Tubular container comprising microporous drug delivery matrix for glaucoma treatment, and manufacturing method therefor

Abstract

The present disclosure relates to a tubular container comprising a microporous drug delivery matrix for glaucoma treatment, and a manufacturing method therefor. According to the present disclosure, the tubular container comprising a microporous drug delivery matrix for glaucoma treatment can be provided, the container enabling glaucoma to be effectively treated through continuous drug delivery into the eye such that the quality of life of a patient can be improved. In addition, the tubular container comprising a microporous drug delivery matrix for glaucoma treatment, according to the present disclosure, has a tip-formed shape at one or both ends thereof so as to have a structural feature facilitating drug delivery into the eye and, at the same time, enable continuous release of the drug, and thus can be expected to overcome the limitations of a conventional drug delivery system and, further, be effectively used with respect to regenerative medicine and pharmacology.

Description

Tubular container containing a microporous drug delivery matrix for the treatment of glaucoma and method of manufacturing the same

[0001] The present disclosure relates to a tubular container comprising a microporous matrix for drug delivery for the treatment of glaucoma and a method for manufacturing the same. More specifically, it relates to a tubular container comprising a microporous matrix for drug delivery for the treatment of glaucoma capable of treating glaucoma by including a porous polymer with a leaf-like laminated structure in a tubular outer layer and loading a drug thereon, thereby enabling sustained-release of the loaded drug.

[0002]

[0003] Glaucoma is a progressive ophthalmic disease that can lead to visual field defects and blindness due to optic nerve damage, and it is considered one of the leading causes of blindness worldwide. While elevated intraocular pressure is known to be a major risk factor for glaucoma, it can also occur in patients with normal pressure, involving multifaceted causes and pathological mechanisms. In particular, in countries that have entered an aging society, the number of patients is increasing rapidly, leading to a growing medical and social burden. According to the World Health Organization (WHO), approximately 76 million people worldwide suffered from glaucoma in 2020, of whom about 11 million were blind. In Korea as well, about 2% of adults aged 40 and older were diagnosed with glaucoma, and this rate increased to over 10% for those aged 70 and older, indicating that the number of patients is rising alongside the aging population (Non-patent Literature 0001).

[0004] Currently, the primary goal of glaucoma treatment is to lower intraocular pressure to inhibit optic nerve damage and delay disease progression. To achieve this, drug therapy is primarily used. Drug treatment focuses mainly on lowering intraocular pressure, and prostaglandin analogs such as latanoprost are the most widely used. Latanoprost is a drug that effectively reduces intraocular pressure by increasing the outflow of aqueous humor through the trabecular meshwork and sclera; patient compliance is generally high due to the convenience of once-daily administration. In addition, drugs such as beta-blockers, alpha-2 agonists, and carbonic anhydrase inhibitors are prescribed either in combination or alone, depending on the situation.

[0005] However, due to the nature of glaucoma treatment, medication must be administered directly into the eye daily over a long period of several months, causing significant fatigue in patients. Therefore, an approach that provides continuous and steady medication is essential, and continuous research and technological development in this regard are required. The development of drug delivery systems capable of increasing the duration of drug action and enabling continuous, sustained-release delivery will play an important role in improving existing direct ocular administration methods, thereby slowing the progression of glaucoma and enhancing the quality of life for patients (Non-patent Literature 0002).

[0006] Numerous studies are being conducted on drug delivery systems as an innovative approach to maximize therapeutic effects and minimize systemic toxicity. Conventional drug delivery methods rely primarily on simple drug diffusion mechanisms, resulting in problems such as a lack of precise targeting, low bioavailability, and severe side effects caused by high doses.

[0007] For example, chemotherapy drugs are accompanied by high toxicity and cause side effects that damage even healthy tissues due to off-target effects.

[0008] Recently developed drug delivery systems combine nanotechnology and biomaterial engineering to be designed for drugs to selectively reach specific tissues or cells. Such systems contribute to extending drug half-lives, maintaining drug concentrations within the therapeutic range, and simultaneously minimizing side effects. However, limitations such as incomplete drug targeting, potential toxicity of drug delivery materials, rapid initial release, and still short release durations remain challenges that need to be addressed.

[0009] To address the problem of such instability, methods for chemically binding drugs to biomaterials or nanoparticles using click chemistry are being developed, but there are still limitations to clinical use due to the use of toxic solvents through chemical fixation, reduced drug activity, and complex fixation processes (Non-patent literature 0003, 0004).

