Trans-sclera continuous drug delivery device for eye disease treatment and preparation method of trans-sclera continuous drug delivery device

Abstract

The invention discloses a transsclera continuous drug delivery device for eye disease treatment and a preparation method thereof. The device comprises an arc body, a wing-shaped fixing plate and a fixing band. A groove is formed in the bottom surface of the arc body; the two wing-shaped fixing plates are symmetrically arranged on the two sides of the arc body. The two wing-shaped fixing plates are respectively accommodated under the abdomen of the external rectus and under the abdomen of the lower rectus; the fixing belts are fixedly connected to the bottom face of the arc body, and gaps are formed between the fixing belts and the inner wall of the groove and used for storing medicine films; the ends, away from the arc body, of the two-wing-shaped fixing plates are spaced, and the arc body and the two-wing-shaped fixing plates are integrally in a C shape. The eye drops can be well attached to eyeballs, compression on the eyeballs is reduced, free rotation of the eyeballs is not affected, wearing comfort and medicine bioavailability are improved, medicine components are prevented from leaking to the keratoconjunctival surface and fascia tissue, medicine is prevented from going into blood pressure circulation through conjunctival blood vessels and lymphatic vessels, and the risk of side effects of the whole body is reduced; and toxicity and adverse reactions are reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and in particular to a transscleral continuous drug delivery device for treating eye diseases and a preparation method thereof. Background Art

[0002] At present, the main routes of drug administration in the eye include ocular surface drops, intravitreal injections, intravenous administration, and transscleral administration. However, due to the unique anatomical and physiological structure of the eyeball and the existence of multiple biological barriers, such as the corneal epithelial barrier, the blood-aqueous barrier, and the blood-retinal barrier, the effective delivery of drugs into the eye faces many challenges. How to effectively deliver drugs to intraocular tissues to treat posterior segment diseases (such as age-related macular degeneration, retinal vascular diseases, chronic uveitis, and infectious endophthalmitis, etc.) has become a research hotspot in the field of ophthalmic disease treatment. The existence of the corneal epithelial barrier and the blood-aqueous barrier limits the ability of ocular surface drops to reach effective therapeutic concentrations in intraocular tissues, especially in the posterior segment tissues. Although intravenous administration can deliver drugs to the posterior segment tissues of the eye, the concentration of drugs in the intraocular tissues is not enough to reach effective therapeutic levels due to the obstruction of the blood-retinal barrier. At the same time, large-dose intravenous administration may lead to systemic drug toxicity and adverse reactions.

[0003] Intravitreal drug injection is currently recognized as one of the effective means of treating posterior segment diseases. Although this method can achieve a high drug concentration in the eye in a short period of time, frequent injections may increase the risk of potential complications such as infectious endophthalmitis and retinal toxicity. The transscleral drug delivery route has become a research focus in recent years to explore drug delivery in the posterior segment of the eye due to its advantages of high scleral drug permeability and safety. However, how to deliver drugs to the target tissues in the posterior segment of the eye at effective therapeutic concentrations through the transscleral route remains a key challenge in research.

[0004] The sclera occupies five-sixths of the entire ocular surface area, and its main component is uniformly arranged and loosely structured collagen fibers. Therefore, compared with the cornea, the sclera has a larger drug absorption area and higher drug permeability, especially for hydrophilic drugs, which are easier to penetrate the sclera. Many scholars at home and abroad have studied the permeability of the sclera to different drugs, including betamethasone, oligonucleotides, albumin, and anti-angiogenic factor drugs. Studies have shown that the absorption of drugs on the sclera is based on the steady-state flow of drugs through the sclera, which means that the drug must have a long enough contact with the sclera surface to achieve a steady-state flow. Transscleral drug delivery, also known as peribulbar drug delivery, includes subconjunctival injection, sub-Tenon capsule injection, retrobulbar and peribulbar injection. Compared with other routes of administration, transscleral drug delivery has the advantages of large drug absorption area, high drug permeability and less trauma. Compared with intraocular injection, transscleral drug delivery avoids intraocular interference caused by piercing the eyeball, and there are no systemic side effects caused by intravenous injection. In addition, compared with ocular surface medication, transscleral drug delivery does not require frequent medication, is more effective, and has higher patient compliance.

