Preparation method for lacrimal canalicular insert and lacrimal canalicular insert

Abstract

A preparation method for a lacrimal canalicular insert, and a lacrimal canalicular insert. The method comprises: mixing and dispersing a buffer solution, an organic solvent, a hydrogel precursor, and an insoluble active ingredient with an average particle size of 20 μm or less to obtain a mixed solution, wherein the mass concentration of the active ingredient is 2.5%-20% based on the buffer solution; and placing the mixed solution in a sleeve with the diameter of 0.5-2.0 mm for standing to obtain a hydrogel; and step 3: axially stretching the hydrogel 1.1-10 times and drying at 20-30 °C and 20-40% RH for 2-24 h to obtain the lacrimal canalicular insert. According to the preparation method, the dispersing performance of the loaded drug can be improved, and bubbles in the hydrogel can be discharged, and quality control in the production process of the lacrimal canalicular insert is guaranteed.

Description

Preparation method of lacrimal canaliculus insert and lacrimal canaliculus insert TECHNICAL FIELD

[0001] The present application relates to the technical field of lacrimal canaliculus inserts, in particular to a preparation method of lacrimal canaliculus insert and a lacrimal canaliculus insert prepared therefrom. BACKGROUND

[0002] Many eye diseases, such as cataract, glaucoma, fungal keratitis, dry eye, macular degeneration of the fundus, retinal disease, ocular surface allergy and the like, all involve local administration to the eye. In the existing clinical treatment of these eye diseases, eye drops are the most commonly used administration form. Because eye drops are non-invasive and easy to administer, eye drops are the most common method for treating eye diseases, accounting for 90% of all ophthalmic drugs on the market. The conjunctival sac of a human being contains only 20 μL of liquid, while 1 drop of eye drops is about 50-60 μL. Due to rapid blinking and tear clearance, the bioavailability of eye drops is very low, only 1-5%. Therefore, maintaining an effective therapeutic concentration of these drugs requires frequent administration, resulting in poor patient compliance and a high incidence of adverse reactions.

[0003] Therefore, other effective ophthalmic delivery systems are needed. Various formulations for ophthalmic delivery systems, such as eye ointments, eye suspensions and eye gels, which are in research, development and already on the market, have to some extent prolonged the residence time of drugs on the ocular surface. However, they have not been widely used because of some shortcomings, such as ointments causing blurred vision. At the same time, eye suspensions and eye gels also have a residence time of at most several tens of minutes on the ocular surface, and still require long-term administration for chronic eye diseases; for rapidly progressive infectious diseases such as fungal keratitis, suspensions still require eye drops several dozen times to several hundred times a day, which cannot fundamentally solve the problem.

[0004] As a new dosage form, lacrimal canaliculus inserts have shown good ability in drug release. Ophthalmic lacrimal canaliculus inserts refer to a drug and a matrix mixed to form a preparation, which is inserted into the lacrimal canaliculus of the eyelid without invasion, so that the active ingredient is released slowly and continuously. Compared with traditional eye drops, lacrimal canaliculus inserts have the advantage of increasing ocular residence time, thereby prolonging the action time of the active ingredient. Depending on the delivery matrix and the means of implementation, the sustained-release time can be from several days to several months.

[0005] The drug release principle of the lacrimal canaliculus insert can be summarized as the gradual diffusion release of drug particles in the matrix under the infiltration of tears, mainly through the process of diffusion. This release process conforms to the 0th order release model, also known as the zero-order release model, which is characterized by a constant drug release rate independent of time, and is affected by the drug concentration in the infiltration medium. Therefore, under this release model, the drug can be released at a relatively stable rate for a long time, thereby achieving a sustained therapeutic effect.

[0006] Specifically, the matrix in the lacrimal canaliculus insert is a hydrogel that can uniformly distribute drug particles in its dry state. When the insert is placed in the lacrimal canaliculus, tears begin to infiltrate the matrix, causing it to gradually change to a gel state while bringing drug diffusion into the tears. In this process, drug particles gradually dissolve or disperse into tears and eventually achieve drug release through the diffusion of tears in the eye.

[0007] Compared to general suspensions, the composition of lacrimal canaliculus inserts is strictly regulated by the national standard, and the "2020 Chinese Pharmacopoeia First Supplement" also explicitly states that "ophthalmic inserts should not add bacteriostatic agents or antioxidants or inappropriate additives." Generally, the preparation of suspensions requires the addition of suspending agents or cosolvents, wetting agents, and other additives to help drug particles stabilize and uniformly distribute. Lacrimal canaliculus inserts are not suitable for adding these substances to control the uniform distribution of drugs in the liquid. Especially after the matrix is dried, there is a risk of exceeding the safe percentage of auxiliary materials. However, many drugs have low solubility in water, and when they are loaded into lacrimal canaliculus inserts made of hydrogel, without the addition of suspending agents or cosolvents, wetting agents, and other additives to help drug particles stabilize and uniformly distribute, the drug may not disperse uniformly and may produce bubbles, resulting in uneven surfaces or drug particle adhesion on the surface of the lacrimal canaliculus insert, making the surface of the lacrimal canaliculus insert uneven, with burrs or cracks, leading to poor patient compliance when applying the lacrimal canaliculus insert. The uneven distribution of drugs in the lacrimal canaliculus insert also causes inconsistent drug release rates in certain areas, with some areas having too fast release rates and others having too slow release rates, thereby affecting the consistency and predictability of the therapeutic effect and failing to provide stable therapeutic effects.

[0008] In addition, the quality and stability of the drug directly affect the therapeutic effect and safety. For an eye drug delivery system such as a lacrimal canaliculus insert, uniformity is particularly important because even minor differences can affect the drug release rate and therapeutic effect. Therefore, consistency between batches needs to be ensured during production.

[0009] CN 102395401 B discloses a polyethylene glycol derivative as a precursor cross-linked formed hydrogel lacrimal canaliculus plug, which comprises microspheres encapsulating drugs and dispersed in the hydrogel, although no additional agent is added in its preparation process, but it uses dichloromethane as a solvent to dissolve the poorly soluble drugs, and dichloromethane is a solvent of the first type (should be avoided) in the Chinese Pharmacopoeia 2020 edition. At the same time, the production process of the drug-encapsulated microspheres is complex and the quality verification is cumbersome, which greatly increases the economic cost and time cost of drug research and development.

[0010] Therefore, there is an urgent need to develop a method for preparing a drug-loaded lacrimal canaliculus insert without using a solvent of the first type (should be avoided) to uniformly disperse the corresponding drugs, while the method is simple to operate and low in cost. SUMMARY

[0011] To solve the above technical problems, the inventors of the present application have found, through a large number of experiments, that the combination of a poorly soluble active ingredient with a specific particle size and a specific organic solvent can have a synergistic effect, so that the drug active ingredient in the subsequently prepared hydrogel is uniformly distributed, the surface of the hydrogel is smooth and free of bubbles, thereby obtaining a preparation method of a lacrimal canaliculus insert. According to the preparation method of the present application, the process is simple, and no complex process for producing drug-encapsulated microspheres is needed, nor is a solvent of the first type (should be avoided) used, so that the drug can be uniformly dispersed in the lacrimal canaliculus insert, and at the same time, the obtained lacrimal canaliculus insert has a smooth surface, no burrs, no cracks and no bubbles, thereby improving the quality of the lacrimal canaliculus insert and improving the comfort of the user. On this basis, the present application is completed.

