Injectable hydrogel rod using crosslinked hydrogel, its manufacturing method and biomedical use

Abstract

The present invention relates to an injectable hydrogel rod using a crosslinked hydrogel, a manufacturing method thereof, and a biomedical use thereof. According to the present invention, the injectable hydrogel rod is manufactured by adjusting the contents of polymers, enzymes, and hydrogen peroxide at a certain ratio, thereby controlling the initial release amount of a drug injected into the hydrogel rod and exhibiting sustained release above the effective pharmacological concentration for a long period of time compared to existing hydrogel-based injectable implants, and significantly reducing excretion into surrounding tissues, thereby enhancing the therapeutic effect and significantly reducing side effects.

Description

[Technical field]

[0001] The present invention relates to a hydrogel rod for injection into the body using a crosslinked hydrogel, a method for producing the same, and biomedical applications thereof. [Background technology]

[0002] Hydrogel is a jelly-like material formed by physicochemical crosslinking of polymers dissolved in an aqueous phase. It is hydrophilic and easily absorbs water, and its strength and shape can be easily adjusted, so it is used as a tissue engineering support or drug delivery. Hydrogel is also actively researched as an alternative to methods with low drug delivery efficiency in the body due to its excellent biocompatibility, biodegradability, drug release control, and minimally invasive properties that can undergo phase transition after injection into the body. The main purpose of hydrogel as a drug delivery medium is to release a drug at a therapeutic concentration or higher at the diseased site for a long period of time, thereby eliminating the need for frequent injections that can cause side effects and discomfort such as pain. For example, in the case of chronic age-related macular degeneration, a protein drug called a VEGF antagonist must be injected into the eye for treatment, but the half-life in the eye is within 2 weeks, and the duration of efficacy is short, at 1 to 2 months. Therefore, to obtain the maximum effect of VEGF antagonists, they must be injected into the eye almost every month. This not only causes a lot of inconvenience and side effects to patients, but also imposes a large economic burden. Therefore, injectable hydrogels have been developed as a promising intraocular protein drug delivery vehicle.

[0003] However, injectable hydrogels release an initial excessive amount of drug before the phase transition occurs after injection, which limits the control of drug release rate for diseases that require long-term drug efficacy. In order to control the drug release rate, crosslinked hydrogels that undergo phase transition must be injected, but crosslinked hydrogels are solidified and cannot be injected into the body because they are in an inconsistent form. Therefore, the present inventors have newly developed a long-term protein drug release controlled injectable implant (Hydrogel rod) using crosslinked hydrogels. Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention relates to an injectable hydrogel rod for controlling the release of protein drugs using a crosslinked hydrogel, its manufacturing method and its use, and aims to provide an injectable hydrogel rod that exhibits sustained release characteristics by controlling the contents of polymers, enzymes and hydrogen peroxide. [Means for solving the problem]

[0005] In order to achieve the above-mentioned objects, the present invention provides an injectable hydrogel rod comprising: a rod-shaped hydrogel matrix made of a polymer substituted with a phenol derivative, in which the phenol derivatives introduced into the side chains of the polymer are bonded to each other and crosslinked; and a drug loaded within the hydrogel matrix.

[0006] The present invention also provides an implant material that includes the hydrogel rod that is injected into the body.

[0007] The present invention also provides a drug delivery device comprising the above-mentioned injectable hydrogel rod.

[0008] The present invention also provides a method for producing a hydrogel rod, the method comprising the steps of: preparing a mold having rod-shaped holes; preparing a solution in which a phenol derivative-substituted polymer, a drug, and an enzyme are dissolved; sequentially injecting the solution and hydrogen peroxide into the holes in the mold, and then crosslinking the hydrogel; separating the crosslinked hydrogel from the mold; and freeze-drying the separated hydrogel to produce a hydrogel rod,

[0009] The present invention provides a method for producing an injectable hydrogel rod, characterized in that the mixing ratio of the polymer in which a phenol derivative is substituted, the enzyme, and hydrogen peroxide is 10:0.1-0.5:0.1-0.5 by volume. Effect of the Invention