[0005] In the prior art, the invention patent with publication number CN117771163A applied by this research team based on the previous research results discloses a drug for treating eye diseases and its continuous drug delivery device and preparation method. However, the instructions for use of the continuous drug delivery device use succinic anhydride and pyridine to dissolve triamcinolone acetonide to obtain a drug gel, which is released from the drug storage cavity of the drug delivery device. The gel stability of the drug is general. As the water in the drug gel is released, semi-solid drug clumps are easily formed and adsorbed inside the drug storage cavity. They cannot be well attached to the sclera surface, thereby affecting the bioavailability of some drugs. The drug gel is also easy to seep into the corneal conjunctival surface of the eye surface, which may increase the adverse reaction of the drug to the eye surface tissue. In addition, the drug storage cavity structure of the drug delivery device is relatively large and may cause a certain degree of compression on the eyeball. After the wing-shaped fixing plates on both sides of the device are implanted under the extraocular muscles, the movement of the extraocular muscles may be affected due to the resistance of the device itself, so that the free rotation of the eyeball is restricted.

[0006] To this end, a transscleral continuous drug delivery device for treating eye diseases and a preparation method thereof are proposed. Summary of the invention

[0007] The purpose of the present invention is to provide a transscleral continuous drug delivery device for treating eye diseases and a preparation method thereof, aiming to solve or improve at least one of the above-mentioned technical problems.

[0008] To achieve the above object, the present invention provides the following solution: The present invention provides a transscleral continuous drug delivery device for treating eye diseases, comprising:

[0009] An arc body, wherein the top surface of the arc body is set as a smooth surface, and the bottom surface of the arc body is provided with a groove;

[0010] Wing-shaped fixing plates, two of which are symmetrically arranged on both sides of the arc body; the two wing-shaped fixing plates are respectively inserted under the belly of the lateral rectus muscle and the belly of the inferior rectus muscle;

[0011] A fixing belt, wherein a plurality of the fixing belts are provided, and the plurality of the fixing belts are fixedly connected to the bottom surface of the arc body, and a gap is provided between the fixing belt and the inner wall of the groove, and the gap is used for storing the medicine film;

[0012] The arc body, the two wing-shaped fixing plates and the plurality of fixing belts are integrally formed, a gap is provided at one end of the two wing-shaped fixing plates away from the arc body, and the arc body and the two wing-shaped fixing plates are in a C shape as a whole.

[0013] According to a trans-scleral continuous drug delivery device for treating eye diseases provided by the present invention, there are two fixing belts, the two fixing belts are symmetrically fixed on the bottom surface of the arc body, and a gap is provided between the two fixing belts.

[0014] According to the transscleral continuous drug delivery device for treating eye diseases provided by the present invention, the length of the gap is 1.2 mm to 1.8 mm.

[0015] According to the transscleral continuous drug delivery device for treating eye diseases provided by the present invention, the thickness of the arc body is 2.5 mm to 3.5 mm.

[0016] According to the transscleral continuous drug delivery device for treating eye diseases provided by the present invention, the width of the arc body is 15 mm to 25 mm.

[0017] According to a transscleral continuous drug delivery device for treating eye diseases provided by the present invention, the distance between one end of the wing-shaped fixing plate away from the arc body and the top surface of the arc body is 40 mm to 60 mm.

[0018] According to the transscleral continuous drug delivery device for treating eye diseases provided by the present invention, the cross-sectional shape of the wing-shaped fixing plate is an arc shape.

[0019] The present invention also provides a method for preparing a transscleral sustained drug delivery device for treating eye diseases, comprising the following steps:

[0020] Step 1, obtaining a digital model of a continuous drug delivery device;

[0021] Step 2: Making a 3D model of the continuous drug delivery device: Segment the virtual digital model into a number of continuous cross-sections, then transmit the data of the digital model to a 3D printer, and use the liquid photosensitive resin to perform laser scanning and printing in the 3D printer by utilizing the property that the liquid photosensitive resin can be quickly cured under ultraviolet laser beam irradiation, and spray the material layer by layer to make a three-dimensional master mold;

[0022] Step 3: Post-processing of the 3D model of the continuous drug delivery device: taking out the master mold on the printing platform and cleaning it with alcohol in an ultrasonic cleaner to remove the uncured resin covering the master mold;

[0023] Step 4: Use a cutter to remove the support structure on the master mold, and paint the surface of the master mold. After standing and drying, the master mold is cured;

[0024] Step 5: Use thermoplastic polyurethane elastomer material for re-molding: Mix thermoplastic polyurethane elastomer materials DPI8400A and B, stir evenly and inject into the master mold obtained in step 4, react for 45 minutes until the soft glue hardness reaches 40A to 50A, demold and dry to obtain a continuous drug delivery device that can be implanted under the Tenon capsule.

[0025] According to the method for preparing a transscleral continuous drug delivery device for treating eye diseases provided by the present invention, in the step 2, the thickness of each layer of the sprayed material is 0.1 mm.