[0012] An object of the present application is to provide a preparation method of a lacrimal canaliculus insert.

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

[0014] According to one aspect of the present application, there is provided a preparation method of a lacrimal canaliculus insert, which comprises:

[0015] Step 1: mixing, dispersing a buffer, an organic solvent, a hydrogel precursor and a poorly soluble active ingredient with 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%, preferably 4%-10%, based on the buffer;

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

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

[0018] The above steps are described in detail below.

[0019] Step 1:

[0020] In step 1, the buffer, organic solvent, hydrogel precursor, and poorly soluble active ingredient with 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 application, the poorly soluble (or insoluble) active ingredient refers to a drug for treating eye diseases with a solubility of less than 0.01 g in 100 g of water at room temperature 20°C, and preferably the active ingredient is selected from: dexamethasone, tacrolimus, lifitegrast, 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 drug active ingredient, and the surface of the lacrimal canaliculus insert prepared is rough and uneven, resulting in unqualified final product.

[0023] There is no particular limitation on the source of the active ingredient, as long as it meets the requirements of the lacrimal canaliculus insert for the drug and the particle size requirements of the present application. For example, the active ingredient can be a commercially available active ingredient product that meets the particle size requirements, or the active ingredient product that meets the particle size requirements can be obtained by micronizing the commercially available large particle size active ingredient.

[0024] There is no particular limitation on the method of micronization, and any suitable micronization method in the relevant field can be used, as long as it can obtain an active ingredient product that meets the particle size requirements and is suitable for use in the lacrimal canaliculus insert. For example, spray drying, grinding, ball milling, etc. can be used, but are not limited thereto.

[0025] The micronization can be performed before mixing, or it can be performed simultaneously during mixing. For example, an additional step of micronizing the poorly soluble active ingredient to obtain an active ingredient that meets the particle size requirements can be added before step 1. Alternatively, the poorly soluble active ingredient can be mixed with part or all of the other ingredients (such as the organic solvent, buffer, and / or hydrogel precursor) and then micronized.

[0026] The inventors of the present application have found through a large number of experiments that, without the addition of an organic solvent, if no suspending agent is added, the mixed solution is prone to show a stratification phenomenon, with the drug sinking to the bottom, and the drug particles being difficult to disperse uniformly, resulting in the prepared lacrimal canaliculus insert having a rough surface with concave-convex, and the final product being unqualified. However, as described in the background art, according to the national standard, additional agents including suspending agents are not allowed to be used in lacrimal canaliculus inserts. Surprisingly, the inventors have found that the use of a specific organic solvent can further promote the dispersion of the active ingredient, and can make the insoluble active ingredient uniformly dispersed and remain in the form of a gel without the additional addition of additives such as suspending agents, wetting agents, and flocculants.

[0027] According to the present application, 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 an organic solvent that is miscible with water and has a boiling point of 50-150℃. In this case, the organic solvent can not only disperse the poorly soluble active ingredient, but also be miscible with the buffer solution, ensuring that the buffer salt does not precipitate.

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

[0030] The use of the specific organic solvent can improve the solubility of the poorly soluble active ingredient and help the uniform dispersion of the active ingredient. The specific solvent used in the present application has a relatively low boiling point and is volatile, and is substantially volatilized during the drying process of the lacrimal canaliculus insert, with a low residual amount of organic solvent, ensuring the safety of the finished lacrimal canaliculus insert.

[0031] In the present application, the use of a buffer solution can adjust the pH of the finished lacrimal canaliculus insert to be compatible with the pH of the tear fluid, reduce irritation, and improve patient compliance.

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

[0033] Any buffer solution suitable for application to the eye can be used without particular limitation, as long as it can be adjusted to the appropriate pH. The choice of buffer solution is within the scope of a person skilled in the art and can be selected according to the pH of the tear fluid or the pH range that can be tolerated by a normal human eye, and therefore is not described in particular detail so as not to obscure the main inventive points of the present application.

[0034] For example, the buffer solution can be selected from phosphate buffer, citric acid buffer, and acetic acid buffer.

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

[0036] Citric acid buffer refers to a buffer consisting of sodium citrate, citric acid.

[0037] Acetic acid buffer refers to a buffer consisting of acetic acid, sodium acetate.

[0038] In the present invention, a hydrogel precursor is used to form a hydrogel. Any hydrogel precursor known in the art that is suitable for preparing a lacrimal canaliculus insert can be used without particular limitation. The selection of the hydrogel precursor is within the skill of the person skilled in the art, and thus is not described in particular detail so as not to obscure the main inventive 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 comprising a succinimidyl ester group or an amido group functional group, and having a molecular weight of 10k-40k;

[0041] a second hydrogel precursor which is a multi-arm polyethylene glycol comprising an amino group (-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 referred to in the present invention is the weight average molecular weight.

[0043] The hydrogel precursor can further comprise other polyethylene glycol derivatives, such as multi-arm polyethylene glycols substituted with hetero-functional groups comprising a succinimidyl ester group or an amido group or an amino group, as needed.

[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 can be 1:(0.5-2.0), preferably 1:(0.6-1.5).

[0046] Preferably, the first hydrogel precursor is a homofunctionally substituted multi-armed polyethylene glycol containing succinimidyl ester groups, more preferably selected from one or more of tetra-armed-polyethylene glycol succinimidyl succinate (4arm-PEG-SS), octa-armed-polyethylene glycol succinimidyl succinate (8arm-PEG-SS), tetra-armed-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), octa-armed-polyethylene glycol succinimidyl glutarate (8arm-PEG-SG), tetra-armed-polyethylene glycol succinimidyl glutaric acid amide (4arm-PEG-SGA), octa-armed-polyethylene glycol succinimidyl glutaric acid amide (8arm-PEG-SGA), tetra-armed-polyethylene glycol succinimidyl carboxymethyl ester (4arm-PEG-SCM), octa-armed-polyethylene glycol succinimidyl carboxymethyl ester (8arm-PEG-SCM), tetra-armed-polyethylene glycol succinimidyl adipate (4arm-PEG-SAP), octa-armed-polyethylene glycol succinimidyl adipate (8arm-PEG-SAP), tetra-armed-polyethylene glycol succinimidyl carbonate (4arm-PEG-SC), octa-armed-polyethylene glycol succinimidyl carbonate (8arm-PEG-SC), tetra-armed-polyethylene glycol succinimidyl propionate (4arm-PEG-SPA), octa-armed-polyethylene glycol succinimidyl propionate (8arm-PEG-SPA).

[0047] The second hydrogel precursor can be selected from one or more of tetra-armed-polyethylene glycol amine (4arm-PEG-NH2), octa-armed-polyethylene glycol amine (8arm-PEG-NH2).

[0048] In the case of using the specific hydrogel precursor, the hydrophobic region thereof can be combined with the insoluble active ingredient by cross-linking through chemical bonds, thereby helping the active ingredient to be uniformly distributed.

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

[0050] The volume concentration (based on the buffer) of the organic solvent 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 is too small, it can not be able to completely disperse the insoluble active ingredient. If the concentration of the organic solvent in the buffer is too large, the buffer salts can be precipitated, which can affect the formulation molding and pH.

