredient, helping to evenly distribute the poorly soluble active pharmaceutical ingredient and affecting its release.

[0051] In some embodiments, in the degradable lacrimal duct insert according to the present invention, the average particle size D of the poorly soluble active pharmaceutical ingredient is 90 The particle size is 20 μm or less, preferably 10 μm or less, and 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, and the like, for example, 2.0-5.0 μm. Within this particle size range, the active pharmaceutical ingredient is uniformly distributed in the canaliculus insert. When the average particle size is greater than 20 μm, the active ingredient may agglomerate, resulting in uneven dispersion of the active pharmaceutical ingredient, resulting in an uneven and rough surface of the prepared canaliculus insert, and the final product may be unqualified.

[0052] In the present invention, a buffer salt is used to adjust the pH of the canaliculus insert to match the pH of tears, reduce irritation, and improve patient compliance. Generally, the pH of tears is 5.20-8.35. Therefore, the pH of the canaliculus insert is preferably adjusted to 5.20-8.35 using a buffer salt, more preferably to 6.0-7.0, such as 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, etc., with 6.5 being particularly preferred. Any buffer salt suitable for administration to the eye can be used without particular limitation, as long as it can be adjusted to an appropriate pH. The choice of buffer salt is within the purview of those skilled in the art and can be selected based on the pH of tears or the pH range tolerated by the normal human eye. Therefore, a detailed description is not provided to avoid obscuring the main points of the present invention.

[0053] For example, the buffer salt can be selected from phosphate buffer, citrate buffer, and acetate buffer, with phosphate buffer being particularly preferred. Phosphate buffer refers to a buffer salt composed of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, or disodium hydrogen phosphate, sodium dihydrogen phosphate. Citrate buffer refers to a buffer salt composed of sodium citrate and citric acid. Acetate buffer refers to a buffer salt composed of acetic acid and sodium acetate. During the preparation of the lacrimal duct insert according to the present invention, the above-mentioned buffer salts are formulated into a buffer solution for use.

[0054] In some embodiments, each degradable lacrimal duct insert contains 0.01-0.25 mg, such as 0.02-0.20 mg, such as 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 buffer salt, but is not limited thereto.

[0055] In some embodiments, the degradable lacrimal duct insert according to the present invention may contain trace amounts of organic solvents used during the preparation process. 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.

[0056] In some embodiments, the organic solvent is not a solvent belonging to the first category (which should be avoided) as specified in the Chinese Pharmacopoeia 2020 Edition.

[0057] In some embodiments, the organic solvent is miscible with water and has a boiling point of 50-150°C.

[0058] In some embodiments, the organic solvent is one or more selected from 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), isopropyl alcohol (boiling point 82°C), n-propyl alcohol (boiling point 95.8°C), and acetone (boiling point 56°C), but is not limited thereto. In particular, the organic solvent is ethanol, methanol, n-propyl alcohol, or isopropyl alcohol.

[0059] By using these organic solvents during the preparation process, the solubility of poorly soluble active ingredients can be increased, helping to evenly disperse the active ingredients. The specific solvents employed in the present invention have a relatively low boiling point and are volatile. They are largely evaporated during the drying process of the canaliculus insert, resulting in low residual organic solvent levels and ensuring the safety of the finished canaliculus insert.

[0060] Furthermore, compared to general suspensions, the national standard has stricter requirements for the composition of lacrimal inserts. The 2020 First Supplement to the Chinese Pharmacopoeia also explicitly stipulates that "ophthalmic inserts must not contain antibacterial agents, antioxidants, or inappropriate additives." Generally speaking, the preparation of suspensions requires the addition of additives such as suspending agents, cosolvents, and wetting agents to stabilize and evenly distribute drug particles. However, lacrimal inserts are not suitable for the addition of these substances to control the uniform distribution of the drug in the liquid. Especially after the matrix has dried, there is a risk that the excipient additives will exceed the safe dosage percentage.

[0061] Therefore, the degradable lacrimal duct insert according to the present invention does not contain additives such as suspending agents, wetting agents, flocculants, and co-solvents.

[0062] The degradation time of the degradable lacrimal duct insert of the present invention is 70-100 days. Furthermore, the degradation time is 80-100 days.

[0063] In addition to the aforementioned features, the degradable canaliculus insert according to the present invention may share the characteristics of conventional canaliculus inserts. For example, the canaliculus insert may have a diameter of 0.2-0.8 mm and a length of 1-5 mm. Upon contact with water, the canaliculus insert may expand to a diameter of 0.81-2.1 mm and shrink to a length of 0.8-4.0 mm.

[0064] Another aspect of the present invention provides a method for preparing the above-mentioned degradable lacrimal duct insert, comprising the following steps:

[0065] (1) adding an organic solvent to a pH buffer solution to obtain an organic solvent-buffer solution 1;

[0066] (2) adding the multi-arm polyethylene glycol derivative 1 to an organic solvent-buffer 1 to dissolve the mixture to obtain a mixed solution 1;

[0067] (3) adding the poorly soluble active ingredient to the mixed solution 1 to obtain the mixed solution 2;

[0068] (4) adding the multi-arm polyethylene glycol amine to a pH buffer solution or an organic solvent-buffer solution 1 to dissolve the mixture to obtain a mixed solution 3;

[0069] (5) Mixing the mixed solution 2 and the mixed solution 3 to obtain a mixed solution 4;

[0070] (6) injecting the mixed solution 4 into a circular mold, allowing it to stand to form a hydrogel, and then removing the hydrogel from the mold;

[0071] (7) The taken-out hydrogel is stretched, dried, and cut to obtain a finished lacrimal duct insert.

[0072] The following is a detailed description of each of the above steps.

[0073] Step (1):

[0074] In step (1), an organic solvent is first added to a pH buffer solution to obtain an organic solvent-buffer solution 1.

[0075] The organic solvent may be any organic solvent that helps to improve the solubility of poorly soluble active pharmaceutical ingredients and facilitates the uniform dispersion of the active pharmaceutical ingredients.