[0026] According to a method for preparing a transscleral sustained drug delivery device for treating eye diseases provided by the present invention, in the step 5, the mold is reproduced at room temperature of 25° C. and humidity of 60% to 70%;

[0027] In the step 5, after demoulding, the device is placed in a drying oven and dried for 12 hours to obtain a continuous drug delivery device that can be implanted under a Tenon capsule.

[0028] The present invention discloses the following technical effects:

[0029] The arc body and the two-wing fixing plates of the present invention are in a C-shape as a whole, so that the device as a whole can fit the eyeball well and reduce the pressure on the eyeball, thereby not affecting the free rotation of the eyeball, improving the wearing comfort and the bioavailability of the drug, and the gap is used to store the drug film for treating eye diseases. The drug is released from the drug film through passive diffusion and degradation, and the release is more stable, uniform and lasting. At the same time, the drug film can be used to concentrate the drug on the selected sclera surface, so that the drug can fully penetrate the intraocular tissue through the sclera surface, reduce the extravasation of drug components to the corneal conjunctival surface and fascia tissue, avoid the drug from passing through the conjunctival blood vessels and lymphatic vessels to improve blood pressure circulation, reduce the risk of systemic side effects, and can also increase the intraocular drug concentration during trans-scleral administration and improve the bioavailability of the drug;

[0030] The continuous drug delivery device of the present invention is made by 3D printing, and has the advantages of simple preparation process, low cost, good biocompatibility, good safety, high drug loading, continuous and controllable drug delivery, etc.; thermoplastic polyurethane elastomer material is used for re-molding, and the thermoplastic polyurethane elastomer material is an elastomeric block polymer, and its macromolecular main chain contains repeated carbamate functional groups. Compared with other 3D printing materials, the significant advantage of the thermoplastic polyurethane elastomer material is that its soft and hard segments are composed of different materials, so that it has both the high elasticity of rubber and the high strength of plastic; in addition, the thermoplastic polyurethane elastomer material performs well in terms of wear resistance, drug resistance, bacterial resistance, biomedical compatibility and shape memory performance, and is an elastomer material with excellent comprehensive performance, which is very suitable for the preparation of the novel drug delivery device of the present invention;

[0031] The thermoplastic polyurethane elastomer material DPI8400 used in the present invention has the advantages of low viscosity, good fluidity, fast curing and excellent elasticity, etc., and solves the problem that the liquid photosensitive resin material has slight toxicity, may cause allergies to the contactor, and is not suitable for direct use in eyeball implantation. The present invention can control the hardness of the material by adjusting the ratio of the components A and B of DPI8400. Since the smaller the hardness of the thermoplastic polyurethane elastomer material, the greater the shrinkage rate, DPI8400 is adjusted to 40A-50A hardness in the present invention to reduce the dimensional error caused by the shrinkage rate during the physicalization of the model; at the same time, the TPU material with a hardness of 40A-50A can make the drug delivery device after duplication have good softness, appropriate toughness and ductility, so as to better fit the eyeball, provide the function of continuous sustained release of drugs, and reduce the risk of tissue allergic reaction and local irritation, and reduce the occurrence of toxicity and adverse reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0033] Figure 1 The axonometric Figure I ;

[0034] Figure 2 The axonometric Figure II ;

[0035] Figure 3 It is a front view of the present invention;

[0036] Figure 4 A top view of the present invention;

[0037] Figure 5 The figure is a comparison diagram of the drug-time curve (a) and AUC curve (b) of the concentration of triamcinolone acetonide in the vitreous of two groups in the present invention;

[0038] Figure 6 The figure is a comparison diagram of the drug-time curve (a) and AUC curve (b) of the two groups of triamcinolone acetonide concentrations in aqueous humor in the present invention.

[0039] Among them, 1. arc body; 2. groove; 3. airfoil fixing plate; 4. fixing belt. DETAILED DESCRIPTION

[0040] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0041] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0042] Reference Figure 1-Figure 6 The present invention provides a transscleral sustained drug delivery device for treating eye diseases, comprising:

[0043] The arc body 1 has a top surface that is smooth and a bottom surface that is provided with a groove 2;

[0044] Wing-shaped fixing plates 3, two wing-shaped fixing plates 3 are provided, and the two wing-shaped fixing plates 3 are symmetrically arranged on both sides of the arc body 1; the two wing-shaped fixing plates 3 are respectively inserted under the belly of the lateral rectus muscle and the belly of the inferior rectus muscle;

[0045] A fixing belt 4, wherein a plurality of fixing belts 4 are provided, wherein the plurality of fixing belts 4 are fixedly connected to the bottom surface of the arc body 1, and a gap is provided between the fixing belt 4 and the inner wall of the groove 2, and the gap is used for storing the medicine film;