[0010] [Prior Art Literature]

[0011] [Non-patent literature]

[0012] (Non-patent Document 1) Glaucoma Treatment Market - Forecasts from 2023 to 2028, Knowledge Sourcing Intelligence (2023)

[0013] (Non-patent literature 2) Choi JA New classes of glaucoma medical treatment. J. Korean Med. Assoc. 62(9), 497-504 (2019).

[0014] (Non-patent Document 3) Caballero Aguilar, LM, Silva, SM & Moulton, SE Growth factor delivery: Defining the next generation platforms for tissue engineering. J. Control. Release 306, 40-58 (2019).

[0015] (Non-patent Document 4) Shakoor, S., Kibble, E. & El-Jawhari, JJ Bioengineering approaches for delivering growth factors: A focus on bone and cartilage regeneration. Bioengineering 9 (2022).

[0016]

[0017] Against this backdrop, the present disclosure aims to provide a tubular container comprising a microporous drug delivery matrix for the treatment of glaucoma capable of continuous sustained-release drug delivery using a simple, clinically usable method that overcomes the limitations of existing drug delivery systems and maximizes therapeutic efficiency, as well as a method for manufacturing the same.

[0018]

[0019] A tubular container comprising a microporous drug delivery matrix for the treatment of glaucoma according to one embodiment of the present disclosure is characterized by comprising: an outer layer having a structure with both ends open; and a polymer having a leaf-like stacked porous structure inside the outer layer.

[0020] According to one embodiment of the present disclosure, the outer layer preferably comprises a tubular body; a tubular protrusion; and a tapered portion connecting the tubular body and the tubular protrusion.

[0021] According to one embodiment of the present disclosure, a polymer having a leaf-like stacked porous structure may be capable of being filled with a liquid solution and solidified to be supported.

[0022] According to one embodiment of the present disclosure, it is preferable to use a material that can be thermally deformed at 50 to 200°C for the outer layer in order to support a polymer having a leaf-like laminated porous structure inside.

[0023] According to one embodiment of the present disclosure, the outer layer may use one or more materials selected from thermoplastic polyurethane, polytetrafluoroethylene, silicone, polyvinyl chloride, polyethylene, polysulfone, and polypropylene.

[0024] According to one embodiment of the present disclosure, it is preferable that the length of the outer layer is 5 to 100 mm, the inner diameter is 0.1 to 50 mm, and the outer diameter is 1 to 60 mm.

[0025] According to a preferred embodiment of the present disclosure, it is preferable that the outer layer has a tip-forming shape on either or both of the end surfaces.

[0026] According to one embodiment of the present disclosure, it is preferable that the length of the portion where the tip forming is formed is 0.5 to 10 mm and the inner diameter is 0.05 to 25 mm.

[0027] According to one embodiment of the present disclosure, it is preferable to use a polymer having a leaf-layered porous structure that is capable of forming a leaf-layered porous structure, selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid copolymer, polycaprolactone copolymer, poly(lactic acid-co-ε-polyhydroxybutyric acid-hydroxyvaleric acid copolymer), poly(dioxanone), and poly(phosphoester).

[0028] According to one embodiment of the present disclosure, the porous structure of a polymer having a leaf-like layered porous structure may be capable of carrying a drug.

[0029] According to one embodiment of the present disclosure, the drug may be any one selected from proteins, growth factors, cytokines, hormones, mRNA, pDNA, peptides, steroids, and non-steroidal therapeutic agents.

[0030] According to a preferred embodiment of the present disclosure, the drug is characterized by sustained release from the porous structure of a polymer having a leaf-like layered porous structure.

[0031]

[0032] The method for manufacturing a microporous drug delivery matrix for the treatment of glaucoma according to the present disclosure may comprise the steps of: manufacturing an outer layer; manufacturing one or both ends of the outer layer into a tip-forming structure; adding a polymer solution into the outer layer; and immersing the outer layer with the added polymer solution in a non-solvent to form a leaf-like stacked porous structure.

[0033] According to a preferred embodiment of the present disclosure, the outer layer may be extruded using one or more materials selected from thermoplastic polyurethane, polytetrafluoroethylene, silicone, polyvinyl chloride, polyethylene, polysulfone, and polypropylene.

[0034] According to a preferred embodiment of the present disclosure, the outer layer is preferably manufactured in the form of a tube.

[0035] In addition, according to a preferred embodiment of the present disclosure, the tip forming structure of either or both ends of the outer layer may be formed by applying heat at a temperature of 50 to 200°C to the outer layer.

[0036] According to a preferred embodiment of the present disclosure, the method is characterized by further including the step of loading a drug onto a porous structure of a polymer having a formed leaf-like layered porous structure, thereby enabling sustained release of the drug.

