Preparation method of lacrimal ductule insertion agent and lacrimal ductule insertion agent

Abstract

The invention relates to a preparation method of a lacrimal ductule insertion agent and the lacrimal ductule insertion agent. The method comprises the following steps: mixing and dispersing a buffer solution, an organic solvent, a hydrogel precursor and an indissolvable active component with an average particle size of less than 20 [mu] m to obtain a mixed solution, with the buffer solution as a reference, the mass concentration of the active component being 2.5-20%; placing the mixed solution in a sleeve with the diameter of 0.5-2.0 mm for standing, so as to obtain hydrogel; 3, the hydrogel is axially stretched by 1.1-10 times and dried for 2-24 hours at the temperature of 20-30 DEG C and the RH of 20-40%, and the lacrimal canaliculus insertion agent is obtained. According to the preparation method, the dispersing performance of the loaded medicine can be improved, bubbles in the hydrogel can be discharged, and the quality control in the production process of the lacrimal canaliculi insertion agent can be guaranteed.

Description

Technical Field

[0001] The present invention relates to the technical field of lacrimal canaliculus inserts, and in particular to a preparation method of a lacrimal canaliculus insert and the lacrimal canaliculus insert prepared thereby. Background Art

[0002] Many ocular diseases, such as cataracts, glaucoma, fungal keratitis, dry eye, macular degeneration, retinopathy, and ocular surface allergies, involve topical administration to the eye. Eye drops are the most commonly used dosage form in current clinical treatments for these ocular diseases. Because they are non-invasive and easy to administer, they are the most common method for treating ocular diseases, accounting for 90% of all marketed medications for ophthalmic diseases. The human conjunctival sac holds only 20 μL of fluid, while one drop of eye drops contains approximately 50–60 μL. Due to blinking and rapid clearance through tears, the bioavailability of eye drops is very low, at only 1–5%. Therefore, maintaining effective therapeutic concentrations of these drugs requires frequent administration, resulting in poor patient compliance and a high incidence of adverse reactions.

[0003] Therefore, alternative effective ophthalmic delivery systems are needed. Various ophthalmic delivery system formulations, such as eye ointments, ophthalmic suspensions, and ophthalmic gels, are currently under research, development, and are already on the market. These formulations extend the drug's residence time on the ocular surface to a certain extent. However, they remain relatively unused due to several drawbacks, such as the blurred vision caused by ointments. Furthermore, ophthalmic suspensions and ophthalmic gels only remain on the ocular surface for a maximum of tens of minutes, necessitating long-term administration for chronic ocular diseases. For rapidly progressive infectious diseases like fungal keratitis, suspension formulations still require eye drops administered dozens to twenty times daily, failing to fundamentally address the problem.

[0004] As a new dosage form, canaliculus inserts have demonstrated impressive capabilities in sustained-release drugs. Ophthalmic canaliculus inserts are a drug-matrix mixture 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, canaliculus inserts have the advantage of increasing the retention time in the eye, thereby prolonging the duration of action of the active ingredient. Depending on the delivery matrix and delivery method, sustained-release times can range from several days to several months.

[0005] The drug release mechanism of lacrimal canaliculus inserts can be summarized as the gradual diffusion of drug particles from the matrix under the infiltration of tear fluid, primarily through diffusion. This release process conforms to the zero-order release model, characterized by a constant drug release rate that is independent of time and influenced by the drug concentration in the infiltrating medium. Therefore, under this release model, the drug can be released at a relatively stable rate over an extended period, achieving a sustained therapeutic effect.

[0006] Specifically, the matrix in the canaliculus insert is a hydrogel that evenly distributes drug particles in its dry state. When the insert is placed in the canaliculus, tears begin to soak the matrix, gradually transforming it into a gel state and simultaneously diffusing the drug into the tears. During this process, the drug particles gradually dissolve or disperse into the tears, and through diffusion throughout the eye, the tears ultimately release the drug.

[0007] Compared to general suspensions, the national standard has stricter requirements for the composition of canaliculus 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, 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, canaliculus inserts are not suitable for adding these substances to control drug distribution in the liquid. Especially after the matrix has dried, there is a risk that the amount of excipient additives may exceed the safe dosage percentage. However, many drugs are not highly soluble in water. When loaded into canaliculus inserts made of hydrogels, without the addition of suspending agents, cosolvents, wetting agents, and other additives to stabilize and evenly distribute drug particles, uneven drug dispersion and air bubbles can occur. This can lead to uneven surfaces and drug particle adhesion. This can cause uneven surfaces, burrs, and cracks, leading to poor patient compliance. The uneven dispersion of drugs in the lacrimal canalicular insert also results in inconsistent drug release rates in the canalicular insert. The drug release rate in some parts is too fast, while the release rate in other parts is too slow, thereby affecting the consistency and predictability of the therapeutic effect and failing to provide a stable therapeutic effect.

[0008] 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.

[0009] CN 102395401 B discloses a hydrogel lacrimal duct plug formed by cross-linking a polyethylene glycol derivative as a precursor. The plug comprises drug-encapsulated microspheres dispersed within the hydrogel. Although no additives are added during the preparation process, dichloromethane is used as a solvent to dissolve poorly soluble drugs. Dichloromethane is classified as a Class I solvent (which should be avoided) in the Chinese Pharmacopoeia (2020 edition). Furthermore, the production process for the drug-encapsulated microspheres is complex, and quality verification is tedious, significantly increasing the economic and time costs of drug development.

[0010] In view of this, there is an urgent need to develop a method for preparing drug-loaded lacrimal duct inserts that can uniformly disperse the corresponding drugs without using the first type of solvent (which should be avoided), and is simple to operate and low-cost. Summary of the Invention

[0011] In response to the above technical problems, the inventors of the present invention have discovered through extensive experiments that the combination of a poorly soluble active ingredient with a specific particle size and a specific organic solvent can play a synergistic role, so that the active pharmaceutical ingredient in the subsequently prepared hydrogel is evenly distributed, and the hydrogel surface is smooth and free of bubbles, thereby obtaining a method for preparing a lacrimal canaliculus insert. The preparation method according to the present invention is simple in process, does not require the use of a complex process for producing drug-encapsulated microspheres, and does not use the first type of solvent (which should be avoided), that is, the drug can be evenly dispersed in the lacrimal canaliculus insert. At the same time, the surface of the resulting lacrimal canaliculus insert is smooth, burr-free, crack-free, and bubble-free, thereby improving the quality of the lacrimal canaliculus insert and improving the comfort of the user. The present invention was completed on this basis.