[0046] The arc body 1, the two wing-shaped fixing plates 3 and the plurality of fixing belts 4 are integrally formed, and a gap is provided at one end of the two wing-shaped fixing plates 3 away from the arc body 1, so that the arc body 1 and the two wing-shaped fixing plates 3 are in a C shape as a whole; in this embodiment, the length of the gap between the two wing-shaped fixing plates 3 is 40 mm to 80 mm;

[0047] With such a configuration, the device is implanted under the Tenon capsule of the eyeball through minimally invasive surgery. The top surface of the arc body 1 is set as a smooth surface to isolate the direct contact between the drug film and the conjunctiva, reduce the absorption of the drug film through the conjunctival blood vessels and the clearance metabolism through the lymphatic vessels; the two wing-shaped fixing plates 3 are respectively inserted under the belly of the lateral rectus muscle and the belly of the inferior rectus muscle, and the fixing stability is relatively high;

[0048] The arc body 1 and the two-wing fixing plates 3 in the present invention are in a C-shape as a whole, so that the device as a whole can fit the eyeball well and reduce the pressure on the eyeball, thereby not affecting the free rotation of the eyeball, improving the wearing comfort and the bioavailability of the drug, and the gap is used to store the drug film for treating eye diseases. The drug is released from the drug film through passive diffusion and degradation, and the release is more stable, uniform and lasting. At the same time, the drug film can be used to concentrate the drug on the selected sclera surface, so that the drug can fully penetrate the intraocular tissue through the sclera surface, reduce the extravasation of drug components to the corneal conjunctival surface and fascia tissue, avoid the drug from passing through the conjunctival blood vessels and lymphatic vessels to improve blood pressure circulation, reduce the risk of systemic side effects, and can also increase the intraocular drug concentration during trans-scleral administration and improve the bioavailability of the drug.

[0049] According to a further optimization scheme, the number of the fixing belts 4 is two, the two fixing belts 4 are symmetrically fixed on the bottom surface of the arc body 1, and a gap is provided between the two fixing belts 4; in this embodiment, the length of the gap between the two fixing belts 4 is 10 mm to 40 mm.

[0050] According to a further optimization scheme, the length of the gap is 1.2 mm to 1.8 mm, and is preferably 1.5 mm in this embodiment.

[0051] According to a further optimization scheme, the thickness of the arc body 1 is 2.5 mm to 3.5 mm, and is preferably 3.0 mm in this embodiment.

[0052] According to a further optimization scheme, the width of the arc body 1 is 15 mm to 25 mm, and is preferably 20 mm in this embodiment.

[0053] According to a further optimization scheme, the distance between the end of the airfoil fixing plate 3 away from the arc body 1 and the top surface of the arc body 1 is 40 mm to 60 mm, preferably 50 mm in this embodiment, so that the overall length of the device is about 50 mm.

[0054] According to a further optimization scheme, the cross-sectional shape of the airfoil fixing plate 3 is an arc shape.

[0055] The present invention also provides a method for preparing a transscleral sustained drug delivery device for treating eye diseases, comprising the following steps:

[0056] Step 1, obtaining a digital model of a continuous drug delivery device;

[0057] Step 2: Making a 3D model of a continuous drug delivery device: dividing the virtual digital model into a series of continuous cross-sections, then converting the digital model into a standard subdivision language (STL) file recognizable by a 3D printer, and transmitting the data to the 3D printer. By utilizing the rapid solidification property of liquid photosensitive resin under ultraviolet laser beam irradiation, the liquid photosensitive resin is used for laser scanning and printing in the 3D printer, and the material is sprayed layer by layer to make a three-dimensional master mold. In this embodiment, the 3D printer uses a high-precision Liantai SLA printer, and the liquid photosensitive resin uses GodartTM8228 resin.

[0058] Step 3: Post-processing of the 3D model of the continuous drug delivery device: taking out the master mold on the printing platform and cleaning it with alcohol in an ultrasonic cleaner to remove the uncured resin covering the master mold;

[0059] Step 4: Use a cutter to remove the support structure on the master mold, and paint the surface of the master mold. After standing and drying, the master mold is cured;

[0060] Step 5: Use thermoplastic polyurethane elastomer material (TPU) for re-molding: Mix thermoplastic polyurethane elastomer materials DPI8400A and B, stir evenly and inject into the master mold obtained in step 4, react for 45 minutes until the hardness of the soft glue reaches 40A to 50A, demold and dry to obtain a continuous drug delivery device that can be implanted under the Tenon capsule;

[0061] The present invention adopts SLA light-curing molding technology, which mainly uses liquid photosensitive resin as raw material. Ultraviolet light of specific wavelength and intensity is focused on the surface of the liquid photosensitive resin, so that it solidifies from point to line and from line to surface in sequence, thereby completing the molding of a layer section. Compared with other 3D printing technologies, SLA combined with liquid photosensitive resin has significant advantages such as fast processing speed, high molding accuracy, high surface finish and high material utilization rate.