[0037]

[0038] According to the present disclosure, a tubular container comprising a microporous drug delivery matrix for the treatment of glaucoma can be provided, which can effectively treat glaucoma through continuous drug delivery into the eye and improve the quality of life of the patient.

[0039] A tubular container comprising a microporous drug delivery matrix for the treatment of glaucoma according to the present disclosure has a structural feature that facilitates drug delivery into the eye by having a tip-forming shape on one or both ends.

[0040] In addition, the tubular container containing the microporous drug delivery matrix for the treatment of glaucoma of the present disclosure is expected to overcome the limitations of existing drug delivery systems and be usefully utilized in regenerative medicine and pharmacological aspects, as it enables continuous release of the drug.

[0041]

[0042] FIG. 1 is a diagram showing the tip-forming process of Example 1 of the present disclosure.

[0043] FIG. 2 is a drawing showing a structure (A) in which tip forming is formed on both ends of a tube-shaped end, and a structure (B) in which tip forming is formed on only one end of a tube-shaped end.

[0044] Figure 3 shows a scanning electron microscope image of the leaf-like stacked structure separated from the tube after fabrication of the microporous drug delivery matrix prepared according to Example 1, observing the surface of both (upper and lower) entrances and the internal morphology.

[0045] Figure 4 is a schematic diagram of a method for measuring release behavior using a tubular container with a layered leaf structure containing LAT.

[0046] Figure 5 is a graph showing the release amount measured by loading 0.3 mg and 1 mg of LAT into a tubular container formed with a layered leaf structure of Examples 2 and 3. A is a graph showing the daily release and cumulative release amount measured after loading 0.3 mg of LAT into a tube formed with a layered leaf structure (Example 2), and B is a graph showing the daily release and cumulative release amount measured after loading 1 mg of LAT into a tube formed with a layered leaf structure (Example 3).

[0047] FIG. 6 is an example of a tubular container of the present disclosure.

[0048] FIG. 7 is an example of a tubular container of the present disclosure that includes a sealing portion.

[0049] FIG. 8 is another example of a tubular container of the present disclosure.

[0050]

[0051] The present disclosure will be described in more detail below.

[0052] The terms used in this specification are used to describe specific embodiments and are not intended to limit the disclosure.

[0053] As used herein, the singular form may include the plural form unless the context clearly indicates otherwise. Additionally, as used herein, “comprise” and / or “comprising” specify the presence of the mentioned features, numbers, steps, actions, parts, elements, and / or groups thereof, and do not exclude the presence or addition of one or more other features, numbers, actions, parts, elements, and / or groups.

[0054] The present disclosure relates to a tubular container comprising a microporous drug delivery matrix for the treatment of glaucoma and a method for manufacturing the same.

[0055] A tubular container comprising a microporous drug delivery matrix according to one embodiment of the present disclosure is characterized by having an outer layer having a structure with both ends open, and a structure comprising a polymer having a leaf-like stacked porous structure inside the outer layer.

[0056] The term "microporous drug delivery matrix" as used throughout the specification of this disclosure implies that the polymer contained within the outer layer has a leaf-stacking porous structure, similar to a stack of numerous fallen leaves, and that this structure is similar to a structure in which fine pores are interconnected.

[0057] In particular, it is preferable that the outer layer of the drug delivery matrix of the present disclosure has a tube shape. According to the present disclosure, by having a tube shape with both ends open (open structure), a polymer solution having a liquid leaf-like stacked porous structure is filled inside and solidified to be supported.

[0058] According to one embodiment of the present disclosure, the outer layer has a tube shape, wherein the tube has a length of 5 to 100 mm, an inner diameter of 0.1 to 50 mm, and an outer diameter of 1 to 60 mm, which is preferable for forming a leaf-layered porous structure that is a delay agent for delaying insertion into the eye and release of the enclosed drug.

[0059] The tube-shaped outer layer of the present disclosure is preferably extruded using one or more materials selected from thermoplastic polyurethane, Teflon (polytetrafluoroethylene), silicone, polyvinyl chloride, polyethylene, polysulfone, and polypropylene.

[0060] The above-mentioned outer layer forming material has a heat deformation temperature of 50 to 200°C and is composed of materials that are easy to manufacture into a tube shape.

[0061] In addition, according to one embodiment of the present disclosure, the outer layer may have either one or both of its end surfaces in a tip-forming shape. Here, "tip-forming shape" refers to a tube having a terminal end with a diameter smaller than that of the body that can be inserted into the eyeball, and by having said shape, it has the characteristic of increasing ease of insertion into the eyeball and reducing foreign body sensation.