[0076] In some embodiments, the organic solvent is miscible with water and has a boiling point of 50-150°C.

[0077] In some embodiments, the organic solvent is not a solvent belonging to the first category (which should be avoided) as specified in the Chinese Pharmacopoeia 2020 Edition.

[0078] In some embodiments, the organic solvent is one or more selected from 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), and acetone (boiling point 56°C), but is not limited thereto.

[0079] The pH buffer solution is a solution formed by dissolving the aforementioned buffer salt in water, with a pH of 5.20-8.35, preferably 6.0-7.0, and more preferably 6.5. The pH buffer solution can be commercially available or can be prepared according to a formula, and the present invention is not limited thereto. The description of the buffer salt is the same as above and will not be repeated here.

[0080] 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%, more preferably 8-20%, for example 8%, 10%, 12%, 15%, 20%, etc. Within this concentration range, the poorly soluble active ingredient is uniformly dispersed, and this concentration ensures that the buffer salt in the buffer does not precipitate.

[0081] Step (2):

[0082] In step (2), the multi-arm polyethylene glycol derivative 1 is added to an organic solvent-buffer 1 to dissolve it, thereby obtaining a mixed solution 1. The description of the multi-arm polyethylene glycol derivative 1 is the same as that described above and will not be repeated here.

[0083] The concentration of the multi-arm polyethylene glycol derivative 1 in the mixed solution 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 ensure that the multi-arm polyethylene glycol derivative 1 has an appropriate concentration in the final mixed solution 4 to form a hydrogel.

[0084] Step (3):

[0085] In step (3), the poorly soluble active ingredient of the drug is added to the mixed solution 1 to obtain the mixed solution 2.

[0086] The description of the poorly soluble active ingredient is the same as above and will not be repeated here.

[0087] The pharmaceutical active ingredient meeting the particle size requirements may be commercially available, or an active ingredient product meeting the particle size requirements may be obtained by micronizing an active ingredient having a large particle size.

[0088] There are no particular limitations on the micronization method; any suitable micronization method known in the relevant art may be employed, as long as the particle size requirements are met and the product is suitable for use in lacrimal duct inserts. Examples include, but are not limited to, spray drying, grinding, and ball milling.

[0089] The micronization treatment can be performed before adding the active pharmaceutical ingredient to the mixed solution 1, or can be performed simultaneously during the mixing. For example, a step of micronizing the active pharmaceutical ingredient to obtain an active pharmaceutical ingredient that meets the particle size requirements can be added to step (3), or the active pharmaceutical ingredient can be mixed with part or all of the mixed solution 1 before micronization.

[0090] There is no particular limitation on the method for mixing the active pharmaceutical ingredients, and the mixture may be mixed by any suitable method (eg, ultrasound, stirring, shaking, homogenization, etc.). In some embodiments, ultrasound mixing may be used to achieve uniform mixing.

[0091] Step (4):

[0092] In step (4), the multi-arm polyethylene glycol amine is added to a pH buffer solution or an organic solvent-buffer solution 1 to dissolve the mixture to obtain a mixed solution 3.

[0093] The concentration of the multi-arm polyethylene glycol amine in the mixed solution 3 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 pH buffer or organic solvent-buffer 1 to fully dissolve the multi-arm polyethylene glycol amine and ensure that the multi-arm polyethylene glycol amine has an appropriate concentration in the final mixed solution 4 to form a hydrogel.

[0094] Step (4) can be performed simultaneously with steps (1) to (3) or sequentially.

[0095] Step (5):

[0096] In step (5), the mixed solution 2 and the mixed solution 3 are mixed to obtain a mixed solution 4.

[0097] Mixing can be achieved by any suitable mixing means (eg, stirring, sonication, homogenization, etc.).

[0098] Preferably, the mixing is accomplished by homogenization, for example, using a homogenizer at a pressure of 100-500 MPa.

[0099] The homogenization treatment under the above-mentioned high-pressure conditions can further promote the dispersion of the mixed solution, and the high pressure and shear force can decompose or remove the agglomerates of the active ingredients in the lacrimal duct insert.

[0100] The homogenization pressure is 100-500 MPa, preferably 200-450 MPa, more preferably 250-400 MPa, such as 280 MPa, 300 MPa, 350 MPa, 400 MPa, etc., but not limited thereto. Under these conditions, agglomerates of poorly soluble active pharmaceutical ingredients can be removed by high-pressure decomposition, which is beneficial for the uniform dispersion of the poorly soluble active pharmaceutical ingredients. If the pressure is too high, the hydrogel precursor may break, affecting gelation, while if the pressure is too low, the agglomerates of the poorly soluble active ingredients may not be completely removed.

[0101] The speed for homogenization can be 100-500 rpm, preferably 150-400 rpm, more preferably 200-400 rpm, such as 240 rpm, 300 rpm, 320 rpm, 400 rpm, etc., but not limited thereto. Under such conditions, it is advantageous to decompose the agglomerates of the poorly soluble active ingredient by high shear force, which is beneficial for the uniform dispersion of the poorly soluble pharmaceutical active ingredient. If the speed is too high, the hydrogel precursor may be severely destroyed by the high shear force, affecting gelation, while if the speed is too low, the agglomerates of the poorly soluble active ingredient may not be completely removed.

[0102] The temperature of the homogenization treatment is not particularly limited, and the homogenization treatment can be performed at room temperature to 40°C.

[0103] 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 not limited thereto.

[0104] 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 not limited thereto.

[0105] Within the above concentration range, the swelling range of the prepared lacrimal duct insert can be guaranteed to be consistent with the tolerance of the lacrimal duct tissue, and the degradation time can be guaranteed to be within the range of 70-100 days. If the concentration of the multi-arm polyethylene glycol derivative 1 and the multi-arm polyethylene glycol amine is too high, the prepared lacrimal duct insert will swell excessively, causing pressure on the lacrimal duct tissue and reducing patient compliance; while if the concentration is too low, the degradation time will be far lower than the desired degradation time, requiring patients to frequently replace the lacrimal duct insert, reducing patient compliance.