[0062] With such a configuration, the continuous drug delivery device of the present invention is made by 3D printing, and has the advantages of simple preparation process, low cost, good biocompatibility, good safety, high drug loading, continuous and controllable drug delivery, etc.; thermoplastic polyurethane elastomer material (TPU) is used for re-molding, and thermoplastic polyurethane elastomer material (TPU) is an elastomeric block polymer, and its macromolecular main chain contains repeated carbamate functional groups. Compared with other 3D printing materials, the significant advantage of thermoplastic polyurethane elastomer material (TPU) is that its soft and hard segments are composed of different materials, so that it has both the high elasticity of rubber and the high strength of plastic; in addition, thermoplastic polyurethane elastomer material (TPU) performs well in wear resistance, drug resistance, bacterial resistance, biomedical compatibility and shape memory performance, and is an elastomeric material with excellent comprehensive performance, which is very suitable for the preparation of the novel drug delivery device of the present invention;

[0063] The thermoplastic polyurethane elastomer material DPI8400 used in the present invention has the advantages of low viscosity, good fluidity, fast curing and excellent elasticity, etc., and solves the problem that the liquid photosensitive resin material has slight toxicity, may cause allergies to the contactor, and is not suitable for direct use in eyeball implantation. The present invention can control the hardness of the material by adjusting the ratio of the components A and B of DPI8400. Since the smaller the hardness of the thermoplastic polyurethane elastomer material (TPU), the greater the shrinkage rate, DPI8400 is adjusted to 40A-50A hardness in the present invention to reduce the dimensional error caused by the shrinkage rate during the physicalization of the model; at the same time, the TPU material with a hardness of 40A-50A can make the drug delivery device after duplication have good softness, appropriate toughness and ductility, so as to better fit the eyeball, provide the function of sustained sustained release of drugs, and reduce the risk of tissue allergic reaction and local irritation, and reduce the occurrence of toxicity and adverse reactions.

[0064] To further optimize the solution, in step 2, the thickness of each layer of the sprayed material is 0.1 mm.

[0065] To further optimize the scheme, in step 5, the mold is replicated at room temperature of 25°C and humidity of 60% to 70%;

[0066] In step five, after demoulding, the device is placed in a drying oven and dried for 12 hours to obtain a continuous drug delivery device that can be implanted under a Tenon capsule.

[0067] The present invention also provides a drug film for treating eye diseases, which is a triamcinolone acetonide drug film; the triamcinolone acetonide drug film comprises the following components: acetone, triamcinolone acetonide, polycaprolactone, dichloromethane and polytetrafluoroethylene; the present invention transforms the original drug gel into a drug film form, which can significantly improve the solubility and effective content of triamcinolone acetonide; triamcinolone acetonide is slowly released from the drug film through passive diffusion and degradation, ensuring that the drug release process is more stable, uniform and lasting.

[0068] The present invention also provides a method for preparing a drug film for treating eye diseases, comprising the following steps:

[0069] S1: 1.4 g of triamcinolone acetonide powder was dissolved in acetone and the volume was adjusted to 100 ml to obtain a 14 mg / ml TA solution;

[0070] S2: 1.0 g polycaprolactone was dissolved in dichloromethane and the volume was adjusted to 100 ml to obtain a 10 mg / ml PCL solution;

[0071] S3: The two were mixed in a volume ratio of 24:76 and then magnetically stirred, and the theoretical drug loading of TA in the mixed solution reached 30%;

[0072] S4: spraying the mixed solution evenly on a polytetrafluoroethylene plate, placing the sprayed drug film in a vacuum drying oven, and drying at room temperature for 48 hours to form a triamcinolone acetonide drug film. The drug for treating eye diseases in the present invention is released from the drug film by passive diffusion and degradation, and the release is more stable, uniform and lasting.

[0073] Animal experiment process:

[0074] The animal experiment of the present invention is divided into two groups: the experimental group uses the drug delivery device of the present invention to carry the triamcinolone acetonide film, and the control group uses subconjunctival injection. 48 New Zealand white rabbits are randomly divided into two groups, each group is set with 8 drug delivery time points, and there are 3 rabbits at each time point.