[0062] In one embodiment of the present disclosure, the portion in which the tip forming is formed has a length of 0.5 to 10 mm from one or both ends of the end cross-section of the outer layer, and has an inner diameter of 0.05 to 25 mm and an outer diameter of 1 to 60 mm, which is preferable for insertion into the eyeball.

[0063] The method of forming the tip forming described above is characterized by applying heat at a temperature of 50 to 200°C to the corresponding outer layer area for forming the tip forming, so as to have the length and inner diameter, that is, to be formed thinner than the inner diameter of the outer layer initially formed in the shape of a tube.

[0064] If, as in the present disclosure, a tip forming structure is not formed on one or both ends of the outer layer and the tube has the same size (outer diameter and inner diameter) along the entire length direction (e.g., a straw-like shape), it is not only difficult to support a porous polymer with a leaf-like laminated structure inside the outer layer, but even if supported, the porous polymer with a leaf-like laminated structure included may escape, so it is undesirable.

[0065] In addition, when the outer layer is formed only in a tube shape without forming a tip-forming structure on one or both ends of the outer layer as in the present disclosure, the drug is released in all directions, resulting in a reduced sustained-release effect intended in the present disclosure. On the other hand, when a tip-forming structure as in the present disclosure is formed, the portion where the drug can be released into the tip-forming region is limited while the drug is accumulated inside a relatively thick tube, thereby making sustained-release of the drug easier.

[0066] Meanwhile, according to one embodiment of the present disclosure, one side of the tubular container of the present disclosure is formed as a tubular body, the other side as a narrow extension portion, and the area between the body and the extension portion is formed as a tapered portion. The extension portion is formed as a tubular protruding portion as a tapered end portion, so that a fluid such as a drug can pass through it.

[0067] According to one embodiment of the present disclosure, the tubular container of the present disclosure may have a structure comprising a polymer having a leaf-like laminated porous structure within a tube of an outer layer having the tube shape.

[0068] According to the present disclosure, the polymer having the leaf-like laminated porous structure is biocompatible and biodegradable, and is preferably one or more selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid copolymer, polycaprolactone copolymer, poly(lactic acid-co-ε-polyhydroxybutyric acid-hydroxyvaleric acid copolymer), poly(dioxanone), and poly(phosphoester).

[0069] Meanwhile, various types of drugs can be loaded into the porous structure of a polymer having a leaf-like stacked porous structure included within the matrix of the present disclosure.

[0070] A drug according to one embodiment of the present disclosure may be any one selected from proteins, growth factors, cytokines, hormones, mRNA, pDNA, peptides, steroids, and non-steroidal therapeutic agents for the treatment of glaucoma.

[0071] According to one embodiment of the present disclosure, if the drug is a steroid or a non-steroidal therapeutic agent, the therapeutic agent may be used for the treatment of glaucoma.

[0072] In addition, the above drug has sustained-release characteristics that allow it to be continuously released for up to about 28 days from the porous structure of a polymer having a leaf-layered porous structure, thereby providing a microporous drug delivery matrix for the treatment of glaucoma that can effectively treat glaucoma through continuous drug delivery into the eye and improve the patient's quality of life.

[0073] Hereinafter, a method for manufacturing a tubular container comprising a microporous drug delivery matrix for the treatment of glaucoma according to the present disclosure is described in detail.

[0074] A method for manufacturing a tubular container including a microporous drug delivery matrix for treating glaucoma according to one embodiment of the present disclosure may comprise the steps of: manufacturing an outer layer; manufacturing one or both ends of the outer layer into a tip-forming structure; adding a polymer solution into the outer layer; and immersing the outer layer with the added polymer solution in a non-solvent to form a leaf-like stacked porous structure.

[0075] According to one embodiment of the present disclosure, the outer layer is preferably manufactured in the form of a tube. Specifically, a tube having a predetermined thickness and length is manufactured by extrusion molding using a material for forming the outer layer.

[0076] The next step is to manufacture one or both ends of the outer layer of the tube shape into a tip-forming structure. For example, the manufactured tube is inserted into a mantle having a predetermined thickness and excellent release properties, and then heat at a temperature of 50 to 200°C is applied to a predetermined length from the end of the tube to shrink the tube to a predetermined size and create a tip-forming shape. Afterward, the tip-formed tube is cut on both sides to match the target length, and then the final tip-formed tube can be manufactured.

[0077] As disclosed in the present disclosure, by manufacturing one or both ends of the outer layer in a tube shape as tip-forming structures, it is possible to achieve an easy effect when injecting drugs into the eye.