[0106] Step (6):

[0107] In step (6), the mixed solution 4 is injected into a circular mold, allowed to stand to form a hydrogel, and then the hydrogel is taken out of the mold.

[0108] The circular mold can be any mold suitable for forming a hydrogel into a shape for producing a lacrimal canaliculus insert, such as a flexible tube or a mold with a circular void. In some embodiments, the circular mold can be selected from a silicone tube with a diameter of 0.5 mm to 2 mm or a polytetrafluoroethylene tube with a diameter of 0.5 mm to 2 mm.

[0109] There is no particular limitation on the standing conditions, and any suitable conditions in the art may be used as long as a hydrogel is formed. For example, the standing condition may be performed at 10-50° C. and 0.05-0.2 MPa for more than 5 minutes, for example, 10 minutes, but the present invention is not limited thereto.

[0110] During the standing process, the functional group A in the multi-arm polyethylene glycol derivative 1 (the relevant structure is shown as ) and the -NH2 in the multi-arm polyethylene glycol amine (the related structure is represented by R2-NH2) can undergo the reaction formula I above to produce a cross-linked structure.

[0111] Step (7):

[0112] In step (7), the taken-out hydrogel is stretched axially to increase its length, and then dried and cut to obtain a finished lacrimal duct insert.

[0113] Step (7) can be performed by any suitable method in the art. It does not involve the inventive point of the present invention and is therefore not described in detail to avoid obscuring the innovative point of the present invention.

[0114] In some embodiments, the stretching ratio of the lacrimal duct insert is 1.1-10 times, for example, 1.5, 2., 3, 4, 5, 6, 7, 8, 9 times, etc. Here, the stretching ratio refers to the change ratio of the length of the hydrogel.

[0115] The drying may be performed once or multiple times until the organic solvent and water content in the lacrimal duct insert meet the specification requirements.

[0116] In some embodiments, the drying is performed at 20-30° C. and 20-40% RH for 2-24 hours, but the present invention is not limited thereto.

[0117] In the present invention, the word "comprise" or its variations, such as "include", "contain", "have" will be understood to include the stated elements, integers or steps, or a combination of elements, integers or steps, but does not exclude the addition of other elements, integers or steps, or a combination of elements, integers or steps.

[0118] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs. Although similar or equivalent methods and materials described herein may be used in the practice or testing of the present invention, suitable methods and materials will be described below. In the event of conflict, this specification (including definitions) shall prevail. In addition, the materials, methods, and embodiments are merely illustrative and are not intended to be restrictive.

[0119] “At least one of A, B, and C” has the same meaning as “at least one of A, B, or C,” and both include the following combinations of A, B, and C: A only, B only, C only, the combination of A and B, the combination of A and C, the combination of B and C, and the combination of A, B, and C. “A and / or B” includes the following three combinations: A only, B only, and the combination of A and B.

[0120] In this disclosure, unless otherwise specified, "plurality" means two or more.

[0121] Unless otherwise specified, the numerical ranges listed in the present invention include the endpoints and all points between the endpoints that are increased or decreased by the smallest unit of the endpoints and all sub-ranges composed of these points.

[0122] Unless otherwise indicated, the numerical values in the present invention represent approximate measurements or limits of the range of embodiments that include minor deviations from the given values and have approximately the values mentioned as well as the exact values mentioned. Except for the final example described in detail, all numerical values of parameters (e.g., quantities or conditions) in this application document (including the appended claims) should be understood as being modified by the term "about" in all cases, regardless of whether "about" actually appears before the numerical value. "About" means that the numerical value described allows for slight imprecision (some approach to precision in the value; approximately or reasonably close to the value; approximately). If the imprecision provided by "about" is not understood in this ordinary sense in the art, "about" as used herein at least represents the variation that can be produced by ordinary methods of measuring and using these parameters. For example, "about" can include a variation of 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 aspects, a variation of less than or equal to 0.01%.

[0123] The present invention has been described in detail above, but the present invention is not limited to the above content. In order to keep the description of the embodiments of the present invention clear and concise, the present invention omits detailed descriptions of known functions and known components.

[0124] Beneficial effects

[0125] The lacrimal duct insert of the present invention has the following advantages in actual preparation and use:

[0126] 1. Homogenize the mixture of matrix, buffer salts and active ingredients of the drug for treating dry eye to ensure uniform distribution of the active ingredients in the finished lacrimal duct insert.

[0127] 2. The degradation time of the lacrimal duct insert is related to the ratio of matrix components and can be as long as 70-100 days.

[0128] 3. The process of the lacrimal duct insert is stable and can meet the requirements of mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0129] Figure 1 : Pharmacokinetic data of the lacrimal canaliculus insert determined in Example 6. DETAILED DESCRIPTION

[0130] The present invention will be described below through specific embodiments. However, it should be understood that these embodiments are merely illustrative and are not intended to limit the present invention and its uses. In addition, this document is not limited by any theory described in the aforementioned prior art or invention summary or the following specific embodiments or examples. The described embodiments are part of the embodiments of the present invention, not all of them. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. The comparative examples provided are only for illustrating the technical effects of the present invention and are not considered in any way to belong to the prior art.

[0131] Unless otherwise specified, the raw materials used in the present invention are all commercially available pharmaceutical reagents that meet the requirements of ophthalmic medication.

[0132] Raw materials and instruments:

[0133] Tacrolimus raw material was purchased from Aladdin, and its average particle size was 60 μm.

[0134] Dexamethasone raw material was purchased from Aladdin, and its average particle size was 50 μm.

[0135] Litaurist was purchased from Aladdin, and its average particle size was 53 μm.

[0136] Indomethacin was purchased from Aladdin with an average particle size of 65 μm.

[0137] 10k, 4-arm-polyethylene glycol succinimidyl adipate (4arm-PEG-SAP) was purchased from Beijing Jiankai Technology Co., Ltd.