[0012] One object of the present invention is to provide a method for preparing a lacrimal duct insert.

[0013] Another object of the present invention is to provide a lacrimal duct insert prepared by the method.

[0014] According to one aspect of the present invention, there is provided a method for preparing a lacrimal duct insert, the method comprising:

[0015] Step 1: Mixing and dispersing a buffer solution, an organic solvent, a hydrogel precursor, and a poorly soluble active ingredient having an average particle size of 20 μm or less, preferably 10 μm or less, to obtain a mixed solution, wherein the mass concentration of the active ingredient is 2.5%-20%, preferably 2.5%-15%, and preferably 4%-10%, based on the buffer solution;

[0016] Step 2: placing the mixed solution in a cannula with a diameter of 0.5-2.0 mm and allowing it to stand to obtain a hydrogel; and

[0017] Step 3: The hydrogel is axially stretched 1.1-10 times and dried at 20-30° C. and 20-40% RH for 2-24 hours to obtain a lacrimal canaliculus insert.

[0018] The following is a detailed description of each of the above steps.

[0019] Step 1:

[0020] In step 1, a buffer solution, an organic solvent, a hydrogel precursor and a poorly soluble active ingredient having an average particle size of 20 μm or less, preferably 10 μm or less are mixed and dispersed to obtain a mixed solution.

[0021] In the present invention, the poorly soluble (or insoluble) active ingredient refers to a drug for treating eye diseases whose solubility in 100g of water at room temperature of 20°C is less than 0.01g. Preferably, the active ingredient is selected from: dexamethasone, tacrolimus, ritalidomide, voriconazole, latanoprost, etc.

[0022] In some embodiments, the average particle size of the poorly soluble active ingredient is 20 μm or less, preferably 10 μm or less, for example, 2.8 μm, 3.0 μm, 3.5 μm, 4.3 μm, etc. When the average particle size is greater than 20 μm, the active ingredient may agglomerate, resulting in uneven dispersion of the active pharmaceutical ingredient, and the resulting punctal insert may have an uneven and rough surface, resulting in a substandard final product.

[0023] There are no particular limitations on the source of the active ingredient, as long as it meets the drug requirements of the canaliculus insert and the particle size requirements of the present invention. For example, the active ingredient can be a commercially available active ingredient product that meets the particle size requirements, or a commercially available large-particle active ingredient can be micronized to obtain an active ingredient product that meets the particle size requirements.

[0024] 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.

[0025] Micronization can be performed before or during mixing. For example, a micronization step can be performed on the poorly soluble active ingredient before step 1 to obtain an active ingredient with the required particle size. Alternatively, the poorly soluble active ingredient can be mixed with some or all of the other ingredients (e.g., an organic solvent, a buffer, and / or a hydrogel precursor) before micronization.

[0026] The inventors of the present invention have found through extensive experiments that, in the absence of an organic solvent, if no suspending agent is added, the mixed solution is prone to stratification, with some of the drug sinking to the bottom and the drug particles being difficult to disperse evenly, resulting in an uneven and rough surface of the prepared canaliculus insert, and the final product being unqualified. However, as described in the background art, according to national standards, additives including suspending agents are not allowed to be used in canaliculus inserts. Surprisingly, the inventors have further promoted the dispersion of the active ingredient by adding a specific organic solvent, and can evenly disperse and maintain the insoluble active ingredient until it forms a gel without the addition of additional additives such as suspending agents, wetting agents, and flocculants.

[0027] According to the present invention, the organic solvent does not use the solvent belonging to the first category (which should be avoided) specified in the "Chinese Pharmacopoeia 2020 Edition".

[0028] In some embodiments, the organic solvent is miscible with water and has a boiling point of 50-150° C. In this case, the organic solvent can disperse the poorly soluble active ingredient and is miscible with the buffer solution to prevent the buffer salt from precipitating.

[0029] According to one embodiment of the present invention, the organic solvent is preferably selected from one or more of methanol (boiling point 67.4°C), ethanol (boiling point 78.4°C), acetic acid (boiling point 118°C), isopropanol (boiling point 82°C), n-propanol (boiling point 95.8°C), acetone (boiling point 56°C), etc., but is not limited thereto.

[0030] The use of this specific organic solvent can improve the solubility of poorly soluble active ingredients and facilitate uniform dispersion of the active ingredients. The specific solvent employed in the present invention has a relatively low boiling point and is volatile. It substantially evaporates during the drying process of the canaliculus insert, resulting in low residual organic solvent levels and ensuring the safety of the finished canaliculus insert.

[0031] In the present invention, the pH of the finished lacrimal duct insert can be adjusted by using a buffer solution to adapt to the pH of tear fluid, thereby reducing irritation and improving patient compliance.

[0032] Preferably, a buffer is used to adjust the pH to 6.0-7.0.

[0033] Any buffer suitable for ocular administration can be used without particular limitation, as long as it can be adjusted to an appropriate pH. The choice of buffer is within the purview of those skilled in the art and can be selected based on the pH of tear fluid or the pH range tolerated by the normal human eye. Therefore, a detailed description is omitted to avoid obscuring the main points of the present invention.

[0034] For example, the buffer can be selected from phosphate buffer, citrate buffer, and acetate buffer.

[0035] Phosphate buffer refers to a buffer composed of dipotassium hydrogen phosphate, potassium dihydrogen phosphate or disodium hydrogen phosphate, sodium dihydrogen phosphate.

[0036] Citric acid buffer refers to a buffer composed of sodium citrate and citric acid.

[0037] Acetate buffer refers to a buffer composed of acetic acid and sodium acetate.

[0038] In the present invention, a hydrogel precursor is used to form a hydrogel. Any hydrogel precursor known in the art suitable for preparing a lacrimal canaliculus insert can be used without particular limitation. The choice of hydrogel precursor is within the purview of those skilled in the art, and therefore, will not be described in detail to avoid obscuring the main points of the present invention.

[0039] According to one embodiment of the present invention, the hydrogel precursor comprises:

[0040] A first hydrogel precursor, which is a multi-arm polyethylene glycol containing succinimide ester or amide functional groups and has a molecular weight of 10k-40k;

[0041] The second hydrogel precursor is a multi-arm polyethylene glycol containing amino groups (-NH2) and having a molecular weight of 10k-20k.