[0078] The next step involves adding a polymer solution into the tube-shaped outer layer and immersing it in a non-solvent to form a leaf-layered porous structure within the outer layer.

[0079] Specifically, a polymer having a layered leaf-like porous structure is sufficiently dissolved in a suitable solvent or melted to form a solution. Then, the solution is transferred to a syringe of a predetermined size and slowly injected into one opening of a tube. Once the polymer solution is immersed in the entire interior of the tube, it is immersed in a non-solvent for a certain period of time, washed several times with distilled water once every hour, and then freeze-dried to obtain a tube with a porous structure resembling a layered leaf.

[0080] According to one embodiment of the present disclosure, the method may further include the step of loading a drug onto a porous structure of a polymer having a leaf-like layered porous structure formed inside a tube.

[0081] According to the present disclosure, the type of drug loaded in a tube having a leaf-layered structure may preferably be a protein, growth factor, cytokine, hormone, mRNA, pDNA, peptide, steroid, or non-steroidal therapeutic agent for the treatment of glaucoma.

[0082] It is preferable to slowly inject the drug into one side of the tube containing the drug at the inlet of the tube having a leaf-layered porous structure, and then allow it to diffuse evenly into the leaf-layered porous structure through diffusion.

[0083]

[0084] Preferred embodiments of the present disclosure will be described in detail below. The following embodiments are intended only to illustrate the present disclosure and should not be interpreted as limiting the scope of the present invention. Furthermore, while the following embodiments have been illustrated using specific compounds, it is obvious to those skilled in the art that equivalents can be used to achieve an equivalent or similar effect.

[0085]

[0086] Example 1: Preparation of a microporous drug delivery matrix for the treatment of glaucoma

[0087] 1) Tube manufacturing and tip-forming process

[0088] A tube shape was produced by extrusion molding using Lubrizol’s TECOFLEX EG-93a thermoplastic polyurethane (TPU). In one embodiment, the outer diameter of the tube is approximately 0.9 to 1.1 mm, the inner diameter is approximately 0.72 to 0.88 mm, and the length is approximately 10.8 to 16.5 mm.

[0089] Next, the above-manufactured tube was inserted into a SUS mantle coated with mPTFE, and then the tube was heat-shrinked using a heat gun at 150°C to create a tip-forming shape with an outer diameter of 0.6 mm and an inner diameter of 0.4 mm up to 2 mm from the end of the tube. (Refer to Fig. 1A)

[0090] Afterward, the heat shrink tube was detached from the SUS mantle using a scalpel, and the tip-formed tube was cut on both sides to the target length to produce the final tip-formed tube (see Fig. 1 B, C). The design of the tube and a photograph of the manufactured tube are shown in Fig. 2 (unit mm).

[0091] In the embodiment illustrated in FIG. 2A, the total length of the tube is about 15 mm (±10%), which may include a range of about 13.5 mm to 16.5 mm. The outer diameter of the tube is about 1.0 mm (±10%), which may be about 0.9 mm to 1.1 mm, and the inner diameter is about 0.8 mm (±10%), which may be about 0.72 mm to 0.88 mm. At each end of the tube, a tip-forming portion with a length of about 2 mm (±10%) is formed, which includes a range of about 1.8 mm to 2.2 mm. The outer diameter of the tip-forming portion is about 0.6 mm (±10%), which may be about 0.54 mm to 0.66 mm, and the inner diameter may be about 0.4 mm (±10%), which may be about 0.36 mm to 0.44 mm.

[0092] In the embodiment illustrated in FIG. 2B, the total length of the tube may be about 12 mm (±10%), ranging from about 10.8 mm to 13.2 mm. The outer diameter of the tube is about 1.0 mm (±10%; about 0.9 mm to 1.1 mm), and the inner diameter is about 0.8 mm (±10%; about 0.72 mm to 0.88 mm). A tip-forming portion approximately 2 mm (±10%) in length is formed at one end of the tube, covering a range of about 1.8 mm to 2.2 mm. The outer diameter of the tip-forming portion may be about 0.6 mm (±10%; about 0.54 mm to 0.66 mm), and the inner diameter may be about 0.4 mm (±10%; about 0.36 mm to 0.44 mm).

[0093] In addition, in addition to the structure shown in the embodiment of FIG. 2, it can be formed into a tube-shaped structure as shown in FIG. 6 to FIG. 8, and in this case, the tip forming portion can correspond to a tubular protrusion.