[0051] The mass concentration of the hydrogel precursor (based on the buffer) can be 5%-20%, preferably 10%-20%, such as 10%, 12%, 16%, 20%, etc. If the concentration of the hydrogel precursor in the buffer is too small, the hydrogel obtained by the reaction will be soft and flat, and cannot be shaped. If the concentration of the hydrogel precursor in the buffer is too large, the shaped hydrogel will swell too much, especially in the diameter direction, and will cause compression to the lacrimal canaliculus tissue after being inserted into the lacrimal canaliculus.

[0052] The mass concentration of the active ingredient (based on the buffer) can be 2.5%-20%, preferably 4%-10%, such as 6%, 8%, 10%, etc. If the amount of the active ingredient is too small, the drug efficacy will be insufficient. If the amount of the active ingredient is too large, it will not be uniformly dispersed in the matrix, and the surface of the lacrimal canaliculus insert prepared will be rough and cannot be used.

[0053] Moreover, 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), such as 1:0.6, 1:0.7, 1:0.8, etc. If the poorly soluble active ingredient is too small, the drug efficacy of the lacrimal canaliculus insert obtained will be insufficient. If the poorly soluble active ingredient is too large, it will be difficult to be uniformly dispersed in the organic solvent.

[0054] When the volume ratio or the weight ratio of the buffer, the organic solvent, the hydrogel precursor, and the poorly soluble active ingredient is within the above range, the lacrimal canaliculus insert desired in the present application can be successfully prepared,

[0055] According to one embodiment of the present application, 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 is out of the above range, the active ingredient may agglomerate to cause the surface of the hydrogel to be rough, or the active ingredient may be too small to reach the effective dose.

[0057] Step 2:

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

[0059] The sleeve is preferably a polytetrafluoroethylene tube or a silica gel 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 application, in Step 2, before standing, a step of homogenizing the mixed solution under a pressure of 100-500 MPa is further included.

[0062] By the homogenization treatment under the above high pressure condition, the dispersion of the mixed solution can be further promoted, and the high pressure and shearing force can decompose or remove the agglomerates of the active ingredient in the lacrimal canal insert.

[0063] The pressure for the homogenization treatment is 100-500 MPa, preferably 200-450 MPa, and more preferably 250-400 MPa, such as 280 MPa, 300 MPa, 350 MPa, 400 MPa, etc. Under this condition, the agglomerates of the poorly soluble active ingredient can be decomposed and removed by the high pressure. If the pressure is too high, the hydrogel precursor will be broken, affecting the gelation. If the pressure is too low, the agglomerates of the poorly soluble active ingredient cannot be completely removed.

[0064] The rotation speed for the homogenization treatment can be 100-500 rpm, preferably 150-400 rpm, and more preferably 200-400 rpm, such as 240 rpm, 300 rpm, 320 rpm, 400 rpm, etc. Under this condition, the agglomerates of the poorly soluble active ingredient can be removed by the high shearing force. If the rotation speed is too high, the hydrogel precursor will be severely damaged due to the high shearing force, affecting the gelation. If the rotation speed is too low, the agglomerates of the poorly soluble active ingredient cannot be completely removed.

[0065] The temperature for the homogenization treatment is not particularly limited and 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 canal insert. Specifically, the hydrogel is axially stretched by 1.1-10 times and dried at 20-30°C and 20-40% RH for 2-24 hours to obtain the lacrimal canal insert.

[0068] The stretching multiple refers to the change multiple of the hydrogel in the axial (length) direction.

[0069] The temperature in Step 3 is 20-30°C. Below this temperature, the organic solvent will be difficult to volatilize, and the residual amount will be higher than the safe amount specified in the pharmacopoeia. Above this temperature, the hydrogel itself will be broken, affecting the stability of the active ingredient.

[0070] The relative humidity in Step 3 is 20-40% RH. Below this humidity, the hydrogel will be difficult to dry and even collapse and not form a shape. Above this humidity, the hydrogel will dry too quickly, and the surface of the hydrogel will be broken.

[0071] In the method according to the present application, no suspending agent, wetting agent, flocculating agent, or latent solvent is added, so that a lacrimal canal insert with uniformly dispersed drug, smooth surface, no burr, no crack, and no bubble is obtained.

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

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

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

[0075] According to one embodiment of the present application, the lacrimal canaliculus insert contains more than 0 and less than or equal to 1000 ppm of the organic solvent, preferably contains more than 0 and less than or equal to 100 ppm of the organic solvent, more preferably contains more than 0 and less than or equal to 60 ppm of the organic solvent, such as 1-1000 ppm, 1-100 ppm, 1-60 ppm of the organic solvent, and does not contain additional agents selected from suspending agents, wetting agents, flocculating agents, and cosolvents. Advantages

[0076] The method for controlling the uniformity of dispersion in the preparation of the lacrimal canaliculus insert of the present application can improve the dispersion performance of the loaded drug and expel the bubbles in the hydrogel, thereby ensuring the quality control during the production of the lacrimal canaliculus insert. In actual preparation and use, the present application has the following advantages:

[0077] First, the water-insoluble or poorly water-soluble drugs can be uniformly dispersed and loaded into the lacrimal canaliculus insert, which can improve the bioavailability of these drugs and thus improve the drug effect by taking advantage of the long-acting and sustained-release advantages of the lacrimal canaliculus insert. The present application breaks through the limitations of difficult administration of poorly soluble drugs and can meet the needs of patients with different eye diseases and solve the difficulties of no effective drugs for eye diseases or poor therapeutic effect in reality.

[0078] Second, the uniformly dispersed drugs can effectively avoid the generation of bubbles in the hydrogel. The method disclosed in the present application does not cause problems in the safety of the lacrimal canaliculus insert itself and has the advantages of being economical and effective. Of course, the expulsion of bubbles is also an important link in the quality control during actual production.

[0079] Thirdly, the present application avoids the use of additional agents selected from suspending agents, wetting agents, flocculating agents, and latent solvents by adding a solvent; meanwhile, according to the requirements of residual solvents in the Pharmacopoeia and ICH documents, the maximum limit of methanol is 3000 ppm, and the maximum limit of ethanol, acetic acid, n-propanol, isopropanol, and acetone is 5000 ppm. However, the residual amount of the organic solvent in the present application is much lower than the limit. DETAILED DESCRIPTION

[0080] The present application will be described below through specific embodiments. However, it should be understood that these embodiments are only illustrative, and are not intended to limit the present application and its uses. Furthermore, the present application is not limited by any theory described in the foregoing prior art or the summary or the following specific embodiments or examples.

[0081] The micronization treatment of the present application is performed using a QS-100 type jet mill, and other conventional methods in the prior art can also be used.

[0082] The particle size or average particle size in the present application is the average particle size D90 measured by a Dandong Bettersize laser particle size analyzer.

[0083] The high-pressure homogenization treatment of the present application is performed using a high-pressure homogenizer instrument.

[0084] The dispersion of the drug is determined by observing the surface of the finished lacrimal canaliculus insert: the lacrimal canaliculus insert with uniform dispersion of drug particles has a smooth surface, no burrs, and no cracks; and the lacrimal canaliculus insert with uneven dispersion of drug particles has a surface with concave-convex or drug particles attached.

[0085] Raw materials and instruments:

[0086] The dexamethasone raw material is purchased from Aladdin, and the average particle size is 60 μm.

[0087] The tacrolimus raw material is purchased from Aladdin, and the average particle size is 50 μm.