[0075] The specific steps of the animal experiment in the experimental group are as follows:

[0076] 1. Anesthesia Preparation:

[0077] The rabbit was captured and weighed, and then 0.3 ml / kg of Lumianning was injected intramuscularly. At the same time, the corneal reflex of the rabbit was tested to evaluate the depth of anesthesia.

[0078] During the anesthesia process, levofloxacin eye drops were applied to the eyes 3 times to prevent infection; Alkain topical anesthetic was applied to the eyes 3 times.

[0079] 2. Eye treatment:

[0080] After the rabbit is completely anesthetized, use an eyelid speculum to fully expose the eyeball. Use a syringe to take 0.5 ml of iodine III to flush the conjunctival sac, let it stand for 30 seconds, and then thoroughly flush the conjunctival sac with normal saline.

[0081] 3. Implantation of drug film:

[0082] An incision was made in the Tenon's capsule on the temporal side of the right eye of the rabbit, about 3 mm away from the corneal limbus, to expose the space under the Tenon's capsule as much as possible. The lateral rectus muscle was carefully bluntly separated with hemostats.

[0083] The drug film is placed in the gap between the groove 2 structure of the drug delivery device and the fixing belt 4, the two wing-shaped fixing plates 3 of the drug delivery device are placed under the two rectus muscles, the arc body 1 groove 2 structure of the device is filled under the Tenon capsule, and the incision is sutured. This design is convenient for minimally invasive implantation, the device is compact and portable, and the wing-shaped fixing plates 3 on both sides are implanted under the rectus muscles and fit the surface of the eyeball in an arc shape. In this way, the power of the rectus muscles is used to fix the device, and the involvement of the extraocular muscles is reduced. The groove structure fits the surface of the eyeball tightly, so that the drug film can contact the sclera surface to the greatest extent, reduce the extravasation of the drug to the corneal conjunctival surface, thereby increasing the amount of drug attached to the sclera surface, prolonging the residence time of the drug on the sclera surface, reducing adverse reactions to the cornea and conjunctiva and systemic side effects, reducing the clearance metabolism of the drug through the conjunctival blood vessels and lymphatic vessels, and improving the transscleral penetration and effective concentration of the drug.

[0084] 4. Anti-infection treatment:

[0085] Use levofloxacin eye drops to fight infection, once every 5 minutes, for a total of 3 times.

[0086] 5. Eyeball sampling:

[0087] The right eyeball was removed, and the muscles, conjunctiva and fascia on the surface of the eyeball were cut off to fully expose the sclera of the eyeball.

[0088] Use normal saline to remove the residual solution on the surface of the eyeball and use clean gauze to dry the eyeball.

[0089] 6. Collection of aqueous humor:

[0090] Use a 1 ml syringe to horizontally puncture the anterior chamber 1.5 mm inside the corneal limbus, collect about 0.1-0.2 ml of aqueous humor, and store it at -80℃ for measuring the concentration of triamcinolone acetonide in the aqueous humor.

[0091] 7. Vitreous humor collection:

[0092] Use normal saline to remove the residual solution on the surface of the eyeball and use clean gauze to dry the eyeball.

[0093] The sclera was cut open, and the vitreous fluid was extracted into a 1.5 ml centrifuge tube using a 2.5 ml syringe and stored at -80°C for the determination of the concentration of triamcinolone acetonide in the vitreous.

[0094] The specific process of the control group animal experiment is as follows:

[0095] 1. Anesthesia Preparation:

[0096] The rabbit was captured and weighed, and then 0.3 ml / kg of Lumianning was injected intramuscularly. At the same time, the corneal reflex of the rabbit was tested to evaluate the depth of anesthesia.

[0097] 2. Eye treatment:

[0098] During the anesthesia process, levofloxacin eye drops were applied to the eyes 3 times to prevent infection; Alkain topical anesthetic was applied to the eyes 3 times.

[0099] 3. Conjunctival sac irrigation:

[0100] After the rabbit is completely anesthetized, use an eyelid speculum to fully expose the eyeball. Use a syringe to take 0.5 ml of iodine III to flush the conjunctival sac, let it stand for 30 seconds, and then thoroughly flush the conjunctival sac with normal saline.

[0101] 4. Drug injection:

[0102] Use a 1 ml syringe to take 1 ml of triamcinolone acetonide injection aqueous solution and slowly inject it subconjunctivally in the right eye of the rabbit.

[0103] 5. Handle the injection port:

[0104] After the injection is completed, use toothless forceps to clamp the puncture site for 30 seconds to ensure that the drug does not leak out, and then remove the syringe.

[0105] 6. Anti-infection treatment:

[0106] Use levofloxacin eye drops to fight infection, once every 5 minutes, for a total of 3 times.