[0138] 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2) was purchased from Beijing Jiankai Technology Co., Ltd.

[0139] 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG) was purchased from Beijing Jiankai Technology Co., Ltd.

[0140] 10k, 4-arm-polyethylene glycol succinimidyl carboxymethyl ester (4arm-PEG-SCM) was purchased from Beijing Jiankai Technology Co., Ltd.

[0141] 10k means the weight average molecular weight of the polyethylene glycol segment is 10000D.

[0142] Other reagents were commercially available pharmaceutical reagents.

[0143] Degradation time detection method:

[0144] The canaliculus insert was inserted into the lower canaliculus of both eyes of adult New Zealand rabbits. The canaliculus was tested for the presence of the insert at the specified time. If present, the canaliculus insert had not yet been completely degraded. If not, the canaliculus insert was considered completely degraded. The degradation time of the canaliculus insert was calculated as the time from the previous test date to the current test date.

[0145] Example 1: Lacrimal Canalicular Insert 1

[0146] Preparation of lacrimal canaliculus insert 1

[0147] Components Mass (g) / 100 pieces 10k,4arm-PEG-SAP 0.030 10k,4arm-PEG-NH2 0.030 Tacrolimus 0.040 Anhydrous ethanol 0.050 Sodium dihydrogen phosphate, disodium hydrogen phosphate 0.006 Water for injection 0.495

[0148] The tacrolimus raw material was micronized to obtain an average particle size of 2.8 μm.

[0149] Prepare phosphate buffer with sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection to a pH of 6.5.

[0150] The anhydrous ethanol was diluted with the above phosphate buffer to obtain 0.54 ml of an ethanol solution with a volume fraction of 8%.

[0151] Weigh 0.030 g of 10k,4arm-PEG-SAP and dissolve it in 0.30 ml of the above ethanol solution to obtain mixed solution 1;

[0152] Weigh 0.040 g of tacrolimus and add it to mixed solution 1, fully disperse it, and ultrasonicate it to obtain mixed solution 2;

[0153] Weigh 0.030 g of polyethylene glycol amine (PEG-NH2) and dissolve it in 0.24 ml of the above ethanol solution to obtain a mixed solution 3;

[0154] Mixed solutions 2 and 3 were mixed and subjected to high-pressure homogenization (300 MPa, 400 rpm) to obtain mixed solution 4;

[0155] Inject the mixed solution 4 into a 2.0 mm diameter silicone tube using a syringe and let it stand to form a gel. After about 10 minutes, peel the formed hydrogel off the silicone tube.

[0156] The peeled hydrogel was placed on a stretching machine and stretched 3 times along the hydrogel axis to increase its length;

[0157] The stretched hydrogel was placed in an environment of 25° C. and 30% RH and dried for 12 hours to obtain a long rod-shaped lacrimal duct insert with a diameter of 0.50 mm. After cutting, multiple finished lacrimal duct inserts 1 with a diameter of about 0.50 mm and a length of 3.0 mm were obtained.

[0158] Observation on the in vivo degradation of lacrimal canaliculus insert 1

[0159] New Zealand adult rabbits were divided into 6 groups, with 3 rabbits in each group. The lacrimal canaliculus of both eyes of each rabbit was inserted with lacrimal canaliculus insert 1.

[0160] The New Zealand rabbits in each group were killed and their eyes dissected at 40, 60, 70, 80, 90, and 100 days.

[0161] After autopsy, it was observed that the canaliculus intercalator was still present in the rabbit canaliculi at 40, 60, 70, 80, and 90 days, but on day 100, the canaliculus intercalator was no longer present in 5 / 6 of the rabbit canaliculi. The results are shown in Table 1.

[0162] Table 1: In vivo degradation of lacrimal canaliculus insert 1

[0163]

[0164] Wherein: "L" represents the inferior lacrimal canaliculus of the left eye, "R" represents the inferior lacrimal canaliculus of the right eye; "+" represents the presence of a lacrimal canaliculus insert in the lacrimal canaliculus; "-" represents the absence of a lacrimal canaliculus insert in the lacrimal canaliculus.

[0165] Therefore, the degradation time of the lacrimal duct insert 1 is 90-100 days.

[0166] Example 2: Lacrimal Canalicular Insert 2

[0167] Preparation of lacrimal canaliculus insert 2

[0168] Components Mass (g) / 100 pieces 10k,4arm-PEG-SAP 0.020 10k,4arm-PEG-SG 0.010 10k,4arm-PEG-NH2 0.030 Dexamethasone 0.030 n-Propanol 0.075 Sodium dihydrogen phosphate, disodium hydrogen phosphate 0.006 Water for injection 0.495

[0169] The dexamethasone raw material was micronized to obtain an average particle size of 3.5 μm.

[0170] Prepare phosphate buffer with sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection to a pH of 6.5.

[0171] The n-propanol was diluted with the phosphate buffer to obtain 0.56 ml of a 12% n-propanol solution.

[0172] Weigh 0.020 g of 10k,4-arm-PEG-SAP and 0.010 g of 10k,4-arm-PEG-SG and dissolve them in 0.30 ml of the above n-propanol solution to obtain a mixture 1;

[0173] Weigh 0.030 g of dexamethasone and add it to mixed solution 1, fully disperse it, and ultrasonicate it to obtain mixed solution 2;

[0174] Weigh 0.030 g of 10k,4arm-PEG-NH2 and dissolve it in 0.26 ml of the above n-propanol solution to obtain mixed solution 3;

[0175] Mixed solutions 2 and 3 were mixed and subjected to high-pressure homogenization (400 MPa, 300 rpm) to obtain mixed solution 4;

[0176] Inject the mixed solution 4 into a 2.0 mm diameter silicone tube using a syringe and let it stand to form a gel. After about 10 minutes, peel the formed hydrogel off the silicone tube.