[0088] The voriconazole is purchased from Aladdin, and the average particle size is 53 μm.

[0089] 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG) is purchased from Beijing KeyGen Biotech Co., Ltd.

[0090] 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2) is purchased from Beijing KeyGen Biotech Co., Ltd.

[0091] 10k, 4-arm-polyethylene glycol succinimidyl adipate (4arm-PEG-SAP) is purchased from Beijing KeyGen Biotech Co., Ltd.

[0092] 10k, 4-arm-polyethylene glycol succinimidyl carboxymethyl ester (4arm-PEG-SCM) was purchased from Beijing KeyGen Biotech Co., Ltd.

[0093] 10k, 8-arm-polyethylene glycol succinimidyl adipate (8arm-PEG-SAP) was purchased from Beijing KeyGen Biotech Co., Ltd.

[0094] 10k, 4-arm-polyethylene glycol succinimidyl propionate (4arm-PEG-SPA) was purchased from Beijing KeyGen Biotech Co., Ltd.

[0095] 10k represents the weight average molecular weight of the polyethylene glycol segment is 10000D.

[0096] Example 1: lacrimal canaliculus insert 1

[0097] The dexamethasone raw material was micronized to obtain micronized dexamethasone with an average particle size of 3.5 μm;

[0098] 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate and 0.495 g of water for injection were weighed to prepare a phosphate buffer with a pH of 6.5;

[0099] The above phosphate buffer was used to dilute ethanol to obtain an ethanol solution with a volume fraction of 10%;

[0100] 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), 0.030 g of micronized dexamethasone were weighed;

[0101] The above raw materials were dispersed using the diluted ethanol solution, at this time the concentration of the hydrogel precursor relative to the buffer was 12%, and the concentration of the active ingredient was 6%, and the mixture was obtained by thoroughly mixing and ultrasonic treatment;

[0102] The mixture was treated by high pressure homogenization (300 MPa, 300 rpm);

[0103] The mixture was injected into a cannula with a diameter of 2.0 mm using a syringe;

[0104] After waiting for the gelation, the formed hydrogel was taken out of the cannula;

[0105] The hydrogel was stretched by 3 times along the axial direction, so that its length was increased;

[0106] The stretched hydrogel was placed in an environment of 25°C, 30% RH for continuous drying for 12 h;

[0107] A plurality of finished lacrimal canaliculus inserts with a diameter of about 0.50 mm and a length of about 3 mm were obtained by cutting.

[0108] The surface of the lacrimal canaliculus insert was observed under 10 times microscope, and it was found that the surface of the lacrimal canaliculus insert was regular and smooth without burr or crack.

[0109] The finished lacrimal canaliculus insert was soaked in a culture dish containing artificial tears for 24 hours.

[0110] The leaching liquid was collected, and the residual ethanol in the leaching liquid was determined by gas chromatography. The result showed that the residual ethanol was 11.2 ppm.

[0111] Before and after soaking, the size of the lacrimal canaliculus insert was as follows: before soaking, the diameter was 0.49±0.03 mm, and the length was 2.92±0.04 mm; after soaking, the diameter was 2.13±0.07 mm, and the length was 1.44±0.02 mm.

[0112] It can be proved by visual observation that the drug particles are uniformly dispersed in the process of preparing the lacrimal canaliculus insert.

[0113] Example 2: Lacrimal canaliculus insert 2

[0114] The tacrolimus raw material was micronized to obtain micronized tacrolimus with an average particle size of 2.8 μm;

[0115] Sodium dihydrogen phosphate 0.002 g, disodium hydrogen phosphate 0.004 g, and water for injection 0.495 g were weighed to prepare a phosphate buffer with a pH of 6.5;

[0116] The phosphate buffer was used to dilute ethanol to obtain an ethanol solution with a volume fraction of 10%;

[0117] 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 were weighed;

[0118] The above raw materials were dispersed using the diluted ethanol solution, and at this time, the concentration of the hydrogel precursor relative to the buffer was 12%, and the concentration of the active ingredient was 6%. The mixture was mixed and ultrasonicated to obtain a mixed solution;

[0119] The mixed solution was subjected to high-pressure homogenization (300 MPa, 300 rpm) treatment;

[0120] The mixed solution was injected into a sleeve with a diameter of 2.0 mm using a syringe;

[0121] The formed hydrogel was taken out of the sleeve after waiting for gelation;

[0122] The hydrogel was stretched by 3 times along the axial direction to increase the length;

[0123] The stretched hydrogel was placed in a 25℃, 30% RH environment for continuous drying for 12h;

[0124] The cutting obtained a plurality of finished canaliculus insert agents with a diameter of about 0.50mm and a length of about 3mm.

[0125] Under 10x microscope, it was found that the surface of the canaliculus insert agent was regular and smooth, without burrs or cracks.

[0126] The finished canaliculus insert agent was soaked in a culture dish containing artificial tears for 24h.

[0127] The leaching liquid was collected, and the ethanol residue in the leaching liquid was determined by gas chromatography. The result was that the ethanol residue was 8.3ppm.

[0128] Before and after soaking, the size of the canaliculus insert agent was as follows: before soaking: diameter 0.50±0.02mm, length 2.97±0.05mm; after soaking: diameter 1.99±0.03mm, length 1.53±0.07mm.

[0129] According to the visual observation, it can be proved that the drug particles have been uniformly dispersed in the process of preparing the canaliculus insert agent.

[0130] Example 3: Canaliculus insert agent 3

[0131] The tacrolimus raw material was micronized to obtain micronized tacrolimus with an average particle size of 2.8μm;

[0132] 0.002g of sodium dihydrogen phosphate, 0.004g of disodium hydrogen phosphate and 0.495g of water for injection were weighed to prepare a phosphate buffer with a pH of 6.5;

[0133] The above phosphate buffer was used to dilute ethanol to obtain an ethanol solution with a volume fraction of 15%;

[0134] 0.030g of 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG), 0.030g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2) and 0.030g of micronized tacrolimus were weighed;

[0135] The above raw materials were dispersed using the diluted ethanol solution, at this time the concentration of the hydrogel precursor relative to the buffer was 12%, and the concentration of the active ingredient was 6%, and the mixture was obtained by fully mixing and ultrasonic treatment;

[0136] The mixture was treated by high-pressure homogenization (300MPa, 300rpm);

[0137] The mixture was injected into a sleeve with a diameter of 2.0mm using a syringe;

[0138] Wait for gelation, and take the shaped hydrogel out of the sleeve;

[0139] Stretch the hydrogel axially 3 times, so that its length increases;

[0140] Dry the stretched hydrogel at 25℃, 30% RH for 12 hours;

[0141] Cut to obtain a plurality of finished lacrimal canaliculus inserts with a diameter of about 0.50 mm and a length of about 3 mm.

[0142] Observe under a 10x microscope, and find that the surface of the lacrimal canaliculus insert is regular and smooth, without burrs or cracks.

[0143] Soak the finished lacrimal canaliculus insert in a culture dish containing artificial tears for 24 hours.

[0144] Collect the leachate, and use gas chromatography to determine the residual ethanol in the leachate. The result is 13.3 ppm of residual ethanol.

[0145] Before and after soaking, the size of the lacrimal canaliculus insert is as follows: before soaking: diameter 0.50±0.02 mm, length 2.97±0.05 mm; after soaking: diameter 1.99±0.03 mm, length 1.53±0.07 mm.