[0094]

[0095] 2) Introduction of a leaf-layered porous structure inside the tube

[0096] Polycaprolactone (PCL, Evonik) is mixed with tetragylcol (Sigma) at 60°C with stirring. The polymer solution is transferred to a syringe and slowly injected into one opening of a tube. Once the entire tube is filled with the polymer solution, it is immersed in an ethanol solution for 1 hour. The tube is washed with distilled water once every hour for a total of 6 hours, and then freeze-dried to produce a tube with a laminated leaf structure.

[0097]

[0098] Experimental Example 1: Confirmation of porous structure formed inside the tube

[0099] After fabricating the microporous drug delivery matrix prepared according to Example 1, the leaf-like stacked structure was carefully separated from the tube, and the shape of both entrances and the interior was observed using a scanning electron microscope (Fig. 3).

[0100] Referring to Figure 3, it can be observed that pores ranging in size from several hundred nm to several tens of μm are formed at both entrances of the tube. It can also be seen that a layered leaf structure is formed in the interior. This indicates that while circular pores appear at the entrance where the PCL solution came into direct contact with ethanol, serving as channels for direct solvent exchange between tetraglycol (the solvent of PCL) and ethanol, the interior, where direct exchange with ethanol is impossible, forms a unique structure resembling an irregular, layered leaf due to the precipitation and aggregation of PCL polymer chains as the temperature decreases.

[0101]

[0102] Example 2: Preparation of a microporous drug delivery matrix for glaucoma treatment in which a drug is loaded in a porous structure

[0103] 10 μL (LAT 0.3, 1.0 mg) of a latanoprost (LAT, Sigma) solution dissolved in ethanol is slowly injected into one inlet of a tube having a leaf-shaped laminated porous structure formed in the matrix prepared in Example 1 above. Through diffusion, the LAT solution diffuses evenly into the PCL leaf-shaped laminated structure. Afterward, the ethanol is air-dried to produce a tube having a leaf-shaped laminated structure loaded with LAT.

[0104]

[0105] Comparative Example 1: Preparation of a matrix having an empty tip-forming tube

[0106] 1) of Example 1) A hollow tip-forming tube containing nothing inside was used as Comparative Example 1 and compared with the present disclosure by performing only the tube manufacturing and tip-forming processes.

[0107]

[0108] Experimental Example 1: Emission Test of LAT

[0109] Examples 2 and 3, which are tubes with a laminated leaf structure loaded with LAT, were fixed to the wall of an EP tube using a silicone ring so that LAT could be released from one opening as shown in Fig. 4. Then, 1 mL of phosphate buffered saline (PBS) was added and stored at 37°C and 50 rpm. Every 1, 3, 5, 7, 14, 21, and 28 days, 1 mL of the stored solution was collected and replaced with 1 mL of fresh PBS.

[0110] In the case of Comparative Example 1 above, an attempt was made to inject the drug, but it flowed out of the tube and could not be injected, and as a result, the LAT release experiment could not be conducted.

[0111]

[0112] Experimental Example 2: Construction of LAT Standard Calibration Curve and Measurement of Emission Behavior

[0113] To construct the standard calibration curve for LAT, a 1 mg LAT standard was dissolved in HPLC-grade methanol (Burdick & Jackson) and filtered through a 0.2 µm filter (Satorius Steim, Mini Sat Rc 25) to prepare standard calibration samples at concentrations of 100, 50, 25, 12.5, and 6.25 ppm. 20 μL of the prepared standard calibration samples were injected into a high-performance liquid chromatography (HPLC) system for analysis, yielding a calibration curve equation of y = 19979x - 19060, and R 2 A standard curve for quantitative analysis was established with a value of 0.9996. For the detection of LAT, the mobile phase consisted of 70% acetonitrile containing 0.1% formic acid and 30% distilled water, and the analysis was performed by injecting the sample at a rate of 1 mL per minute (Table 1). Based on the conditions in Table 1, the LAT emission behavior of Examples 2 and 3 was measured and is shown in Figure 5.

[0114] Equipment Name: Shimadzu (Nexera) Column: Avantor ace, C-18 (4.6 mm x 150 mm) / Particle size: 5 µm / Pore size: 100 Å Flow rate: 1 ml / min Column temperature: 25°C UV wavelength: 210 nm Mobile phase: Solvent A: ACN (formic acid 0.1%) 70%, Solvent B: Water 30%

[0115] Referring to the results in Fig. 5, a sustained-release pattern was observed in Examples 2 and 3, where the drug was continuously released for up to 28 days, and the release amount began to decrease after 14 days. It is believed that the reason for the continuous release for more than 28 days, despite being a low-molecular-weight substance, is due to the low solubility in PBS and the hydrophobic properties of LAT, which causes delayed diffusion within the large surface area of ​​the leaf-like layered structure. Additionally, it can be seen that the release period was delayed because the release inlet was limited to the inlet portion (tip-forming region) of the tube.