[0042] Unless the context clearly indicates otherwise, the molecular weight of the multi-arm polyethylene glycol mentioned in the present invention is the weight average molecular weight.

[0043] If desired, the hydrogel precursor may further include other polyethylene glycol derivatives, such as multi-arm polyethylene glycol substituted with a succinimide ester group, an amide group, or an amino group.

[0044] In some embodiments, the hydrogel precursor consists of the first and second hydrogel precursors described above.

[0045] The weight ratio of the first and second hydrogel precursors may be 1:(0.5-2.0), preferably 1:(0.6-1.5).

[0046] Preferably, the first hydrogel precursor is a multi-arm polyethylene glycol substituted with a homofunctional group containing a succinimide ester group, more preferably selected from four-arm-polyethylene glycol succinimidyl succinate (4arm-PEG-SS), eight-arm-polyethylene glycol succinimidyl succinate (8arm-PEG-SS), four-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), eight-arm-polyethylene glycol succinimidyl glutarate (8arm-PEG-SG), four-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SGA), eight-arm-polyethylene glycol succinimidyl glutarate (8arm-PEG-SGA), four-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SGA), eight-arm-polyethylene glycol succinimidyl glutarate (8arm-PEG-SGA), four-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG ...SG), eight-arm-polyethylene glycol succinimidyl glutarate (8arm-PEG-SGA), four-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), four-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), eight-arm-polyethylene glycol succinimidyl glut One or more of aminocarboxymethyl ester (4arm-PEG-SCM), eight-arm-polyethylene glycol succinimidyl carboxymethyl ester (8arm-PEG-SCM), four-arm-polyethylene glycol succinimidyl adipate (4arm-PEG-SAP), eight-arm-polyethylene glycol succinimidyl adipate (8arm-PEG-SAP), four-arm-polyethylene glycol succinimidyl carbonate (4arm-PEG-SC), eight-arm-polyethylene glycol succinimidyl carbonate (8arm-PEG-SC), four-arm-polyethylene glycol succinimidyl propionate (4arm-PEG-SPA), and eight-arm-polyethylene glycol succinimidyl propionate (8arm-PEG-SPA).

[0047] The second hydrogel precursor can be selected from one or more of four-arm-polyethylene glycol amine (4arm-PEG-NH2) and eight-arm-polyethylene glycol amine (8arm-PEG-NH2).

[0048] When the specific hydrogel precursor is selected, it is cross-linked into a gel through chemical bonds, and its hydrophobic region can combine with the insoluble active ingredient to help the active ingredient to be evenly distributed.

[0049] According to one embodiment of the present invention,

[0050] The volume concentration of the organic solvent (based on the buffer solution) can be 5%-40%, preferably 5%-30%, more preferably 8%-20%, for example 8%, 10%, 12%, 15%, etc.; if the concentration of the organic solvent in the buffer solution is too low, the poorly soluble active ingredient cannot be completely dispersed; if the concentration of the organic solvent in the buffer solution is too high, the buffer salt in the buffer solution will precipitate, affecting the formulation molding and pH.

[0051] The mass concentration of the hydrogel precursor (based on the buffer solution) can be 5%-20%, preferably 10%-20%, for example, 10%, 12%, 16%, 20%, etc.; if the concentration of the hydrogel precursor in the buffer solution is too low, the hydrogel obtained by the reaction will become soft and unformed; if the concentration of the hydrogel precursor in the buffer solution is too high, the formed hydrogel will swell too much, especially in the diameter direction, and will cause compression to the lacrimal canalicular tissue after insertion into the lacrimal canalicular tissue.

[0052] The mass concentration of the active ingredient (based on the buffer solution) can be 2.5%-20%, preferably 4%-10%, for example 6%, 8%, 10%, etc. If the amount of the active ingredient is too small, it will lead to insufficient efficacy; if the amount of the active ingredient is too large, it will cause uneven dispersion in the matrix, and the surface of the prepared lacrimal duct insert will be rough and unusable.

[0053] Moreover, the weight ratio of the organic solvent: the sparingly soluble active ingredient is 1:(0.5-1.0), preferably 1:(0.6-0.8), for example, 1:0.6, 1:0.7, 1:0.8, etc. If the sparingly soluble active ingredient is too little, the obtained lacrimal duct insert will have insufficient efficacy; if the sparingly soluble active ingredient is too much, it will be difficult to disperse evenly in the organic solvent.

[0054] When the volume ratio or weight ratio of the buffer, organic solvent, hydrogel precursor, and poorly soluble active ingredient is within the above range, the lacrimal duct insert that meets the expectations of the present invention can be successfully prepared.

[0055] According to one embodiment of the present invention, the weight ratio of the poorly soluble active ingredient to the hydrogel precursor is 1:(0.5-4).

[0056] When the weight ratio of the micronized active ingredient to the hydrogel precursor exceeds the above range, the active ingredient may agglomerate and cause the surface of the hydrogel to be rough, or the active ingredient may be too little to achieve an effective dose.

[0057] Step 2:

[0058] Step 2 is used to form a hydrogel from the mixed solution prepared in step 1. Specifically, the mixed solution is placed in a cannula with a diameter of 0.5-2.0 mm and allowed to stand to obtain a hydrogel.

[0059] The sleeve is preferably a polytetrafluoroethylene tube or a silicone tube with a diameter of 2.0 mm.

[0060] The standing time is generally 10-30 minutes.

[0061] According to one embodiment of the present invention, in step 2, before standing, the mixed liquid is further subjected to a homogenization treatment at a pressure of 100-500 MPa.

[0062] 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.

[0063] The pressure for homogenization is 100-500 MPa, preferably 200-450 MPa, more preferably 250-400 MPa, for example 280 MPa, 300 MPa, 350 MPa, 400 MPa, etc. Under these conditions, the agglomerates of the poorly soluble active ingredients can be decomposed and removed by high pressure. If the pressure is too high, the hydrogel precursor will break and affect the gelation. If the pressure is too low, the agglomerates of the poorly soluble active ingredients cannot be completely removed.

[0064] The speed for homogenization 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. Under this condition, the agglomerates of the poorly soluble active ingredients can be removed by high shear force. If the speed is too high, the hydrogel precursor will be severely destroyed due to the high shear force, affecting the gelation. If the speed is too low, the agglomerates of the poorly soluble active ingredients cannot be completely removed.