[0177] The peeled hydrogel was placed on a stretching machine and stretched 3 times along the hydrogel axis to increase its length;

[0178] The stretched hydrogel was placed in an environment of 25° C. and 30% RH and dried for 12 hours to obtain a long rod-shaped lacrimal canalicular insert with a diameter of 0.50 mm. After cutting, multiple finished lacrimal canalicular inserts 2 with a diameter of about 0.50 mm and a length of 3.0 mm were obtained.

[0179] Observation on the in vivo degradation of lacrimal canaliculus insert 2

[0180] New Zealand adult rabbits were divided into 6 groups, with 3 rabbits in each group. The lacrimal canaliculus of both eyes of each rabbit was inserted with lacrimal canaliculus insert 2.

[0181] The New Zealand rabbits in each group were killed and their eyes dissected at 40, 60, 70, 80, 90, and 100 days.

[0182] After autopsy, the canaliculi were still filled with the intercalator at 40, 60, 70, and 80 days. At 90 days, only one rabbit had a single canaliculus without the intercalator. By 100 days, the intercalator had completely disappeared from all rabbit canaliculi. The results are shown in Table 2.

[0183] Table 2: In vivo degradation of lacrimal canaliculus insert 2

[0184]

[0185] Wherein: "L" represents the inferior lacrimal canaliculus of the left eye, "R" represents the inferior lacrimal canaliculus of the right eye; "+" represents the presence of a lacrimal canaliculus insert in the lacrimal canaliculus; "-" represents the absence of a lacrimal canaliculus insert in the lacrimal canaliculus.

[0186] Therefore, the degradation time of the lacrimal duct insert 2 is 90-100 days.

[0187] Example 3: Lacrimal Canalicular Insert 3

[0188] Preparation of lacrimal canaliculus insert 3

[0189] Components Mass (g) / 100 pieces 10k,4arm-PEG-SAP 0.020 10k,4arm-PEG-SG 0.020 10k,4arm-PEG-NH2 0.050 Litaurist 0.050 Methanol 0.050 Sodium dihydrogen phosphate, disodium hydrogen phosphate 0.006 Water for injection 0.450

[0190] The ritalistat raw material was micronized to obtain an average particle size of 3.5 μm.

[0191] Prepare phosphate buffer with sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection to a pH of 6.5.

[0192] Methanol was diluted with the phosphate buffer to obtain 0.54 ml of a methanol solution with a volume fraction of 8%.

[0193] Weigh 0.020 g of 10k,4-arm-PEG-SAP and 0.020 g of 10k,4-arm-PEG-SG and dissolve them in 0.30 ml of the above methanol solution to obtain a mixture 1;

[0194] Weigh 0.050 g of ritalidomide and add it to mixed solution 1, fully disperse and ultrasonicate to obtain mixed solution 2;

[0195] Weigh 0.050 g of 10k,4arm-PEG-NH2 and dissolve it in 0.24 ml of the above methanol solution to obtain mixed solution 3;

[0196] Mixed solutions 2 and 3 were mixed and subjected to high-pressure homogenization (300 MPa, 300 rpm) to obtain mixed solution 4;

[0197] Inject the mixed solution 4 into a 2.0 mm diameter silicone tube using a syringe and let it stand to form a gel. After about 10 minutes, peel the formed hydrogel off the silicone tube.

[0198] The peeled hydrogel was placed on a stretching machine and stretched 3 times along the hydrogel axis to increase its length;

[0199] The stretched hydrogel was placed in an environment of 25° C. and 30% RH and dried for 12 hours to obtain a long rod-shaped lacrimal canalicular insert with a diameter of 0.50 mm. After cutting, multiple finished lacrimal canalicular inserts 3 with a diameter of about 0.50 mm and a length of 3.0 mm were obtained.

[0200] Observation on the in vivo degradation of lacrimal canaliculus insert 3

[0201] New Zealand adult rabbits were divided into 6 groups, with 3 rabbits in each group. The lacrimal canaliculus of both eyes of each rabbit was inserted with lacrimal canaliculus insert 3.

[0202] The New Zealand rabbits in each group were killed and their eyes dissected at 40, 60, 70, 80, 90, and 100 days.

[0203] After autopsy, the canaliculus insert was still present in all rabbits at 40, 60, 70, and 80 days. At 90 days, only one rabbit had a single canaliculus without the canaliculus insert. At 100 days, the canaliculus insert was completely absent from all rabbits. The results are shown in Table 3.

[0204] Table 3: In vivo degradation of lacrimal canaliculus insert 3

[0205]

[0206] Wherein: "L" represents the inferior lacrimal canaliculus of the left eye, "R" represents the inferior lacrimal canaliculus of the right eye; "+" represents the presence of a lacrimal canaliculus insert in the lacrimal canaliculus; "-" represents the absence of a lacrimal canaliculus insert in the lacrimal canaliculus.

[0207] Therefore, the degradation time of lacrimal duct insert 3 is 90-100 days.

[0208] Example 4: Lacrimal Canalicular Insert 4

[0209] Preparation of lacrimal canaliculus insert 4

[0210] Components Mass (g) / 100 pieces 10k,4arm-PEG-SAP 0.025 10k,4arm-PEG-SCM 0.010 10k,4arm-PEG-NH2 0.030 Indomethacin 0.040 Anhydrous ethanol 0.050 Sodium dihydrogen phosphate, disodium hydrogen phosphate 0.006 Water for injection 0.450

[0211] The indomethacin raw material was micronized to obtain an average particle size of 4.3 μm.

[0212] Prepare phosphate buffer with sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection to a pH of 6.5.

[0213] The anhydrous ethanol was diluted with the above phosphate buffer to obtain 0.54 ml of an ethanol solution with a volume fraction of 8%.