[0146] According to the visual observation, it can be proved that the drug particles are uniformly dispersed in the process of preparing the lacrimal canaliculus insert.

[0147] Example 4: Lacrimal canaliculus insert 4

[0148] Micronize voriconazole raw material to obtain micronized voriconazole with an average particle size of 3.0 μm;

[0149] 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 a phosphate buffer with a pH of 6.5;

[0150] Use the above phosphate buffer to dilute ethanol to obtain an ethanol solution with a volume fraction of 10%;

[0151] 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;

[0152] Use the diluted ethanol solution to disperse the above raw materials, and at this time, the concentration of the hydrogel precursor relative to the buffer is 12%, and the concentration of the active ingredient is 6%. Mix thoroughly and ultrasonically to obtain a mixture;

[0153] The mixture was treated by high pressure homogenization (350 MPa, 400 rpm);

[0154] The mixture was injected into a 2.0 mm diameter sleeve using a syringe;

[0155] The formed hydrogel was taken out of the sleeve after gelation;

[0156] The hydrogel was stretched 3 times in length along the axial direction;

[0157] The stretched hydrogel was dried in a 25℃, 30% RH environment for 12 hours;

[0158] The finished tear duct insert was cut into multiple pieces with a diameter of about 0.50 mm and a length of about 3 mm.

[0159] The surface of the tear duct insert was smooth and regular, without burrs or cracks, under 10x magnification.

[0160] The finished tear duct insert was soaked in a culture dish containing artificial tears for 24 hours.

[0161] The leachate was collected and the ethanol residue in the leachate was determined using gas chromatography. The ethanol residue was 18.1 ppm.

[0162] The size of the tear duct insert before and after soaking was as follows: 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.

[0163] The drug particles were uniformly dispersed during the preparation of the tear duct insert, as evidenced by visual observation.

[0164] Example 5: Tear duct insert 5

[0165] The voriconazole raw material was micronized to obtain micronized voriconazole with an average particle size of 3.0 μm;

[0166] Sodium dihydrogen phosphate 0.002 g, disodium hydrogen phosphate 0.004 g, and water for injection 0.495 g were weighed to prepare a phosphate buffer with a pH of 6.5;

[0167] The above phosphate buffer was used to dilute acetic acid to obtain a 10% volume fraction acetic acid solution;

[0168] 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG) 0.030 g, 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2) 0.030 g, and micronized voriconazole 0.030 g were weighed.

[0169] The above raw materials were dispersed using a dilute acetic acid solution, 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 obtained by thoroughly mixing and ultrasonic treatment;

[0170] The mixture was subjected to high-pressure homogenization (350 MPa, 400 rpm);

[0171] The mixture was injected into a sleeve with a diameter of 2.0 mm using a syringe;

[0172] The formed hydrogel was taken out of the sleeve after waiting for gelation;

[0173] The hydrogel was stretched by 3 times in the axial direction to increase the length;

[0174] The stretched hydrogel was dried at 25°C and 30% RH for 12 h;

[0175] The finished lacrimal canaliculus insert was cut into multiple pieces with a diameter of about 0.50 mm and a length of about 3 mm.

[0176] Observation under a 10x microscope showed that the surface of the lacrimal canaliculus insert was regular and smooth, without burrs or cracks.

[0177] The finished lacrimal canaliculus insert was soaked in a culture dish containing artificial tears for 24 h.

[0178] The leachate was collected and gas chromatography was used to determine the residual acetic acid in the leachate. The results showed that the residual acetic acid was 15.5 ppm.

[0179] Before and after soaking, the size of the lacrimal canaliculus insert was as follows: 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.

[0180] According to the visual observation, it can be proved that the drug particles were uniformly dispersed during the preparation of the lacrimal canaliculus insert.

[0181] Example 6: Lacrimal canaliculus insert 6

[0182] The voriconazole raw material was micronized to obtain micronized voriconazole with an average particle size of 3.0 μm;

[0183] 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection were weighed to prepare a phosphate buffer with a pH of 6.5;

[0184] The acetic acid was diluted using the above phosphate buffer to obtain an acetic acid solution with a volume fraction of 10%;

[0185] 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), 0.030 g of micronized voriconazole;

[0186] The above raw materials were dispersed using a dilute acetic acid solution, at this time 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 obtained by thoroughly mixing and ultrasonicating;

[0187] The mixture was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0188] The mixture was injected into a sleeve with a diameter of 2.0 mm using a syringe;

[0189] The formed hydrogel was removed from the sleeve after waiting for gelation;

[0190] The hydrogel was stretched 3 times in the axial direction, increasing its length;

[0191] The stretched hydrogel was placed in a 25°C, 30% RH environment for continuous drying for 12 h;

[0192] The finished lacrimal canaliculus insert was cut into multiple pieces with a diameter of about 0.50 mm and a length of about 3 mm.

[0193] Observation under a 10x microscope found that the surface of the lacrimal canaliculus insert was regular and smooth, without burrs or cracks.

[0194] The finished lacrimal canaliculus insert was immersed in a culture dish containing artificial tears for 24 h.

[0195] The leachate was collected and gas chromatography was used to determine the residual acetic acid in the leachate. The results showed that the residual acetic acid was 27.3 ppm.

[0196] Before and after immersion, the size of the lacrimal canaliculus insert was as follows: before immersion: diameter 0.53±0.01 mm, length 2.96±0.05 mm; after immersion: diameter 1.86±0.03 mm, length 1.38±0.02 mm.

[0197] According to the visual observation, it can be proved that the drug particles have been uniformly dispersed in the process of preparing the lacrimal canaliculus insert.

[0198] Example 7: Lacrimal canaliculus insert 7

[0199] The dexamethasone raw material was micronized to obtain micronized dexamethasone with an average particle size of 3.5 μm;

[0200] Sodium dihydrogen phosphate 0.002 g, disodium hydrogen phosphate 0.004 g and water for injection 0.495 g were weighed to prepare a phosphate buffer solution, and the pH was 6.5;

[0201] The acetone was diluted with the phosphate buffer solution to obtain an acetone solution with a volume fraction of 10%;

[0202] 10k, 4-arm-polyethylene glycol succinimidyl hexanoate (4arm-PEG-SAP) 0.030 g, 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2) 0.030 g, and micronized dexamethasone 0.040 g were weighed.

[0203] The above raw materials were dispersed using the diluted acetone solution, and the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 8% relative to the buffer solution. The mixture was obtained by thoroughly mixing and ultrasonicating;

[0204] The mixture was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0205] The mixture was injected into a sleeve with a diameter of 2.0 mm using a syringe;

[0206] The formed hydrogel was removed from the sleeve after waiting for gelation.

[0207] The hydrogel was stretched axially by 3 times to increase its length;

[0208] The stretched hydrogel was dried for 12 h at 25°C and 30% RH.

[0209] A plurality of finished lacrimal canaliculus inserts with a diameter of about 0.50 mm and a length of about 3 mm were obtained by cutting.

[0210] Under 10x magnification, it was found that the surface of the lacrimal canaliculus insert was regular and smooth, without burrs or cracks.

[0211] The finished lacrimal canaliculus insert was soaked in a culture dish containing artificial tears for 24 h.

[0212] The leachate was collected, and the residual acetone in the leachate was determined using gas chromatography. The result was 48.3 ppm of acetone residue.