[0065] The temperature of the homogenization treatment is not particularly limited, and the homogenization treatment can be performed at room temperature to 40°C.

[0066] Step 3:

[0067] Step 2 is used to prepare the hydrogel prepared in step 2 into a lacrimal canaliculus insert. Specifically, the hydrogel is axially stretched 1.1-10 times and dried at 20-30° C. and 20-40% RH for 2-24 hours to obtain the lacrimal canaliculus insert.

[0068] The stretching ratio refers to the change in the hydrogel's axial direction (length direction).

[0069] The temperature of step 3 is 20-30°C. If the temperature is lower than this, the organic solvent will have difficulty in volatilizing and the residual amount will be higher than the safe amount specified in the pharmacopoeia; if the temperature is higher than this, the hydrogel itself will break and affect the stability of the active ingredient.

[0070] The relative humidity in step 3 is 20-40% RH. A humidity lower than this will cause the hydrogel to be difficult to dry or even become soft and unformed; a humidity higher than this will cause the hydrogel to dry too quickly and cracks to appear on the surface.

[0071] According to the method of the present invention, no suspending agent, wetting agent, flocculant or latent solvent is added, and a lacrimal duct insert with uniform drug dispersion, smooth surface, no burrs, no cracks and no bubbles is obtained.

[0072] According to one aspect of the present invention, a lacrimal duct insert prepared according to the above method is provided.

[0073] The active ingredients of the lacrimal duct insert prepared according to the method are evenly dispersed, which can ensure the uniform release of the active ingredients during use and improve the quality control of the lacrimal duct insert.

[0074] According to one embodiment of the present invention, in the lacrimal duct insert, the weight ratio of the buffer salt, the hydrogel polymer and the active ingredient can be 1:(0.05-0.2):(0.02-0.5), preferably 1:(0.1-0.2):(0.04-0.2), for example, 1:0.12:0.06, 1:0.16:0.06, 1:0.12:0.08, etc.

[0075] According to one embodiment of the present invention, the lacrimal duct insert contains greater than 0 and less than or equal to 1000 ppm of the organic solvent, preferably greater than 0 and less than or equal to 100 ppm of the organic solvent, more preferably greater than 0 and less than or equal to 60 ppm of the organic solvent, for example, 1-1000 ppm, 1-100 ppm, 1-60 ppm of organic solvent, and does not contain an additive selected from a suspending agent, a wetting agent, a flocculant, or a latent solvent.

[0076] Beneficial effects

[0077] The method for controlling dispersion uniformity during the preparation of the lacrimal canaliculus insert of the present invention can improve the dispersion performance of the loaded drug, remove bubbles in the hydrogel, and ensure quality control during the production of the lacrimal canaliculus insert. In actual preparation and use, it has the following advantages:

[0078] First, water-insoluble or poorly water-soluble drugs can be evenly dispersed and loaded into the canaliculus insert. Leveraging the long-lasting, sustained-release advantages of the canaliculus insert as a carrier, the bioavailability of these drugs can be increased, thereby enhancing their efficacy. This overcomes the limitations of poorly soluble drugs in terms of delivery, meeting the needs of patients with various eye diseases and resolving the current challenges of untreatable or ineffective treatments.

[0079] Secondly, the uniform dispersion of the drug effectively prevents the formation of bubbles in the hydrogel. The method disclosed in this invention does not pose safety concerns for the lacrimal duct insert itself, while also being cost-effective. Of course, bubble removal is also a crucial aspect of quality control during actual production.

[0080] Third, by adding a solvent, the present invention avoids the use of additives selected from suspending agents, wetting agents, flocculants, and cosolvents. Furthermore, according to the requirements for residual solvents in pharmacopoeias and ICH documents, the maximum limit for methanol is 3000 ppm, and the maximum limit for ethanol, acetic acid, n-propanol, isopropanol, and acetone is 5000 ppm. However, the residual amount of organic solvent in the present invention is far below the limit. DETAILED DESCRIPTION

[0081] The present invention will be described below by way of 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. Furthermore, the present invention is not intended to be bound by any theory described in the foregoing prior art or summary of the invention or in the following specific embodiments or examples.

[0082] The micronization process of the present invention is carried out using a QS-100 air flow mill, and may also be carried out using other conventional methods in the prior art.

[0083] The particle size or average particle size in the present invention is the average particle size D90 measured by Dandong Better Laser Particle Size Analyzer.

[0084] The high-pressure homogenization treatment of the present invention is carried out using a high-pressure homogenizer.

[0085] The drug dispersion is determined by observing the surface of the finished canaliculus insert: a canaliculus insert with uniform drug particle dispersion has a smooth surface without burrs or cracks; whereas a canaliculus insert with uneven drug particle dispersion has uneven surfaces or drug particles attached to the surface.

[0086] Raw materials and instruments:

[0087] Dexamethasone raw material was purchased from Aladdin, and its average particle size was 60 μm.

[0088] Tacrolimus raw material was purchased from Aladdin, and its average particle size was 50 μm.

[0089] Voriconazole was purchased from Aladdin with an average particle size of 53 μm.

[0090] 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG) was purchased from Beijing Jiankai Technology Co., Ltd.

[0091] 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2) was purchased from Beijing Jiankai Technology Co., Ltd.

[0092] 10k, 4-arm-polyethylene glycol succinimidyl adipate (4arm-PEG-SAP) was purchased from Beijing Jiankai Technology Co., Ltd.

[0093] 10k, 4-arm-polyethylene glycol succinimidyl carboxymethyl ester (4arm-PEG-SCM) was purchased from Beijing Jiankai Technology Co., Ltd.

[0094] 10k, 8-arm-polyethylene glycol succinimidyl adipate (8arm-PEG-SAP) was purchased from Beijing Jiankai Technology Co., Ltd.

[0095] 10k, 4-arm-polyethylene glycol succinimidyl propionate (4arm-PEG-SPA) was purchased from Beijing Jiankai Technology Co., Ltd.

[0096] 10k means the weight average molecular weight of the polyethylene glycol segment is 10000D.