[0116] In other words, by impregnating the latanoprost solution onto a leaf-layered porous structure, the drug is immobilized on the surface of the support and within the pores, thereby minimizing exposure to external degradation factors such as light, heat, and hydrolysis, which can improve chemical and physical stability. Furthermore, the unique porous structure of the support effectively suppresses the burst release occurring during the initial release phase, which can reduce the risk of toxicity caused by rapid exposure to high concentrations of the drug.

[0117] Furthermore, since the drug is released gradually through adsorption and desorption processes, unlike simple solution-based release, rapid fluctuations in release caused by the initial moist environment or pH changes can be mitigated. This is attributed to the characteristic of the drug slowly penetrating into the support, which consequently enables continuous and stable sustained-release drug release, making it effective for the treatment of glaucoma.

[0118] Furthermore, when a liquid drug is infiltrated into a polymer having a leaf-like layered porous structure, the drug permeates into the pores of the support, extending the diffusion path, and undergoes gradual desorption from the surface, thereby exhibiting sustained-release characteristics. These structural characteristics control the drug release rate and enable sustained pharmacological effects over a long period.

[0119] Furthermore, the characteristics of the polymer, which possesses a leaf-like layered porous structure, enable long-term drug delivery, thereby providing clinical benefits such as reducing the number of surgeries by extending the treatment cycle. Since drug replacement is possible within the same platform, versatility for the application of various therapeutic agents can be ensured. Therefore, this tubular container system constitutes a superior drug delivery platform in terms of drug stability, toxicity reduction, release control, and treatment convenience.

[0120] FIG. 6 is an example of a tubular container of the present disclosure.

[0121] Referring to FIG. 6, the tubular container (100) may include a tubular body (110) in which a drug is contained, a tapered portion (120) formed such that the diameter gradually decreases at the end of the tubular body, and a tubular protrusion (130) extending from the end of the tapered portion (120). The tubular container (100) of FIG. 6 may be manufactured by the method for manufacturing a tubular container described above.

[0122] Referring to FIG. 6, the tubular body (110) defines a receiving space for accommodating a drug inside, and the cross-section may be semicircular, with one side of the cross-section formed as a curved portion and the other side formed as a flat portion. For example, it includes a flat portion located on the diameter line of the cross-section of the body (110). The semicircular cross-sectional structure can increase stability in a specific direction of the tubular body (210) or allow the body to be fixed or stably positioned in a specific direction during manufacturing molding. Additionally, the coexistence of a partially flat portion and a curved portion provides a structural advantage that allows for fine control of the release pattern.

[0123] Furthermore, configuring the main body in a semicircular shape allows it to structurally correspond with the curvature of the insertion site, thereby reducing localized pressure or friction that may occur in a straight tube structure. As a result, technical effects are achieved in which the burden on the tissue during insertion is alleviated and the positional stability of the device is improved.

[0124] Although not shown in FIG. 6, the tubular body (100) defines a receiving space for containing a drug inside, and its cross-section may include a circular shape. Through this, the body (100) provides a stable volume when containing the drug, thereby ensuring structural stability during manufacturing and molding. Additionally, the internal space is uniform, allowing the drug to maintain a constant concentration distribution and provide a uniform diffusion-based sustained-release.

[0125] A tapered portion (120) with a decreasing diameter is continuously formed at the end of the tubular body (100), and the tapered portion (120) connects the diameter difference between the body (100) and the tubular protrusion (130) to improve the mobility of the drug.

[0126] At the end of the tapered portion (120), a tubular protrusion (130) protruding in the shape of a thin tube is formed, and a narrow-diameter lumen is formed inside the tubular protrusion (130). The drug contained in the main body (100) moves along this lumen and is then released to the outside.

[0127] FIG. 7 is an example of a tubular container of the present disclosure that includes a sealing portion.

[0128] Referring to FIG. 7, one end of the tubular body (110) can be selectively closed by a sealing part (140), and the sealing part (140) is formed in a shape including a flat surface and a curved surface corresponding to the semicircular shape of the body (110). The sealing part (140) corresponds to the cross-sectional shape of the body (110) and seals the entire open end of the body (110) hermetically, thereby blocking exposure to the external environment after drug loading and performing the function of preventing contamination and leakage of the drug.

[0129] FIG. 8 is another example of a tubular container of the present disclosure.