[0213] Before and after soaking, the size of the lacrimal canaliculus insert was as follows: 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.

[0214] According to the visual observation, it can be proved that the drug particles were uniformly dispersed during the preparation of the lacrimal canaliculus insert.

[0215] Example 8: Lacrimal canaliculus insert 8

[0216] The dexamethasone raw material was micronized to obtain micronized dexamethasone with an average particle size of 3.5 μm;

[0217] Sodium dihydrogen phosphate 0.002 g, disodium hydrogen phosphate 0.004 g and water for injection 0.495 g were weighed to prepare a phosphate buffer with a pH of 6.5;

[0218] The above phosphate buffer was used to dilute acetone to obtain an acetone solution with a volume fraction of 10%;

[0219] 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 were weighed;

[0220] The above raw materials were dispersed using the diluted acetone solution, and 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 obtained by thoroughly mixing and ultrasonicating;

[0221] The mixture was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0222] The mixture was injected into a sleeve with a diameter of 2.0 mm using a syringe;

[0223] The formed hydrogel was taken out of the sleeve after waiting for gelation;

[0224] The hydrogel was stretched axially by 3 times to increase its length;

[0225] The stretched hydrogel was placed in an environment of 25°C and 30% RH for continuous drying for 12 h;

[0226] A plurality of finished lacrimal canaliculus inserts with a diameter of about 0.50 mm and a length of about 3 mm were obtained by cutting.

[0227] Observation under a 10x microscope showed that the surface of the lacrimal canaliculus insert was regular and smooth, without burrs or cracks.

[0228] The finished lacrimal canaliculus insert was immersed in a culture dish containing artificial tears for 24 h.

[0229] The leachate was collected, and the residual acetone in the leachate was determined using gas chromatography. The result was 37.9 ppm of residual acetone.

[0230] The size of the lacrimal canaliculus insert before and after soaking is as follows: before soaking, diameter 0.50±0.02mm, length 2.98±0.03mm; after soaking, diameter 1.91±0.03mm, length 1.37±0.04mm.

[0231] It can be proved by visual observation that the drug particles are uniformly dispersed in the process of preparing the lacrimal canaliculus insert.

[0232] Example 9: Lacrimal canaliculus insert 9

[0233] The dexamethasone raw material is micronized to obtain micronized dexamethasone with an average particle size of 3.5μm;

[0234] 0.002g of sodium dihydrogen phosphate, 0.004g of disodium hydrogen phosphate and 0.495g of water for injection are weighed to prepare a phosphate buffer with a pH of 6.5;

[0235] The above phosphate buffer is used to dilute acetone to obtain an acetone solution with a volume fraction of 10%;

[0236] 0.040g of 10k, 4-arm-polyethylene glycol succinimidyl propionate (4arm-PEG-SPA), 0.040g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.030g of micronized dexamethasone are weighed;

[0237] The above raw materials are dispersed using the diluted acetone solution, and the concentration of the hydrogel precursor relative to the buffer is 16%, and the concentration of the active ingredient is 6%. The mixture is obtained by thoroughly mixing and ultrasonicating;

[0238] The mixture is subjected to high-pressure homogenization (300MPa, 300rpm);

[0239] The mixture is injected into a sleeve with a diameter of 2.0mm using a syringe;

[0240] The formed hydrogel is taken out of the sleeve after waiting for gelation;

[0241] The hydrogel is stretched axially by 3 times to increase its length;

[0242] The stretched hydrogel is placed in an environment of 25℃, 30%RH for continuous drying for 12h;

[0243] A plurality of finished lacrimal canaliculus inserts with a diameter of about 0.50mm and a length of about 3mm are obtained by cutting.

[0244] Under 10x magnification, it is found that the surface of the lacrimal canaliculus insert is regular and smooth, without burrs or cracks.

[0245] The finished lacrimal canaliculus insert is soaked in a culture dish containing artificial tears for 24h.

[0246] The leaching solution was collected and the residual acetone in the leaching solution was determined by gas chromatography. The result was 51.5 ppm of residual acetone.

[0247] The size of the canaliculus insert before and after soaking was as follows: before soaking, diameter 0.48 ± 0.04 mm, length 3.02 ± 0.02 mm; after soaking, diameter 1.88 ± 0.04 mm, length 1.40 ± 0.03 mm.

[0248] It can be proved by visual observation that the drug particles are uniformly dispersed during the preparation of the canaliculus insert.

[0249] Example 10: Canaliculus insert 10

[0250] The tacrolimus raw material was micronized to obtain micronized tacrolimus with an average particle size of 2.8 μm;

[0251] Sodium dihydrogen phosphate 0.002 g, disodium hydrogen phosphate 0.004 g and water for injection 0.495 g were weighed to prepare a phosphate buffer with a pH of 6.5;

[0252] The above phosphate buffer was used to dilute ethanol to obtain an ethanol solution with a volume fraction of 10%;

[0253] 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 were weighed;

[0254] The above raw materials were dispersed using the diluted ethanol solution, and at this time the concentration of the hydrogel precursor relative to the buffer was 12%, and the concentration of the active ingredient was 6%. The mixture was obtained by thoroughly mixing and ultrasonicating;

[0255] The mixture was injected into a sleeve with a diameter of 2.0 mm using a syringe;

[0256] The formed hydrogel was taken out of the sleeve after waiting for gelation;

[0257] The hydrogel was stretched by 3 times along the axial direction to increase the length;

[0258] The stretched hydrogel was placed in an environment of 25°C and 30% RH for continuous drying for 12 h;

[0259] A plurality of finished canaliculus inserts with a diameter of about 0.50 mm and a length of about 3 mm were obtained by cutting.

[0260] Observation under a 10x microscope showed that the surface of the canaliculus insert was regular and smooth, without burrs or cracks.

[0261] The finished lacrimal canaliculus insert was immersed in a culture dish containing artificial tears for 24 h.

[0262] The leaching liquid was collected and the ethanol residue in the leaching liquid was determined using gas chromatography. The result was 9.7 ppm of ethanol residue.

[0263] Before and after immersion, the size of the lacrimal canaliculus insert was as follows: before immersion: diameter 0.52 ± 0.03 mm, length 2.98 ± 0.02 mm; after immersion: diameter 1.96 ± 0.05 mm, length 1.55 ± 0.04 mm.

[0264] It can be proved by visual observation that the drug particles are uniformly dispersed during the preparation of the lacrimal canaliculus insert.

[0265] Comparative Example 1:

[0266] The tacrolimus raw material was micronized to obtain micronized dexamethasone with an average particle size of 2.8 μm;

[0267] Sodium dihydrogen phosphate 0.002 g, disodium hydrogen phosphate 0.004 g and water for injection 0.495 g were weighed to prepare a phosphate buffer with a pH of 6.5;

[0268] 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG) 0.030 g, 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2) 0.030 g, and micronized tacrolimus 0.030 g were weighed.

[0269] The above raw materials were dispersed using the above phosphate buffer, at this time the concentration of the hydrogel precursor relative to the buffer was 12%, and the concentration of the active ingredient was 6%, and the mixture was obtained by thoroughly mixing and ultrasonicating;

[0270] It was found that the mixture showed a stratification phenomenon, with the drug sinking to the bottom, and the drug particles being difficult to disperse uniformly.