[0214] Weigh 0.025 g of 10k,4-arm-PEG-SAP and 0.010 g of 10k,4-arm-PEG-SCM and dissolve them in 0.30 ml of the above ethanol solution to obtain a mixture 1;

[0215] Weigh 0.040 g of indomethacin and add it to mixed solution 1, fully disperse it, and ultrasonicate it to obtain mixed solution 2;

[0216] Weigh 0.030 g of 10k,4arm-PEG-NH2 and dissolve it in 0.24 ml of the above ethanol solution to obtain mixed solution 3;

[0217] Mixed solutions 2 and 3 were mixed and subjected to high-pressure homogenization (200 MPa, 300 rpm) to obtain mixed solution 4;

[0218] Inject the mixed solution 4 into a 2.0 mm diameter silicone tube using a syringe and let it stand to form a gel. After about 10 minutes, peel the formed hydrogel off the silicone tube.

[0219] The peeled hydrogel was placed on a stretching machine and stretched 3 times along the hydrogel axis to increase its length;

[0220] The stretched hydrogel was placed in an environment of 25° C. and 30% RH and dried for 12 hours to obtain a long rod-shaped lacrimal canalicular insert with a diameter of 0.50 mm. After cutting, multiple finished lacrimal canalicular inserts 4 with a diameter of about 0.50 mm and a length of 3.0 mm were obtained.

[0221] Observation on the in vivo degradation of lacrimal canaliculus insert 4

[0222] New Zealand adult rabbits were divided into 6 groups, with 3 rabbits in each group. The lacrimal canaliculus of both eyes of each rabbit was inserted with lacrimal canaliculus insert 4.

[0223] The New Zealand rabbits in each group were killed and their eyes dissected at 40, 60, 70, 80, 90, and 100 days.

[0224] After autopsy, the canaliculus insert was still present in the rabbits' tear canaliculi at 40, 60, and 70 days. On day 80, the canaliculus insert was no longer present in the right inferior canaliculus of one rabbit. On day 90, the canaliculus insert was no longer present in 5 / 6 of the rabbits' tear canaliculi. The results are shown in Table 4.

[0225] Table 4: In vivo degradation of lacrimal canaliculus insert 4

[0226]

[0227] Wherein: "L" represents the inferior lacrimal canaliculus of the left eye, "R" represents the inferior lacrimal canaliculus of the right eye; "+" represents the presence of a lacrimal canaliculus insert in the lacrimal canaliculus; "-" represents the absence of a lacrimal canaliculus insert in the lacrimal canaliculus.

[0228] Therefore, the degradation time of the lacrimal duct insert 4 is 80-90 days.

[0229] Example 5: Lacrimal Canalicular Insert 5

[0230] Preparation of lacrimal canaliculus insert 5

[0231] Components Mass (g) / 100 pieces 10k,4arm-PEG-SAP 0.015 10k,4arm-PEG-SCM 0.025 10k,4arm-PEG-NH2 0.040 Tacrolimus 0.040 n-Propanol 0.075 Sodium dihydrogen phosphate, disodium hydrogen phosphate 0.006 Water for injection 0.425

[0232] The tacrolimus raw material was micronized to obtain an average particle size of 2.8 μm.

[0233] Prepare phosphate buffer with sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection to a pH of 6.5.

[0234] The n-propanol was diluted with the phosphate buffer to obtain 0.56 ml of a 12% n-propanol solution.

[0235] Weigh 0.015 g of 10k,4-arm-PEG-SAP and 0.025 g of 10k,4-arm-PEG-SCM and dissolve them in 0.30 ml of the above n-propanol solution to obtain a mixture 1;

[0236] Weigh 0.040 g of tacrolimus and add it to mixed solution 1, fully disperse it, and ultrasonicate it to obtain mixed solution 2;

[0237] Weigh 0.040 g of 10k,4arm-PEG-NH2 and dissolve it in 0.26 ml of the above n-propanol solution to obtain mixed solution 3;

[0238] Mixed solutions 2 and 3 were mixed and subjected to high-pressure homogenization (300 MPa, 300 rpm) to obtain mixed solution 4;

[0239] Inject the mixed solution 4 into a 2.0 mm diameter silicone tube using a syringe and let it stand to form a gel. After about 10 minutes, peel the formed hydrogel off the silicone tube.

[0240] The peeled hydrogel was placed on a stretching machine and stretched 3 times along the hydrogel axis to increase its length;

[0241] The stretched hydrogel was placed in an environment of 25° C. and 30% RH and dried for 12 hours to obtain a long rod-shaped lacrimal canalicular insert with a diameter of 0.50 mm. After cutting, multiple finished lacrimal canalicular inserts 5 with a diameter of about 0.50 mm and a length of 3.0 mm were obtained.

[0242] Observation on the in vivo degradation of lacrimal canaliculus insert 5

[0243] New Zealand adult rabbits were divided into 6 groups, with 3 rabbits in each group. The lacrimal canaliculus of both eyes of each rabbit was inserted with a lacrimal canaliculus insert 5.

[0244] The New Zealand rabbits in each group were killed and their eyes dissected at 40, 60, 70, 80, 90, and 100 days.

[0245] After autopsy, it was observed that the canaliculus insert was still present in the rabbit canaliculi at 40, 60, 70, and 80 days. At 90 days, the canaliculus insert was no longer present in one-third of the rabbit canaliculi. At 100 days, the canaliculus insert was no longer present in five-sixths of the rabbit canaliculi. The results are shown in Table 5.

[0246] Table 5: In vivo degradation of lacrimal canaliculus insert 5

[0247]

[0248] Wherein: "L" represents the inferior lacrimal canaliculus of the left eye, "R" represents the inferior lacrimal canaliculus of the right eye; "+" represents the presence of a lacrimal canaliculus insert in the lacrimal canaliculus; "-" represents the absence of a lacrimal canaliculus insert in the lacrimal canaliculus.

[0249] Therefore, the degradation time of lacrimal duct insert 5 is 90-100 days.

[0250] Example 6: Pharmacokinetic properties of lacrimal canaliculus inserts

[0251] The tacrolimus-loaded lacrimal canaliculus insert 5 prepared in Example 5 was used as a model to evaluate the pharmacokinetic properties of the lacrimal canaliculus insert.