[0010] According to the present invention, the contents of polymer, enzyme and hydrogen peroxide are adjusted to a certain ratio to prepare an injectable hydrogel rod, thereby controlling the initial release amount of the drug injected into the hydrogel rod and demonstrating sustained release above the effective pharmacological concentration for a long period of time compared to existing hydrogel-based injectable implants, and significantly reducing elimination into surrounding tissues and significantly reducing side effects. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a schematic diagram showing a method for manufacturing a GPT hydrogel rod according to the present invention (a); FIG. 2 is a photographed image of the shape of the GPT hydrogel rod manufactured according to the present invention; and FIG. 3 is a schematic diagram showing the fabrication of an injector for the GPT hydrogel rod manufactured according to the present invention (c). [Diagram 2] 1 is a table (a) showing the manufacturing conditions of the hydrogel rod to be injected into the body according to the present invention, and a graph (b) showing the evaluation of the mechanical strength of the hydrogel rod to be injected into the body according to the present invention by adjusting the degree of crosslinking. [Diagram 3]1A is a graph showing the amount of drug released by time period from the internally injected hydrogel rod according to the present invention, and FIG. 1B is a graph showing the cumulative release behavior up to 120 days. [Figure 4] FIG. 1A is a schematic diagram of a comparative example of a hydrogel that can be injected internally; FIG. 1B is a schematic diagram of the drug release incubation of a hydrogel rod that can be injected internally of an embodiment; and FIG. 1C is a graph showing the drug release behavior of copper ions released from the accumulated hydrogel of a hydrogel rod that can be injected internally of an embodiment and nitric oxide produced. [Diagram 5] Graph (a) shows the inhibition of HUVEC growth by WST-1 of in vivo injected hydrogels of the examples and comparative examples, and scanning electron microscope (SEM) images (b) showing cell compatibility and growth inhibition through Live / Dead. [Figure 6] FIG. 2 is a schematic diagram of an intraocular injection plan for evaluating the pharmacokinetics of the injectable hydrogel according to the present invention. [Figure 7] Graph (ac) shows the pharmacokinetic results of the internally injected hydrogel rods of the Examples and Comparative Examples in each tissue in the body, and Table (d) shows the drug concentration in each tissue. [Figure 8] 1 shows intraocular ultrasound images taken at different times after the internal injection type hydrogel rod according to the present invention is injected into the eye. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] In the following, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings, in which: FIG. 1 is a block diagram of a semiconductor device according to a first embodiment of the present invention;

[0013] The present inventors have completed the present invention by designing a manufacturing method for a hydrogel rod that can be injected into the body for a long period of time and that can control the release of a protein drug using a crosslinked hydrogel and evaluating the effectiveness of the method.

[0014] The present invention provides an injectable hydrogel rod comprising: a rod-shaped hydrogel matrix made of a polymer substituted with a phenol derivative, in which the phenol derivatives introduced into the side chains of the polymer are bonded to each other and crosslinked; and a drug loaded within the hydrogel matrix.

[0015] The hydrogel matrix has a crosslinking degree of 30 to 80%, 40 to 70%, or 45 to 60%. By having such a crosslinking degree, the hydrogel rod exhibits sustained release characteristics for 3 or 4 months or more by controlling the initial release rate to 10% or less, 7% or less, or 5% or less.

[0016] The rod-shaped hydrogel matrix has a diameter of 0.5 to 0.7 mm, 0.7 to 0.9 mm, or 0.9 to 1.2 mm.

[0017] The rod-shaped hydrogel matrix has a length of 4 to 6 mm, 6 to 8 mm, or 8 to 10 mm.

[0018] The polymer is one or more polymers selected from the group consisting of gelatin, chitosan, heparin, cellulose, dextran, dextran sulfate, chondroitin sulfate, keratan sulfate, dermatan sulfate, alginic acid, collagen, albumin, fibronectin, laminin, elastin, vitronectin, hyaluronic acid, fibrinogen, and hyperbranched polymers.