[0107] 7. Eyeball sampling:

[0108] After the preset administration time point, the right eyeball was removed, and the muscles, conjunctiva and fascia on the surface of the eyeball were cut off to fully expose the sclera of the eyeball.

[0109] 8. Clean the eyeballs:

[0110] Use normal saline to remove the residual solution on the surface of the eyeball and use clean gauze to dry the eyeball.

[0111] 9. Collection of aqueous humor:

[0112] Use a 1 ml syringe to horizontally puncture the anterior chamber 1.5 mm inside the corneal limbus, collect about 0.1-0.2 ml of aqueous humor, and store it at -80℃ for measuring the concentration of triamcinolone acetonide in the aqueous humor.

[0113] 10. Clean the eyes:

[0114] Use normal saline to remove the residual liquid on the surface of the eyeball, and then use clean gauze to dry the eyeball.

[0115] 11. Vitreous humor collection:

[0116] The sclera was cut open, and the vitreous fluid was extracted into a 1.5 ml centrifuge tube using a 2.5 ml syringe and stored at -80°C for the determination of the concentration of triamcinolone acetonide in the vitreous.

[0117] Experimental results:

[0118] From the following chart, it can be preliminarily concluded that after the triamcinolone acetonide film passes through the drug delivery device, it can reach an effective therapeutic concentration in the aqueous humor and vitreous body of the rabbit eye and maintain a certain duration of action.

[0119] In the vitreous tissue, the drug concentration continued to rise from the 1st hour to the 6th hour after injection. The TA concentration in the vitreous tissue reached a peak of 2.440 μg / mL at the 6th hour. Then the concentration slowly decreased until the 14th day. The drug-time curves and AUC curves of the two groups in the vitreous are compared as shown in Figure 2. Figure 5 The pharmacokinetic parameters of triamcinolone acetonide in vitreous tissue of the two groups are shown in Table 1. Statistical analysis by SPSS20.0 showed that the overall comparison of triamcinolone acetonide concentrations between the two groups was statistically different (repeated measures analysis of variance, F=9.378, p=0.011), and the changes in triamcinolone acetonide concentrations between the two groups were in accordance with normal distribution. The independent sample t-test statistical analysis showed that the differences in triamcinolone acetonide concentrations between the two groups were statistically significant at 1h (t=4.788, p=0.009), 3h (t=5.602, p=0.005), 6h (t=2.897, p=0.044) and 24h (t=8.346, p=0.001). The detailed statistical analysis results are shown in Table 2.

[0120] Table 1 Pharmacokinetic parameters of triamcinolone acetonide in vitreous tissue of the two groups

[0121]

[0122] Table 2 Statistical analysis results of triamcinolone acetonide concentrations in vitreous tissue of the two groups

[0123]

[0124]

[0125] In the aqueous humor tissue, triamcinolone acetonide film reaches an effective therapeutic concentration in the local part of the eye and maintains a certain duration of action. The concentration at 0.5h after injection is (0.548±0.346)μg / mL, which is about 50 times the effective therapeutic concentration; then the concentration increases slowly, reaching a peak concentration of (0.763±0.337)μg / mL at 24h, which is about 70 times the effective therapeutic concentration; then the concentration decreases slowly, and the concentration at 14d is (0.023±0.017)μg / mL, which is about 2 times the effective therapeutic concentration. The drug-time curve and AUC curve of the two groups in aqueous humor are compared as shown below. Figure 6The pharmacokinetic parameters of triamcinolone acetonide concentrations in aqueous humor tissue of the two groups are shown in Table 3. Statistical analysis by SPSS 20.0 showed that the overall comparison of triamcinolone acetonide concentrations between the two groups was statistically different (repeated measures analysis of variance, F = 18.567, p = 0.001). The independent sample t test was used to analyze the changes in triamcinolone acetonide concentrations in the two groups that were in accordance with normal distribution, and the Mann-Whitney test was used to analyze the changes in triamcinolone acetonide concentrations that were not in accordance with normal distribution. The results showed that the differences in triamcinolone acetonide concentrations between the two groups were statistically significant at 0.5h (t = -3.654, p = 0.022), 1h (t = -6.02, p = 0.009), 3h (t = -2.941, p = 0.042) and 48h (Z = -1.993, p = 0.046). The detailed statistical analysis results are shown in Table 4.

[0126] Table 3 Pharmacokinetic parameters of triamcinolone acetonide concentration in aqueous humor tissue

[0127]

[0128] Table 4 Statistical analysis results of the concentrations of triamcinolone acetonide in aqueous humor tissue of the two groups

[0129]

[0130] In the description of the present invention, it should be understood that the terms "longitudinal", "lateral", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside" and "outside" etc., indicating orientations or positional relationships, are based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be understood as a limitation on the present invention.