[0252] The performance of punctal insert 5 was evaluated in a rabbit eye model to determine the in vivo relevance of tacrolimus release.

[0253] The canaliculus insert 5 was inserted into the lower canaliculus of rabbits, and tear samples were analyzed by liquid chromatography over a period of 100 days. Figure 1 shown.

[0254] The results showed that the drug in the lacrimal duct insert remained in a sustained release state until it was completely degraded.

[0255] Comparative Example 1: Lacrimal Canalicular Insert 6

[0256] Preparation of lacrimal canaliculus insert 6

[0257] Components Mass (g) / 100 pieces 10k,4arm-PEG-SAP 0.030 10k,4arm-PEG-SG 0.030 10k,4arm-PEG-NH2 0.020 Litaurist 0.050 Methanol 0.050 Sodium dihydrogen phosphate, disodium hydrogen phosphate 0.006 Water for injection 0.450

[0258] The ritalistat raw material was micronized to obtain an average particle size of 3.5 μm.

[0259] Prepare phosphate buffer with sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection to a pH of 6.5.

[0260] Methanol was diluted with the phosphate buffer to obtain 0.54 ml of a methanol solution with a volume fraction of 8%.

[0261] Weigh 0.030 g of 10k,4-arm-PEG-SAP and 0.030 g of 10k,4-arm-PEG-SG and dissolve them in 0.30 ml of the above methanol solution to obtain a mixture 1;

[0262] Weigh 0.030 g of dexamethasone and add it to mixed solution 1, fully disperse it, and ultrasonicate it to obtain mixed solution 2;

[0263] Weigh 0.020 g of 10k,4arm-PEG-NH2 and dissolve it in 0.24 ml of the above methanol solution to obtain mixed solution 3;

[0264] Mixed solutions 2 and 3 were mixed and subjected to high-pressure homogenization (300 MPa, 300 rpm) to obtain mixed solution 4;

[0265] Inject the mixed solution 4 into a 2.0 mm diameter silicone tube using a syringe and let it stand to form a gel. After about 10 minutes, peel the formed hydrogel off the silicone tube.

[0266] The peeled hydrogel was placed on a stretching machine and stretched 3 times along the hydrogel axis to increase its length;

[0267] The stretched hydrogel was placed in an environment of 25°C and 30% RH and dried for 12 hours to obtain a long rod-shaped lacrimal duct insert with a diameter of 0.50 mm. After cutting, multiple finished lacrimal duct inserts 6 with a diameter of about 0.50 mm and a length of 3.0 mm were obtained.

[0268] Observation on the in vivo degradation of lacrimal canaliculus insert 6

[0269] New Zealand adult rabbits were divided into 6 groups, with 3 rabbits in each group. The lacrimal canaliculus of both eyes of each rabbit was inserted with a lacrimal canaliculus insert for 6 seconds.

[0270] The New Zealand rabbits in each group were killed and their eyes dissected at 40, 60, 70, 80, 90, and 100 days.

[0271] After autopsy, it was observed that the canaliculus insert was still present in all rabbit canaliculi at 40 days; at 60 days, the canaliculus insert was no longer present in one-third of the rabbit canaliculi; and at 70 days, the canaliculus insert was no longer present in five-sixths of the rabbit canaliculi. The results are shown in Table 6.

[0272] Table 6: In vivo degradation of lacrimal canaliculus insert 6

[0273]

[0274] Wherein: "L" represents the inferior lacrimal canaliculus of the left eye, "R" represents the inferior lacrimal canaliculus of the right eye; "+" represents the presence of a lacrimal canaliculus insert in the lacrimal canaliculus; "-" represents the absence of a lacrimal canaliculus insert in the lacrimal canaliculus.

[0275] Therefore, the degradation time of the lacrimal duct insert 6 is 60-70 days.

[0276] Comparative Example 2: Lacrimal Canalicular Insert 7

[0277] Preparation of lacrimal canaliculus insert 7

[0278] Components Mass (g) / 100 pieces 10k,4arm-PEG-SAP 0.015 10k,4arm-PEG-SCM 0.015 10k,4arm-PEG-NH2 0.050 Indomethacin 0.040 Anhydrous ethanol 0.050 Sodium dihydrogen phosphate, disodium hydrogen phosphate 0.006 Water for injection 0.450

[0279] The indomethacin raw material was micronized to obtain an average particle size of 4.3 μm.

[0280] Prepare phosphate buffer with sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection to a pH of 6.5.

[0281] The anhydrous ethanol was diluted with the above phosphate buffer to obtain 0.54 ml of an ethanol solution with a volume fraction of 8%.

[0282] Weigh 0.015 g of 10k,4-arm-PEG-SAP and 0.015 g of 10k,4-arm-PEG-SG and dissolve them in 0.30 ml of the above ethanol solution to obtain a mixture 1;

[0283] Weigh 0.040 g of indomethacin and add it to mixed solution 1, fully disperse it, and ultrasonicate it to obtain mixed solution 2;

[0284] Weigh 0.050 g of 10k,4arm-PEG-NH2 and dissolve it in 0.24 ml of the above ethanol solution to obtain mixed solution 3;

[0285] Mixed solutions 2 and 3 were mixed and subjected to high-pressure homogenization (300 MPa, 300 rpm) to obtain mixed solution 4;

[0286] Inject the mixed solution 4 into a 2.0 mm diameter silicone tube using a syringe and let it stand to form a gel. After about 10 minutes, peel the formed hydrogel off the silicone tube.

[0287] The peeled hydrogel was placed on a stretching machine and stretched 3 times along the hydrogel axis to increase its length;

[0288] 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 canalicular insert with a diameter of 0.50 mm. After cutting, multiple finished lacrimal canalicular inserts 7 with a diameter of about 0.50 mm and a length of 3.0 mm were obtained.

[0289] Observation on the in vivo degradation of lacrimal canaliculus insert 7

[0290] New Zealand adult rabbits were divided into 6 groups, with 3 rabbits in each group. The lacrimal canaliculus of both eyes of each rabbit was inserted with lacrimal canaliculus insert 7.