[0019] The phenol derivative is one or more selected from the group consisting of hydroxyphenyl propionic acid, 4-hydroxyphenyl acetic acid, tyrosine, tyramine, tetronic tyramine, and PEG-tyramine.

[0020] The drug may be one or more drugs selected from an ocularly injectable protein therapeutic formulation, a chemical drug, a small molecule therapeutic agent, a gene, a cell or a cell-derived product. Specifically, the protein therapeutic preparations include anti-vascular endothelial growth factor (VEGF) drugs such as ranibizumab, aflibercept, bevacizumab, and brolucizumab, which are used for macular degeneration and diabetic retinopathy, and protein drugs such as rituximab, adalimumab, and infliximab, which are used for other diseases. The chemical drugs include dexamethasone, triamcinolone, ganciclovir, methotrexate, and vancomycin. The small molecule therapeutic agents include sugars, lipids, amino acids, fatty acids, phenolic compounds, and the like. The gene may be an siRNA (anti-VEGF) or the like, and the cell may be a retinal or intraocular cell such as RPE or photoreceptor, stem cell, etc. Although the following description will be given with reference to an example using bevacizumab as a drug, the present invention is not limited to such a drug type, and may include any protein therapeutic preparation, chemical drug, small molecule therapeutic agent, gene, cell, etc. for ophthalmology and various other diseases.

[0021] The hydrogel may form a rod-shaped hydrogel matrix by adjusting the concentrations of polymer, enzyme, and hydrogen peroxide.

[0022] Specifically, the phenol derivative-substituted polymer, enzyme, and hydrogen peroxide may be mixed in a volume ratio of 10:0.1-0.5:0.1-0.5 to form a rod-shaped hydrogel matrix.

[0023] The present invention also provides an implant material for injection into the body, comprising the hydrogel rod for injection into the body. Specifically, the implant material for injection into the body is an implant material for injection into the eye.

[0024] The implant material may be applied to any one selected from the group consisting of the inside of the eye, the extraocular body space, the subcutaneous tissue, and the inside of other organs.

[0025] The present invention also provides a drug delivery device comprising the above-mentioned injectable hydrogel rod.

[0026] The present invention also provides a method for producing a hydrogel rod, the method comprising the steps of: preparing a mold having rod-shaped holes; preparing a solution in which a phenol derivative-substituted polymer, a drug, and an enzyme are dissolved; sequentially injecting the solution and hydrogen peroxide into the holes in the mold, and then crosslinking the hydrogel; separating the crosslinked hydrogel from the mold; and freeze-drying the separated hydrogel to produce a hydrogel rod.

[0027] The present invention provides a method for producing an injectable hydrogel rod, characterized in that the mixing ratio of the polymer in which a phenol derivative is substituted, the enzyme, and hydrogen peroxide is 10:0.1-0.5:0.1-0.5 by volume.

[0028] The step of preparing the mold may include preparing a mold made of one material selected from the group consisting of gelatin, metal, and Teflon, so as to have a rod-shaped hole therein.

[0029] The rod-shaped holes may have a diameter of 0.5 to 1.2 mm and a length of 4 to 10 mm.

[0030] Specifically, the step of preparing the mold may involve pouring a gelatin solution onto the outside of the needle and then solidifying the solution at a temperature of 1 to 10° C. to prepare a gelatin mold.

[0031] The needle has a diameter of 0.5 to 1.2 mm and a length of 4 to 10 mm.

[0032] The gelatin solution may contain 5 to 20 wt % or 5 to 15 wt % gelatin.

[0033] In the step of crosslinking the hydrogel, one or more phenol groups introduced into the side chains of the polymer are bonded to each other through an enzymatic crosslinking reaction between an enzyme and hydrogen peroxide, and crosslinked. Specifically, a rod-shaped hydrogel may be formed through the step of crosslinking the hydrogel.