[0097] Example 1: Lacrimal Canalicular Insert 1

[0098] The dexamethasone raw material is micronized to obtain micronized dexamethasone with an average particle size of 3.5 μm;

[0099] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0100] Dilute ethanol with the above phosphate buffer to obtain a 10% ethanol solution;

[0101] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized dexamethasone;

[0102] The above raw materials were dispersed in a diluted ethanol solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0103] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0104] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0105] Wait for gelation and remove the formed hydrogel from the cannula;

[0106] The hydrogel was stretched 3 times along its axis to increase its length;

[0107] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0108] The cut pieces are used to obtain a plurality of finished lacrimal duct inserts with a diameter of about 0.50 mm and a length of about 3 mm.

[0109] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0110] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0111] The leachate was collected and the residual ethanol in the leachate was measured using gas chromatography. The result showed that the residual ethanol was 11.2 ppm.

[0112] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.49±0.03mm, length 2.92±0.04mm; after soaking: diameter 2.13±0.07mm, length 1.44±0.02mm.

[0113] Appearance observation shows that the drug particles are evenly dispersed during the preparation of the lacrimal duct insert.

[0114] Example 2: Lacrimal Canalicular Insert 2

[0115] The tacrolimus raw material is micronized to obtain micronized tacrolimus with an average particle size of 2.8 μm;

[0116] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0117] Dilute ethanol with the above phosphate buffer to obtain a 10% ethanol solution;

[0118] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized tacrolimus;

[0119] The above raw materials were dispersed in a diluted ethanol solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0120] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0121] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0122] Wait for gelation and remove the formed hydrogel from the cannula;

[0123] The hydrogel was stretched 3 times along its axis to increase its length;

[0124] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0125] The cutting process yields multiple finished lacrimal duct inserts with a diameter of approximately 0.50 mm and a length of approximately 3 mm.

[0126] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0127] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0128] The leachate was collected and the residual ethanol in the leachate was measured using gas chromatography. The result showed that the residual ethanol was 8.3 ppm.

[0129] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.50±0.02mm, length 2.97±0.05mm; after soaking: diameter 1.99±0.03mm, length 1.53±0.07mm.

[0130] Appearance observation shows that the drug particles are evenly dispersed during the preparation of the lacrimal duct insert.

[0131] Example 3: Lacrimal Canalicular Insert 3

[0132] The tacrolimus raw material is micronized to obtain micronized tacrolimus with an average particle size of 2.8 μm;

[0133] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0134] Dilute ethanol with the above phosphate buffer to obtain a 15% ethanol solution;

[0135] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized tacrolimus;

[0136] The above raw materials were dispersed in a diluted ethanol solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0137] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0138] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0139] Wait for gelation and remove the formed hydrogel from the cannula;

[0140] The hydrogel was stretched axially 3 times to increase its length;

[0141] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0142] The cutting process yields multiple finished lacrimal duct inserts with a diameter of approximately 0.50 mm and a length of approximately 3 mm.

[0143] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0144] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0145] The leachate was collected and the residual ethanol in the leachate was measured using gas chromatography. The result showed that the residual ethanol was 13.3 ppm.

[0146] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.50±0.02mm, length 2.97±0.05mm; after soaking: diameter 1.99±0.03mm, length 1.53±0.07mm.

[0147] Appearance observation shows that the drug particles are evenly dispersed during the preparation of the lacrimal duct insert.

[0148] Example 4: Lacrimal Canalicular Insert 4

[0149] The voriconazole raw material is micronized to obtain micronized voriconazole with an average particle size of 3.0 μm;

[0150] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0151] Dilute ethanol with the above phosphate buffer to obtain a 10% ethanol solution;

[0152] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized voriconazole;

[0153] The above raw materials were dispersed in a diluted ethanol solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0154] The mixed solution was subjected to high-pressure homogenization (350 MPa, 400 rpm);

[0155] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0156] Wait for gelation and remove the formed hydrogel from the cannula;

[0157] The hydrogel was stretched 3 times along its axis to increase its length;

[0158] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0159] The cutting process yields multiple finished lacrimal duct inserts with a diameter of approximately 0.50 mm and a length of approximately 3 mm.

[0160] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0161] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0162] The leachate was collected and the residual ethanol in the leachate was measured using gas chromatography. The result showed that the residual ethanol was 18.1 ppm.

[0163] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.52±0.02 mm, length 3.01±0.03 mm; after soaking: diameter 1.92±0.04 mm, length 1.39±0.05 mm.

[0164] Appearance observation shows that the drug particles are evenly dispersed during the preparation of the lacrimal duct insert.

[0165] Example 5: Lacrimal Canalicular Insert 5

[0166] The voriconazole raw material is micronized to obtain micronized voriconazole with an average particle size of 3.0 μm;

[0167] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0168] Dilute acetic acid with the phosphate buffer to obtain a 10% acetic acid solution;

[0169] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized voriconazole;

[0170] The above raw materials were dispersed in a diluted acetic acid solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0171] The mixed solution was subjected to high-pressure homogenization (350 MPa, 400 rpm);

[0172] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0173] Wait for gelation and remove the formed hydrogel from the cannula;

[0174] The hydrogel was stretched 3 times along its axis to increase its length;

[0175] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0176] The cutting process yields multiple finished lacrimal duct inserts with a diameter of approximately 0.50 mm and a length of approximately 3 mm.

[0177] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0178] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0179] The leachate was collected and the residual acetic acid in the leachate was measured using gas chromatography. The result showed that the residual acetic acid was 15.5 ppm.

[0180] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.50±0.02 mm, length 3.03±0.04 mm; after soaking: diameter 1.95±0.04 mm, length 1.41±0.06 mm.

[0181] Appearance observation shows that the drug particles are evenly dispersed during the preparation of the lacrimal duct insert.

[0182] Example 6: Lacrimal Canalicular Insert 6

[0183] The voriconazole raw material is micronized to obtain micronized voriconazole with an average particle size of 3.0 μm;

[0184] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0185] Dilute acetic acid with the phosphate buffer to obtain a 10% acetic acid solution;

[0186] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl carboxymethyl ester (4arm-PEG-SCM), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized voriconazole;

[0187] The above raw materials were dispersed in a diluted acetic acid solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0188] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0189] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0190] Wait for gelation and remove the formed hydrogel from the cannula;

[0191] The hydrogel was stretched 3 times along its axis to increase its length;

[0192] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0193] The cut pieces are used to obtain a plurality of finished lacrimal duct inserts with a diameter of about 0.50 mm and a length of about 3 mm.