[0130] Referring to FIG. 8, the tubular container (200) may include a tubular body (210) in which a drug is contained, a tapered portion (220) formed such that the diameter gradually decreases at the end of the tubular body, and a tubular protrusion (230) extending from the end of the tapered portion (220).

[0131] In the embodiment of FIG. 8, the cross-section of the tubular body (210) is formed as a semicircular cross-section having a partially flat portion. More specifically, the body (210) includes a structure having a curved surface on one side and a flat surface on the other.

[0132] Referring to FIG. 8, the partially flat portion of the main body is located below the centerline, so that a wide curvature area can be formed. That is, the cross-section of the main body (210) is formed with one side having a continuous curved shape with respect to the center axis, and the other side having a flat portion, and the flat portion can be located below the diameter line of the cross-section. In addition, if the curved portion is formed larger, the burden applied to the tissue during insertion is reduced, and the positional stability of the device is improved, thereby obtaining technical effects.

[0133] Through a semicircular cross-sectional structure with a relatively large curved portion, the emission rate is limited, which can enhance the sustained emission effect.

[0134] The embodiments described in this disclosure are merely illustrative for the sake of understanding, and those skilled in the art can make various changes, modifications, and variations within the scope and spirit of this disclosure.

Claims

1. An outer layer having a structure open on both sides; and A tubular container characterized by comprising: a drug delivery matrix for treating glaucoma, comprising a polymer having a leaf-layered porous structure inside the outer layer.

2. In Paragraph 1, The above outer layer A tubular body containing the above drug delivery matrix; Tubular protrusions; and A tubular container comprising: a tapered portion connecting the tubular body and the tubular protrusion.

3. In Paragraph 1, A tube-shaped container in which a polymer having the above-mentioned leaf-layered porous structure can be filled with a liquid solution and solidified to be supported.

4. In Paragraph 1, A tubular container in which the outer layer is made of a material capable of thermal deformation at 50 to 200°C.

5. In Paragraph 1 or Paragraph 4, A tubular container in which the outer layer uses one or more materials selected from thermoplastic polyurethane, polytetrafluoroethylene, silicone, polyvinyl chloride, polyethylene, polysulfone, and polypropylene.

6. In Paragraph 2, A tubular container having an outer layer with a length of 5 to 100 mm, an inner diameter of 0.1 to 50 mm, and an outer diameter of 1 to 60 mm.

7. In Paragraph 1, A tubular container in which the outer layer has a tip-forming shape on either or both of the end surfaces.

8. In Paragraph 7, A tubular container having a length of 0.5 to 10 mm and an inner diameter of 0.05 to 25 mm at the portion where the tip forming is formed.

9. In Paragraph 1, A tubular container having a leaf-layered porous structure, wherein the polymer having the above-mentioned leaf-layered porous structure is one or more selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid copolymer, polycaprolactone copolymer, poly(lactic acid-co-ε-polyhydroxybutyric acid-hydroxyvaleric acid copolymer), poly(dioxanone), and poly(phosphoester), capable of forming a leaf-layered porous structure.

10. In Paragraph 1, A tubular container capable of carrying a drug in the porous structure of a polymer having the above-mentioned leaf-layered porous structure.

11. In Paragraph 10, A tubular container in which the above drug is any one selected from proteins, growth factors, cytokines, hormones, mRNA, pDNA, peptides, steroids, and non-steroidal therapeutic agents for the treatment of glaucoma.

12. In Paragraph 10, A tubular container in which the above drug is released in a sustained-release manner from the porous structure of a polymer having the above leaf-layered porous structure.

13. Step of manufacturing the outer layer; A step of manufacturing one or both ends of the outer layer into a tip-forming structure; A step of adding a polymer solution into the outer layer; and A method for manufacturing a tubular container, comprising the step of immersing an outer layer to which the above-mentioned polymer solution has been added in a non-solvent to form a leaf-layered porous structure.

14. In Paragraph 13, A method for manufacturing a tubular container in which the outer layer is extruded using one or more materials selected from thermoplastic polyurethane, Teflon (polytetrafluoroethylene), silicone, polyvinyl chloride, polyethylene, polysulfone, and polypropylene.

15. In Paragraph 13, A method for manufacturing a tubular container in which the outer layer is manufactured in the form of a tube.

16. In Paragraph 13, A method for manufacturing a tubular container, wherein the tip forming structure of one or both ends of the outer layer is formed by applying heat at a temperature of 50 to 200°C to the outer layer.

17. In Paragraph 13, A method for manufacturing a tubular container, further comprising the step of loading a drug into the porous structure of a polymer having the above-mentioned leaf-layered porous structure.

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