[0291] The New Zealand rabbits in each group were killed and their eyes dissected at 40, 60, 70, 80, 90, and 100 days.

[0292] After autopsy, it was observed that the canaliculus intercalator was present in all rabbit canaliculi at 40 days, while the canaliculus intercalator was no longer present in 1 / 6 of the rabbit canaliculi at 60 days. The results are shown in Table 7.

[0293] Table 7: In vivo degradation of lacrimal canaliculus insert 7

[0294]

[0295] Wherein: "L" represents the inferior lacrimal canaliculus of the left eye, "R" represents the inferior lacrimal canaliculus of the right eye; "+" represents the presence of a lacrimal canaliculus insert in the lacrimal canaliculus; "-" represents the absence of a lacrimal canaliculus insert in the lacrimal canaliculus.

[0296] Therefore, the degradation time of lacrimal duct insert 7 is 40-60 days.

[0297] As can be seen from the above examples, by using the specific formulation of the present invention, particularly by selecting specific hydrogel components and specific ratios, a lacrimal duct insert with a degradation time of 80-100 days can be obtained. Furthermore, during this degradation time, the drug in the insert is continuously released.

[0298] It can be seen from Comparative Examples 1-2 that if the ratio of the hydrogel component exceeds the aforementioned ratio, the resulting lacrimal duct insert will be unstable and easily degraded.

Claims

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

2. The degradable lacrimal duct insert according to claim 1, wherein Each insert contains (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 active pharmaceutical ingredient, (3) 0.01-0.25 mg, preferably 0.02-0.20 mg, of buffer salt.

3. The degradable lacrimal duct insert according to claim 1 or 2, wherein: The multi-arm polyethylene glycol derivative 1 is selected from one or more of multi-arm polyethylene glycol succinimide succinate, multi-arm polyethylene glycol succinimide glutarate, multi-arm polyethylene glycol succinimide glutaramide, multi-arm polyethylene glycol succinimide carboxymethyl ester, multi-arm polyethylene glycol succinimide adipate, multi-arm polyethylene glycol succinimide carbonate, and multi-arm polyethylene glycol succinimide propionate.

4. The degradable lacrimal duct insert according to any one of claims 1 to 3, wherein: In the multi-arm polyethylene glycol derivative 1 and the multi-arm polyethylene glycol amine, the multi-arms are selected from 2-10 arms, preferably 4 arms or 8 arms.

5. The degradable lacrimal duct insert according to any one of claims 1 to 4, wherein: The molecular weight of the polyethylene glycol segments in the multi-arm polyethylene glycol derivative 1 and the multi-arm polyethylene glycol amine is 5000 to 25000D, preferably 8000 to 20000D, and more preferably 10000 to 15000D.

6. The degradable lacrimal duct insert according to any one of claims 1 to 5, wherein: The weight ratio of the multi-arm polyethylene glycol derivative 1 to the multi-arm polyethylene glycol amine is 1:(0.5-1.5), preferably 1:(0.8-1.4), and more preferably 1:(0.85-1.3).

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

8. The degradable lacrimal duct insert according to any one of claims 1 to 7, wherein: The poorly soluble active ingredient is selected from one or more of tacrolimus, cyclosporine, dexamethasone, rifalast, indomethacin, or pharmaceutically acceptable salts thereof.

9. The degradable lacrimal duct insert according to any one of claims 1 to 8, wherein: Average particle size D of poorly soluble active pharmaceutical ingredients 90 It is 20 μm or less, preferably 10 μm or less, in particular 5 μm or less, for example 2.0-5.0 μm.

10. The degradable lacrimal duct insert according to any one of claims 1 to 9, wherein: The buffer salt is selected from phosphate buffer salt, citrate buffer salt, acetate buffer salt, and phosphate buffer salt is particularly preferred.

11. The degradable lacrimal duct insert according to any one of claims 1 to 10, comprising an organic solvent, wherein 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; In particular, the organic solvent is not a solvent belonging to the first category as specified in the Chinese Pharmacopoeia 2020 Edition; Particularly, the organic solvent is miscible with water and has a boiling point of 50-150°C. Particularly, the organic solvent is one or more selected from methanol, ethanol, acetic acid, isopropanol, n-propanol, and acetone. 12 . The degradable lacrimal duct insert according to claim 1 , which does not contain a suspending agent, a wetting agent, a flocculant, and a cosolvent.

13. A method for preparing the degradable lacrimal duct insert according to any one of claims 1 to 12, comprising the following steps: (1) adding an organic solvent to a pH buffer solution to obtain an organic solvent-buffer solution 1; (2) adding the multi-arm polyethylene glycol derivative 1 to an organic solvent-buffer 1 to dissolve the mixture to obtain a mixed solution 1; (3) adding the poorly soluble active ingredient to the mixed solution 1 to obtain the mixed solution 2; (4) adding the multi-arm polyethylene glycol amine to a pH buffer solution or an organic solvent-buffer solution 1 to dissolve the mixture to obtain a mixed solution 3; (5) Mixing the mixed solution 2 and the mixed solution 3 to obtain a mixed solution 4; (6) injecting the mixed solution 4 into a circular mold, allowing it to stand to form a hydrogel, and then removing the hydrogel from the mold; (7) The taken-out hydrogel is stretched, dried, and cut to obtain a finished lacrimal duct insert.

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%, 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 speed of the homogenization is 100-500 rpm; the homogenization is carried out at room temperature to 40° C.; In the mixed solution 4, the concentration of the multi-arm polyethylene glycol derivative 1 is 1-20 w / w%, preferably 2-10%; 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 silicone tube with a diameter of 0.5 mm to 2 mm or a polytetrafluoroethylene tube with a diameter of 0.5 mm to 2 mm; Place at 10-50°C and 0.05-0.2 MPa for more than 5 minutes; In step (7), the stretching ratio of the lacrimal duct insert is 1.1-10 times.

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