[0131] Obviously, the above embodiments of the present invention are merely examples for clearly explaining the present invention, and are not intended to limit the implementation methods of the present invention. For ordinary technical users in the relevant field, other different forms of changes or modifications can be made on the basis of the above description. It is not necessary and impossible to list all the implementation methods here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A transscleral continuous drug delivery device for treating eye diseases, characterized in that: include: An arc body (1), wherein the top surface of the arc body (1) is a smooth surface, and the bottom surface of the arc body (1) is provided with a groove (2); A wing-shaped fixing plate (3), wherein two wing-shaped fixing plates (3) are provided, and the two wing-shaped fixing plates (3) are symmetrically arranged on both sides of the arc body (1); the two wing-shaped fixing plates (3) are respectively inserted under the belly of the lateral rectus muscle and the belly of the inferior rectus muscle; A fixing belt (4), wherein a plurality of the fixing belts (4) are provided, and the plurality of the fixing belts (4) are fixedly connected to the bottom surface of the arc body (1), and a gap is provided between the fixing belt (4) and the inner wall of the groove (2), and the gap is used for storing the medicine film; The arc body (1), the two wing-shaped fixing plates (3) and the plurality of fixing belts (4) are integrally formed, a gap is provided at one end of the two wing-shaped fixing plates (3) away from the arc body (1), and the arc body (1) and the two wing-shaped fixing plates (3) are in a C-shape as a whole.

2. The transscleral sustained drug delivery device for treating eye diseases according to claim 1, characterized in that: There are two fixing belts (4), the two fixing belts (4) are symmetrically fixed to the bottom surface of the arc body (1), and a gap is provided between the two fixing belts (4).

3. The transscleral sustained drug delivery device for treating eye diseases according to claim 1, characterized in that: The length of the gap is 1.2 mm to 1.8 mm.

4. The transscleral sustained drug delivery device for treating eye diseases according to claim 1, characterized in that: The thickness of the arc body (1) is 2.5 mm to 3.5 mm.

5. The transscleral sustained drug delivery device for treating eye diseases according to claim 1, characterized in that: The width of the arc body (1) is 15 mm to 25 mm.

6. The transscleral sustained drug delivery device for treating eye diseases according to claim 1, characterized in that: The distance between the end of the wing-shaped fixing plate (3) away from the arc body (1) and the top surface of the arc body (1) is 40 mm to 60 mm.

7. The transscleral sustained drug delivery device for treating eye diseases according to claim 1, characterized in that: The cross-sectional shape of the wing-shaped fixing plate (3) is an arc shape.

8. A method for preparing a transscleral sustained drug delivery device for treating eye diseases, based on the transscleral sustained drug delivery device for treating eye diseases according to any one of claims 1 to 7, characterized in that: The following steps are involved: Step 1, obtaining a digital model of a continuous drug delivery device; Step 2: Making a 3D model of the continuous drug delivery device: Segment the virtual digital model into a number of continuous cross-sections, then transmit the data of the digital model to a 3D printer, and use the liquid photosensitive resin to perform laser scanning and printing in the 3D printer by utilizing the property that the liquid photosensitive resin can be quickly cured under ultraviolet laser beam irradiation, spray the material layer by layer, and make a three-dimensional master mold; Step 3: Post-processing of the 3D model of the continuous drug delivery device: taking out the master mold on the printing platform and cleaning it with alcohol in an ultrasonic cleaner to remove the uncured resin covering the master mold; Step 4: Use a cutter to remove the support structure on the master mold, and paint the surface of the master mold. After standing and drying, the master mold is cured; Step 5: Use thermoplastic polyurethane elastomer material for re-molding: Mix thermoplastic polyurethane elastomer materials DPI8400A and B, stir evenly and inject into the master mold obtained in step 4, react for 45 minutes until the soft glue hardness reaches 40A to 50A, demold and dry to obtain a continuous drug delivery device that can be implanted under the Tenon capsule.

9. The method for preparing the transscleral sustained drug delivery device for treating eye diseases according to claim 8, characterized in that: In the step 2, the thickness of each layer of the sprayed material is 0.1 mm.

10. The method for preparing the transscleral sustained drug delivery device for treating eye diseases according to claim 8, characterized in that: In the step 5, the mold is reproduced at a room temperature of 25° C. and a humidity of 60% to 70%; In the step 5, after demoulding, the device is placed in a drying oven and dried for 12 hours to obtain a continuous drug delivery device that can be implanted under a Tenon capsule.

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