[0271] After adding the suspending agent hydroxypropyl cellulose to the above mixture and thoroughly mixing, it was found that the mixture had no stratification.

[0272] The mixture was injected into the sleeve according to the process of Example 2 and a plurality of finished lacrimal canaliculus inserts with a diameter of about 0.50 mm and a length of about 3 mm were prepared and cut.

[0273] Under 10 times magnification, it was found that the surface of the lacrimal canaliculus insert was regular and smooth, without burrs or cracks.

[0274] The finished lacrimal canaliculus insert was immersed in a culture dish containing artificial tears for 24 h.

[0275] The size of the canaliculus insert before and after soaking is as follows: 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.

[0276] It can be proved by visual observation that the drug particles in the canaliculus insert are uniformly dispersed after the addition of the suspending agent.

[0277] Comparative Example 2

[0278] Sodium dihydrogen phosphate 0.002 g, disodium hydrogen phosphate 0.004 g and water for injection 0.495 g are weighed to prepare a phosphate buffer solution with pH 6.5;

[0279] The above phosphate buffer solution is used to dilute acetic acid to obtain an acetic acid solution with a volume fraction of 10%;

[0280] 10k, 4-arm-polyethylene glycol succinimidyl carboxymethyl ester (4arm-PEG-SCM) 0.030 g, 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2) 0.030 g, and raw voriconazole 0.030 g are weighed; the particle size of the raw voriconazole is 53 μm;

[0281] The above raw material is dispersed using the above acetic acid solution; at this time, the concentration of the hydrogel precursor relative to the buffer solution is 12%, and the concentration of the active ingredient is 6%; the mixture is obtained by thoroughly mixing and ultrasonicating;

[0282] It is found that the mixture presents a stratification phenomenon, with the drug sinking to the bottom, and the drug particles being difficult to uniformly disperse.

[0283] The suspending agent hydroxypropyl cellulose is added to the above mixture, and after thorough mixing, it is found that the mixture no longer presents a stratification phenomenon.

[0284] The mixture is injected into the cannula according to the process of Example 3, and a plurality of finished canaliculus inserts with a diameter of about 0.50 mm and a length of about 3 mm are prepared and cut.

[0285] Observation under a 10-fold microscope shows that the surface of the canaliculus insert is regular and smooth, without burrs or cracks.

[0286] The finished canaliculus insert is soaked in a culture dish containing artificial tears for 24 h.

[0287] The leachate is collected, and gas chromatography is used to determine the residual acetic acid in the leachate. The result is that the residual acetic acid is 72.7 ppm.

[0288] The size of the canaliculus insert before and after soaking is as follows: before soaking, diameter 0.50±0.02mm, length 3.01±0.05mm; after soaking, diameter 1.58±0.08mm, length 1.72±0.04mm.

[0289] It can be proved by visual observation that the drug particles in the canaliculus insert are uniformly dispersed after the addition of the suspending agent.

[0290] Comparative Example 3

[0291] Sodium dihydrogen phosphate 0.002g, disodium hydrogen phosphate 0.004g and 0.495g of water for injection are weighed to prepare a phosphate buffer, and the pH is 6.5;

[0292] 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG) 0.030g and 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2) 0.030g, 0.030g of raw dexamethasone are weighed; the particle size of the raw dexamethasone is 60μm;

[0293] The above raw material is dispersed using the above phosphate buffer, and at this time, the concentration of the hydrogel precursor relative to the buffer is 12%, and the concentration of the active ingredient is 6%, and the mixture is obtained by fully mixing and ultrasonic treatment;

[0294] The mixture is subjected to high-pressure homogenization (300MPa, 300rpm) treatment;

[0295] It is found that the mixture shows a stratification phenomenon, with the drug sinking to the bottom and a small amount of floating, and the drug particles are difficult to disperse uniformly.

[0296] The suspending agent hydroxypropyl cellulose is added to the above mixture, and after fully mixing, it is found that the drug particles in the mixture still show a stratification phenomenon.

[0297] It is shown that only using the method of high-pressure homogenization cannot uniformly disperse the active ingredient.

[0298] Comparative Example 4

[0299] The dexamethasone raw material is micronized to obtain micronized dexamethasone with an average particle size of 3.5μm;

[0300] Sodium dihydrogen phosphate 0.002g, disodium hydrogen phosphate 0.004g and 0.495g of water for injection are weighed to prepare a phosphate buffer, and the pH is 6.5;

[0301] 10k, 4-arm-polyethylene glycol succinimidyl glutarate (4arm-PEG-SG) 0.030g and 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2) 0.030g, 0.030g of micronized dexamethasone are weighed;

[0302] The raw materials were dispersed using the above phosphate buffer, 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 obtained by thoroughly mixing and ultrasonic treatment;

[0303] The mixture was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0304] It was found that the mixture showed a stratification phenomenon, with the drug sinking to the bottom and a small amount of floating, and the drug particles were difficult to disperse uniformly.

[0305] It was found that the mixture showed a stratification phenomenon, with the drug sinking to the bottom and a small amount of floating, and the drug particles were difficult to disperse uniformly.

[0306] Comparative Example 5

[0307] Phosphate buffer was prepared by weighing 0.002 g of sodium dihydrogen phosphate, 0.004 g of disodium hydrogen phosphate, and 0.495 g of water for injection, and the pH was 6.5;

[0308] The acetone was diluted using the above phosphate buffer to obtain an acetone solution with a volume fraction of 10%;

[0309] 0.030 g of 10k, 4-arm-polyethylene glycol succinimidyl hexanoate (4arm-PEG-SAP), 0.030 g of 10k, 4-arm-polyethylene glycol amine (4arm-PEG-NH2), and 0.040 g of the raw material dexamethasone were weighed, and the particle size of the raw material dexamethasone was 60 μm;

[0310] The raw materials were dispersed using the above phosphate buffer, the concentration of the hydrogel precursor was 12% and the concentration of the active ingredient was 8% relative to the buffer, and the mixture was obtained by thoroughly mixing and ultrasonic treatment;

[0311] The mixture was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0312] The mixture was injected into a sleeve with a diameter of 2.0 mm using a syringe;

[0313] The formed hydrogel was removed from the sleeve after waiting for gelation;

[0314] The hydrogel was stretched axially by 3 times to increase its length;

[0315] The stretched hydrogel was placed in an environment of 25°C and 30% RH for continuous drying for 12 h;

[0316] A long rod-shaped lacrimal canal insert with a diameter of about 0.50 mm was obtained.

[0317] The long rod-shaped lacrimal canaliculus insert is cut to obtain a plurality of finished lacrimal canaliculus inserts with a diameter of 0.50 mm and a length of 3.0 mm.

[0318] Under observation with a 10-fold microscope, it is found that the surface of the lacrimal canaliculus insert has a distinct grainy feeling, is rough, and uneven.

[0319] It is indicated that the method of adding organic solvents and high-pressure homogenization alone cannot uniformly disperse the drug.