[0194] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0195] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0196] The leachate was collected and the residual acetic acid in the leachate was measured using gas chromatography. The result showed that the residual acetic acid was 27.3 ppm.

[0197] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.53±0.01mm, length 2.96±0.05mm; after soaking: diameter 1.86±0.03mm, length 1.38±0.02mm.

[0198] Appearance observation shows that the drug particles are evenly dispersed during the preparation of the lacrimal duct insert.

[0199] Example 7: Lacrimal Canalicular Insert 7

[0200] The dexamethasone raw material is micronized to obtain micronized dexamethasone with an average particle size of 3.5 μm;

[0201] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0202] Dilute acetone with the phosphate buffer to obtain a 10% acetone solution;

[0203] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl adipate (4arm-PEG-SAP), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.040 g of micronized dexamethasone;

[0204] The above raw materials were dispersed in a diluted acetone solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 8% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0205] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0206] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0207] Wait for gelation and remove the formed hydrogel from the cannula;

[0208] The hydrogel was stretched 3 times along its axis to increase its length;

[0209] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0210] The cut pieces are used to obtain a plurality of finished lacrimal duct inserts with a diameter of about 0.50 mm and a length of about 3 mm.

[0211] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0212] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0213] The leachate was collected and the residual acetone in the leachate was determined by gas chromatography. The result showed that the residual acetone was 48.3 ppm.

[0214] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.51±0.02 mm, length 2.85±0.03 mm; after soaking: diameter 1.89±0.04 mm, length 1.28±0.06 mm.

[0215] Appearance observation shows that the drug particles are evenly dispersed during the preparation of the lacrimal duct insert.

[0216] Example 8: Lacrimal Canalicular Insert 8

[0217] The dexamethasone raw material is micronized to obtain micronized dexamethasone with an average particle size of 3.5 μm;

[0218] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0219] Dilute acetone with the phosphate buffer to obtain a 10% acetone solution;

[0220] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl propionate (4arm-PEG-SPA), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized dexamethasone;

[0221] The above raw materials were dispersed in a diluted acetone solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0222] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0223] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0224] Wait for gelation and remove the formed hydrogel from the cannula;

[0225] The hydrogel was stretched 3 times along its axis to increase its length;

[0226] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0227] The cutting process yields multiple finished lacrimal duct inserts with a diameter of approximately 0.50 mm and a length of approximately 3 mm.

[0228] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0229] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0230] The leachate was collected and the residual acetone in the leachate was measured using gas chromatography. The result showed that the residual acetone was 37.9 ppm.

[0231] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.50±0.02mm, length 2.98±0.03mm; after soaking: diameter 1.91±0.03mm, length 1.37±0.04mm.

[0232] Appearance observation shows that the drug particles are evenly dispersed during the preparation of the lacrimal duct insert.

[0233] Example 9: Lacrimal Canalicular Insert 9

[0234] The dexamethasone raw material is micronized to obtain micronized dexamethasone with an average particle size of 3.5 μm;

[0235] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0236] Dilute acetone with the phosphate buffer to obtain a 10% acetone solution;

[0237] Weigh 0.040 g of 10k, 4-arm-polyethylene glycol succinimidyl propionate (4arm-PEG-SPA), 0.040 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized dexamethasone;

[0238] The above raw materials were dispersed in a diluted acetone solution, where the concentration of the hydrogel precursor was 16% and the concentration of the active ingredient was 6% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0239] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0240] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0241] Wait for gelation and remove the formed hydrogel from the cannula;

[0242] The hydrogel was stretched 3 times along its axis to increase its length;

[0243] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0244] The cutting process yields multiple finished lacrimal duct inserts with a diameter of approximately 0.50 mm and a length of approximately 3 mm.

[0245] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0246] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0247] The leachate was collected and the residual acetone in the leachate was measured using gas chromatography. The result showed that the residual acetone was 51.5 ppm.

[0248] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.48±0.04mm, length 3.02±0.02mm; after soaking: diameter 1.88±0.04mm, length 1.40±0.03mm.

[0249] Appearance observation shows that the drug particles are evenly dispersed during the preparation of the lacrimal duct insert.

[0250] Example 10: Lacrimal Canalicular Insert 10

[0251] The tacrolimus raw material is micronized to obtain micronized tacrolimus with an average particle size of 2.8 μm;

[0252] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0253] Dilute ethanol with the above phosphate buffer to obtain a 10% ethanol solution;

[0254] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized tacrolimus;

[0255] The above raw materials were dispersed in a diluted ethanol solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0256] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0257] Wait for gelation and remove the formed hydrogel from the cannula;

[0258] The hydrogel was stretched 3 times along its axis to increase its length;

[0259] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0260] The cut pieces are used to obtain a plurality of finished lacrimal duct inserts with a diameter of about 0.50 mm and a length of about 3 mm.

[0261] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0262] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0263] The leachate was collected and the residual ethanol in the leachate was determined by gas chromatography. The result showed that the residual ethanol was 9.7 ppm.

[0264] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.52±0.03 mm, length 2.98±0.02 mm; after soaking: diameter 1.96±0.05 mm, length 1.55±0.04 mm.

[0265] Appearance observation shows that the drug particles are evenly dispersed during the preparation of the lacrimal duct insert.

[0266] Comparative Example 1:

[0267] The tacrolimus raw material was micronized to obtain micronized dexamethasone with an average particle size of 2.8 μm;

[0268] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0269] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized tacrolimus;

[0270] The above raw materials were dispersed using the above phosphate buffer, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0271] It was found that the mixed solution showed stratification, some drugs sank to the bottom, and the drug particles were difficult to disperse evenly.

[0272] Hydroxypropyl cellulose (a suspending agent) was added to the above mixture, and after thorough mixing, it was found that the mixture had no stratification.

[0273] The mixed solution was injected into the cannula according to the process of Example 2 and prepared and cut to obtain a plurality of finished lacrimal duct inserts with a diameter of about 0.50 mm and a length of about 3 mm.

[0274] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0275] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0276] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.48±0.03 mm, length 3.08±0.06 mm; after soaking: diameter 1.72±0.06 mm, length 1.55±0.08 mm.

[0277] According to appearance observation, it can be proved that after the suspending agent is added, the drug particles in the lacrimal duct insert are evenly dispersed.

[0278] Comparative Example 2:

[0279] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0280] Dilute acetic acid with the phosphate buffer to obtain a 10% acetic acid solution;

[0281] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl carboxymethyl ester (4arm-PEG-SCM), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of raw material voriconazole; the particle size of the raw material voriconazole is 53 μm;

[0282] The above raw materials were dispersed in the acetic acid solution. At this time, the concentration of the hydrogel precursor relative to the buffer solution was 12%, and the concentration of the active ingredient was 6%. The mixture was thoroughly mixed and sonicated to obtain a mixed solution.

[0283] It was found that the mixed solution showed stratification, some drugs sank to the bottom, and the drug particles were difficult to disperse evenly.

[0284] Hydroxypropyl cellulose (a suspending agent) was added to the above mixture and after thorough mixing, it was found that the mixture no longer had any stratification phenomenon.

[0285] The mixed solution was injected into the cannula according to the process of Example 3 and prepared and cut to obtain a plurality of finished lacrimal duct inserts with a diameter of about 0.50 mm and a length of about 3 mm.

[0286] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert was regular and smooth, without burrs or cracks.

[0287] The finished lacrimal duct insert was immersed in a culture dish containing artificial tears for 24 hours.

[0288] The leachate was collected and the residual acetic acid in the leachate was measured using gas chromatography. The result showed that the residual acetic acid was 72.7 ppm.

[0289] Before and after soaking, the dimensions of the lacrimal duct insert were: before soaking: diameter 0.50±0.02 mm, length 3.01±0.05 mm; after soaking: diameter 1.58±0.08 mm, length 1.72±0.04 mm.

[0290] According to appearance observation, it can be proved that after the suspending agent is added, the drug particles in the lacrimal duct insert are evenly dispersed.

[0291] Comparative Example 3

[0292] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0293] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl carbonate (4arm-PEG-SG), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of raw material dexamethasone; the particle size of the raw material dexamethasone is 60 μm;

[0294] The above raw materials were dispersed using the above phosphate buffer, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0295] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0296] It was found that the mixed liquid showed stratification, with some drugs sinking to the bottom and a small amount floating, making it difficult to disperse the drug particles evenly.

[0297] Hydroxypropyl cellulose (a suspending agent) was added to the above mixture and after thorough mixing, it was found that the drug particles in the mixture still had stratification.

[0298] This indicates that the active ingredients cannot be dispersed evenly using only high-pressure homogenization method.

[0299] Comparative Example 4

[0300] The dexamethasone raw material is micronized to obtain micronized dexamethasone with an average particle size of 3.5 μm;

[0301] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0302] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized dexamethasone;

[0303] The above raw materials were dispersed using the above phosphate buffer, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 6% relative to the buffer, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0304] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0305] It was found that the mixed liquid showed stratification, with some drugs sinking to the bottom and a small amount floating, making it difficult to disperse the drug particles evenly.

[0306] This indicates that only micronization and high-pressure homogenization methods cannot disperse the active ingredients evenly.

[0307] Comparative Example 5

[0308] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0309] Dilute acetone with the phosphate buffer to obtain a 10% acetone solution;

[0310] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl adipate (4arm-PEG-SAP), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.040 g of raw material dexamethasone; the particle size of the raw material dexamethasone is 60 μm;

[0311] The above raw materials were dispersed in a diluted acetone solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 8% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0312] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0313] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0314] Wait for gelation and remove the formed hydrogel from the cannula;

[0315] The hydrogel was stretched 3 times along its axis to increase its length;

[0316] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0317] A long rod-shaped lacrimal duct insert with a diameter of about 0.50 mm was obtained.

[0318] The long rod-shaped lacrimal duct insert was cut to obtain a plurality of finished lacrimal duct inserts with diameters of 0.50 mm and 3.0 mm.

[0319] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert had obvious granularity, roughness, and unevenness.

[0320] This indicates that the drug cannot be dispersed evenly by simply adding organic solvents and high-pressure homogenization.

[0321] Comparative Example 6

[0322] The tacrolimus raw material is micronized to obtain micronized tacrolimus with an average particle size of 30 μm;

[0323] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer solution with a pH of 6.5;

[0324] Dilute ethanol with the above phosphate buffer to obtain a 15% ethanol solution;

[0325] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030 g of micronized tacrolimus;

[0326] The above raw materials were dispersed in a diluted ethanol solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 8% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0327] The mixed liquid is subjected to high pressure homogenization treatment;

[0328] Use a syringe to inject the mixed solution into a cannula with a diameter of 2.0 mm;

[0329] Wait for gelation and remove the formed hydrogel from the cannula;

[0330] The hydrogel was stretched 3 times along its axis to increase its length;

[0331] The stretched hydrogel was placed in a 25°C, 30% RH environment and dried for 12 h;

[0332] A long rod-shaped lacrimal duct insert with a diameter of about 0.50 mm was obtained.

[0333] The long rod-shaped lacrimal duct insert was cut to obtain a plurality of finished lacrimal duct inserts with diameters of 0.50 mm and 3.0 mm.

[0334] Observation under a 10x microscope revealed that the surface of the lacrimal duct insert had obvious granularity, roughness, and unevenness.

[0335] The main reason is that the drug particles obtained by micronization are too large and cannot be evenly dispersed in the mixed liquid.

[0336] Comparative Example 7

[0337] The dexamethasone raw material is micronized to obtain micronized dexamethasone with an average particle size of 3.5 μm;

[0338] Weigh 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection to prepare phosphate buffer;

[0339] Dilute acetone with the phosphate buffer to obtain a 10% acetone solution;

[0340] Weigh 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl propionate (4arm-PEG-SPA), 0.040 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.15 g of micronized dexamethasone;

[0341] The above raw materials were dispersed in a diluted acetone solution, where the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 30% relative to the buffer solution, and the mixture was thoroughly mixed and sonicated to obtain a mixed solution;

[0342] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0343] It was found that the mixed liquid showed stratification, with some drugs sinking to the bottom and a small amount floating, making it difficult to disperse the drug particles evenly.

[0344] The main reason is that too much active ingredient is added and it is difficult for the ethanol solution to disperse it evenly.

[0345] It can be seen from the description of the above examples that a qualified lacrimal duct insert can be obtained by using the specific method of the present invention, especially when the raw materials are micronized to a specific particle size and an organic solvent is used.