[0320] Comparative Example 6

[0321] The tacrolimus raw material is micronized to obtain micronized tacrolimus with an average particle size of 30 μm;

[0322] Sodium dihydrogen phosphate 0.002 g, disodium hydrogen phosphate 0.004 g, and water for injection 0.495 g are weighed to prepare a phosphate buffer with a pH of 6.5;

[0323] The above phosphate buffer is used to dilute ethanol to obtain an ethanol solution with a volume fraction of 15%;

[0324] 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 are weighed;

[0325] The above raw materials are dispersed using the diluted ethanol solution, and at this time, the concentration of the hydrogel precursor relative to the buffer is 12%, and the concentration of the active ingredient is 8%. The mixture is fully mixed and ultrasonicated to obtain a mixed solution;

[0326] The mixed solution is subjected to high-pressure homogenization treatment;

[0327] The mixed solution is injected into a sleeve with a diameter of 2.0 mm using a syringe;

[0328] The formed hydrogel is taken out of the sleeve after waiting for gelation.

[0329] The hydrogel is stretched by 3 times in the axial direction to increase the length;

[0330] The stretched hydrogel is placed in an environment of 25°C and 30% RH for continuous drying for 12 h;

[0331] A long rod-shaped lacrimal canaliculus insert with a diameter of about 0.50 mm is obtained.

[0332] The long rod-shaped lacrimal canaliculus insert is cut to obtain a plurality of finished lacrimal canaliculus inserts with a diameter of 0.50 mm and a length of 3.0 mm.

[0333] Under observation with a 10-fold microscope, it is found that the surface of the lacrimal canaliculus insert has a distinct grainy feeling, is rough, and uneven.

[0334] The main reason is that the drug particles obtained by micronization treatment are too large to be uniformly dispersed in the mixed solution.

[0335] Comparative Example 7

[0336] The dexamethasone raw material was micronized to obtain micronized dexamethasone with an average particle size of 3.5 μm;

[0337] Sodium dihydrogen phosphate 0.002 g, disodium hydrogen phosphate 0.004 g and 0.495 g of water for injection were weighed to prepare a phosphate buffer solution;

[0338] The acetone was diluted using the phosphate buffer solution described above to obtain an acetone solution with a volume fraction of 10%;

[0339] 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 were weighed;

[0340] The raw materials were dispersed using the diluted acetone solution, and at this time, the concentration of the hydrogel precursor relative to the buffer solution was 12%, and the concentration of the active ingredient was 30%. The mixture was obtained by thoroughly mixing and ultrasonicating;

[0341] The mixture was subjected to high-pressure homogenization (300 MPa, 300 rpm);

[0342] It was found that the mixture showed a stratification phenomenon, with the drug sinking to the bottom and a small amount floating, and the drug particles were difficult to disperse uniformly.

[0343] The main reason is that too much active ingredient was added, and it was difficult to disperse the active ingredient uniformly in the ethanol solution.

[0344] As can be seen from the description of the above examples, using the specific method of the present application, especially when the raw material is micronized to a specific particle size and an organic solvent is used, a qualified lacrimal canaliculus insert can be obtained.

[0345] As can be seen from Comparative Examples 1-2, only micronization of the raw material or only use of an organic solvent, the drug particles cannot be uniformly dispersed, but after using a suspending agent, the drug can be uniformly dispersed and a lacrimal canaliculus insert can be prepared.

[0346] As can be seen from Comparative Example 3, only high-pressure homogenization of the hydrogel precursor and the drug, the drug particles cannot be uniformly dispersed, and even after using a suspending agent, the drug dispersibility cannot be improved.

[0347] As can be seen from Comparative Example 4, if an organic solvent is not used, the drug particles cannot be uniformly dispersed, and thus a qualified canaliculus insert cannot be prepared.

[0348] As can be seen from Comparative Examples 5-6, if the raw material is not micronized, or if the degree of micronization is not sufficient, even if subsequent high-pressure homogenization is performed, the drug particles cannot be uniformly dispersed, and thus a qualified canaliculus insert cannot be prepared.

[0349] As can be seen from Comparative Example 7, if the proportion of the active ingredient is too large, the drug cannot be uniformly dispersed, and thus a qualified canaliculus insert cannot be prepared.

Claims

1. A preparation method of lacrimal canaliculus insert, comprising: Step 1: mixing and dispersing a buffer, an organic solvent, a hydrogel precursor, and a poorly soluble active ingredient with an average particle size of 20 μm or less to obtain a mixed solution, wherein the mass concentration of the active ingredient is 2.5%-20%, preferably 2.5%-15%, preferably 4%-10%, based on the buffer; Step 2: placing the mixed solution in a sleeve with a diameter of 0.5-2.0 mm to obtain a hydrogel; and Step 3: axially stretching the hydrogel by 1.1-10 times and drying at 20-30°C and 20-40% RH for 2-24 hours to obtain the 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 with a solubility of less than 0.01 g in 100 g of water at room temperature 20°C, and the active ingredient is preferably selected from dexamethasone, tacrolimus, lifitegrast, 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 10 μm or less, 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 is not a solvent belonging to the first category specified in the Chinese Pharmacopoeia 2020, and is an organic solvent that is miscible with water and has a boiling point of 50-150°C, and is 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 a phosphate buffer, a citric acid buffer, and an acetic acid 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 a succinimidyl ester group or an amide group functional group, with a molecular weight of 10k-40k; a second hydrogel precursor which is a multi-arm polyethylene glycol containing -NH2, with a molecular weight of 10k-20k; preferably, the hydrogel precursor consists of the first and second hydrogel precursors described 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 homofunctionally substituted multi-armed polyethylene glycol containing succinimidyl ester groups, more preferably selected from one or more of tetra-armed-polyethylene glycol succinimidyl succinate, octa-armed-polyethylene glycol succinimidyl succinate, tetra-armed-polyethylene glycol succinimidyl glutarate, octa-armed-polyethylene glycol succinimidyl glutarate, tetra-armed-polyethylene glycol succinimidyl glutaric acid diamide, octa-armed-polyethylene glycol succinimidyl glutaric acid diamide, tetra-armed-polyethylene glycol succinimidyl carboxymethyl ester, octa-armed-polyethylene glycol succinimidyl carboxymethyl ester, tetra-armed-polyethylene glycol succinimidyl adipate, octa-armed-polyethylene glycol succinimidyl adipate, tetra-armed-polyethylene glycol succinimidyl carbonate, octa-armed-polyethylene glycol succinimidyl carbonate, tetra-armed-polyethylene glycol succinimidyl propionate, octa-armed-polyethylene glycol succinimidyl propionate; The second hydrogel precursor is selected from one or more of tetra-armed-polyethylene glycol amine, octa-armed-polyethylene glycol amine.

7. The production method according to claim 1, wherein In step 1, The volume concentration of the organic solvent is 5%-40%, preferably 5%-30%, more preferably 8%-20%, based on the buffer; and / or the mass concentration of the hydrogel precursor is 5%-20%, preferably 10%-20%; and / or The weight ratio of the organic solvent: 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 production method according to claim 1, wherein In step 2, Before standing, it further comprises a step of homogenizing the mixture under 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 of claim 1, wherein In steps 1-3, no step of adding a suspending agent, wetting agent, flocculating agent, or latent solvent is included.

10. The lacrimal canaliculus insert prepared by the preparation method of any one of claims 1-9, in particular, the weight ratio of the buffer salt, the hydrogel polymer, and the active ingredient in the lacrimal canaliculus insert 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 more than 0 and less than or equal to 1000 ppm, preferably more than 0 and less than or equal to 100 ppm, more preferably more than 0 and less than or equal to 60 ppm of the organic solvent, and does not contain a suspending agent, wetting agent, flocculating agent, or latent solvent.