[0346] According to Comparative Examples 1-2, it can be seen that the drug particles cannot be evenly dispersed if only the raw materials are micronized or only organic solvents are used. However, after using the suspending agent, the drug can be evenly dispersed and a lacrimal duct insert can be prepared.

[0347] According to Comparative Example 3, it can be seen that only high-pressure homogenization of the hydrogel precursor and the drug cannot disperse the drug particles uniformly, and the use of a suspending agent still cannot improve the dispersibility of the drug.

[0348] It can be seen from Comparative Example 4 that if no organic solvent is used, the drug particles cannot be evenly dispersed, and a qualified lacrimal duct insert cannot be prepared.

[0349] Comparative Examples 5-6 show that when the raw materials are not micronized or the degree of micronization is insufficient, the drug particles cannot be evenly dispersed even after subsequent high-pressure homogenization treatment, and a qualified lacrimal duct insert cannot be prepared.

[0350] It can be seen from Comparative Example 7 that if the proportion of the active ingredient is too large, the drug cannot be dispersed evenly and a qualified lacrimal duct insert cannot be prepared.

Claims

1. A method for preparing a lacrimal duct insert, the method comprising: Step 1: Mixing and dispersing a buffer solution, an organic solvent, a hydrogel precursor, and a poorly soluble active ingredient having an average particle size of less than 20 μm to obtain a mixed solution, wherein the mass concentration of the active ingredient is 2.5%-20%, preferably 2.5%-15%, and preferably 4%-10%, based on the buffer solution; Step 2: placing the mixed solution in a cannula with a diameter of 0.5-2.0 mm and allowing it to stand to obtain a hydrogel; and Step 3: The hydrogel is axially stretched 1.1-10 times and dried at 20-30° C. and 20-40% RH for 2-24 hours to obtain a lacrimal canaliculus insert.

2. The preparation method according to claim 1, wherein In step 1, the poorly soluble active ingredient refers to a drug for treating eye diseases having a solubility of less than 0.01 g in 100 g of water at room temperature of 20° C., and preferably the active ingredient is selected from the group consisting of: dexamethasone, tacrolimus, rifalast, voriconazole, and latanoprost.

3. The preparation method according to claim 1, wherein In step 1, the average particle size of the poorly soluble active ingredient is 20 μm, preferably less than 10 μm, for example, 2.8 μm, 3.0 μm, 3.5 μm, or 4.3 μm.

4. The preparation method according to claim 1, wherein In step 1, the organic solvent does not use the solvent belonging to the first category specified in the "Chinese Pharmacopoeia 2020 Edition", and is an organic solvent that is miscible with water and has a boiling point of 50-150°C, preferably selected from one or more of methanol, ethanol, acetic acid, isopropanol, n-propanol, and acetone.

5. The preparation method according to claim 1, wherein In step 1, the buffer is used to adjust the pH to 6.0-7.0, and is preferably selected from phosphate buffer, citric acid buffer, and acetate buffer.

6. The preparation method according to claim 1, wherein In step 1, the hydrogel precursor comprises: A first hydrogel precursor, which is a multi-arm polyethylene glycol containing succinimide ester or amide functional groups and has a molecular weight of 10k-40k; A second hydrogel precursor, which is a multi-arm polyethylene glycol containing -NH2 and having a molecular weight of 10k-20k; Preferably, the hydrogel precursor consists of the first and second hydrogel precursors mentioned above; Preferably, the weight ratio of the first and second hydrogel precursors is 1:(0.5-2.0), preferably 1:(0.6-1.5); Preferably, the first hydrogel precursor is a multi-arm polyethylene glycol substituted with a homofunctional group containing a succinimide ester group, more preferably selected from four-arm polyethylene glycol succinimide succinate, eight-arm polyethylene glycol succinimide succinate, four-arm polyethylene glycol succinimide glutarate, eight-arm polyethylene glycol succinimide glutarate, four-arm polyethylene glycol succinimide glutarate, eight-arm polyethylene glycol succinimide glutarate, four-arm polyethylene glycol succinimide glutaramide, eight-arm polyethylene glycol succinimide glutaramide, four ... One or more of diamide, four-arm-polyethylene glycol succinimide carboxymethyl ester, eight-arm-polyethylene glycol succinimide carboxymethyl ester, four-arm-polyethylene glycol succinimide adipate, eight-arm-polyethylene glycol succinimide adipate, four-arm-polyethylene glycol succinimide carbonate, eight-arm-polyethylene glycol succinimide carbonate, four-arm-polyethylene glycol succinimide propionate, and eight-arm-polyethylene glycol succinimide propionate; The second hydrogel precursor is selected from one or more of four-arm-polyethylene glycol amine and eight-arm-polyethylene glycol amine.

7. The preparation method according to claim 1, wherein In step 1, Based on the buffer solution, the volume concentration of the organic solvent is 5%-40%, preferably 5%-30%, more preferably 8%-20%; and / or the mass concentration of the hydrogel precursor is 5%-20%, preferably 10%-20%; and / or The weight ratio of the organic solvent to the poorly soluble active ingredient is 1:(0.5-1.0), preferably 1:(0.6-0.8); and / or The weight ratio of the poorly soluble active ingredient to the hydrogel precursor is 1:(0.5-4).

8. The preparation method according to claim 1, wherein In step 2, Before standing, the mixed liquid is further subjected to a homogenization step at a pressure of 100-500 MPa, preferably 200-450 MPa, more preferably 250-400 MPa; and / or The rotation speed for homogenization is 100-500 rpm, preferably 150-400 rpm, more preferably 200-400 rpm.

9. The preparation method according to claim 1, wherein Steps 1 to 3 do not include the steps of adding a suspending agent, a wetting agent, a flocculant, or a co-solvent.

10. A lacrimal canaliculus insert prepared according to the preparation method of any one of claims 1 to 9, wherein, in the lacrimal canaliculus insert, the weight ratio of the buffer salt, the hydrogel polymer, and the active ingredient can be 1:(0.05-0.2):(0.02-0.5), preferably 1:(0.1-0.2):(0.04-0.2); more particularly, the lacrimal canaliculus insert contains greater than 0 and less than or equal to 1000 ppm, preferably greater than 0 and less than or equal to 100 ppm, more preferably greater than 0 and less than or equal to 60 ppm of the organic solvent, and does not contain a suspending agent, a wetting agent, a flocculant, or a cosolvent.