[0034] The polymer is any one or more polymers selected from the group consisting of gelatin, chitosan, heparin, cellulose, dextran, dextran sulfate, chondroitin sulfate, keratan sulfate, dermatan sulfate, alginic acid, collagen, albumin, fibronectin, laminin, elastin, vitronectin, hyaluronic acid, fibrinogen, and hyperbranched polymers.

[0035] The enzyme includes one or more selected from the group consisting of horseradish peroxidase, glutathione peroxidase, haloperoxidase, myeloperoxidase, catalase, hemoprotein, peroxide, peroxiredoxin, animal heme-dependent peroxidases, thyroid peroxidase, vanadium bromoperoxidase, lactoperoxidase, tyrosinase, and catechol oxidase.

[0036] The content of the polymer is 10 to 30 wt % or 15 to 25 wt %.

[0037] The content of the hydrogen peroxide is 0.02 to 0.08 wt%, 0.03 to 0.07 wt%, or 0.035 to 0.06 wt%.

[0038] The concentration of the enzyme is 0.001 to 0.005 mg / ml or 0.002 to 0.004 mg / ml.

[0039] As described above, the injectable hydrogel rod prepared according to the present invention by mixing a polymer, an enzyme and hydrogen peroxide exhibits a crosslinking degree of 20-100%, 30-80%, 40-70% or 45-60%, and thus the hydrogel rod exhibits sustained release characteristics for more than 3 months by controlling the initial release rate to 10% or less, 7% or less or 5% or less.

[0040] In the step of separating from the mold, the rod-shaped hydrogel may be separated from a mold made of one selected from the group consisting of gelatin, metal, and Teflon.

[0041] Specifically, in the step of separating from the mold, gelatin may be dissolved at a temperature of 30 to 40° C., and the gelatin mold may be removed to separate the rod-shaped hydrogel.

[0042] Alternatively, the step of separating the hydrogel from the mold may involve extruding the hydrogel rod into a rod-shaped mold made of metal or Teflon material.

[0043] The freeze-drying can be carried out at a temperature of -70 to -85°C for 12 to 24 hours to produce a hydrogel rod.

[0044] The present invention will be described in detail below with reference to examples to aid in understanding the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those skilled in the art.

[0045] Examples and Comparative Examples

[0046] To manufacture an injectable Gelatin-PEG-Tyramine (GPT) hydrogel rod-shaped drug delivery vehicle, temperature-sensitive gelatin was used as a mold (Figure 1(a)). A needle was fixed in the well of a 48-well plate, and a gelatin solution (10 wt%) at 37°C was added to the outside of the needle, and then the gelatin mold was formed by refrigerating it at 4°C. 1 mL of bevacizumab at a concentration of 25 mg / mL was freeze-dried and dissolved in 250 μL of GPT polymer solution to prepare a GPT polymer solution mixed with the bevacizumab drug at a concentration of 100 mg / mL. Among them, 15μL of GPT polymer solution loaded with 1500μg of bevacizumab was mixed with HRP and H2O2 in a ratio of 9:0.5:0.5, and a total volume of 16.67μL was used to prepare a hydrogel rod. After removing the needle, the GPT hydrogel solution mixed with the bevacizumab drug was added to the inside of the mold to proceed with enzymatic crosslinking. Bevacizumab was loaded at 1500μg, and the concentrations of GPT polymer, HRP, and H2O2 were used as shown in Table 1 below. The phase transition in the mold was proceeded using an enzymatic crosslinking method using HRP / H2O2. After 2 hours of incubation, the gelatin mold was dissolved at 37℃ to obtain a crosslinked GPT hydrogel rod (Figure 1(b)), which was then freeze-dried and stored. To develop an injector for injecting hydrogel rods, a Hamilton syringe wire was attached to the plunger of a 1 ml syringe. The injector can be applied in a similar manner to the commonly used product Ozurdex (Figure 1(c)).

[0047] [Table 1]

[0048] Experimental Example 1 - Mechanical properties

[0049] As shown in FIG. 1, when hydrogel rods were prepared using the compositions of the Example, Comparative Example 1, and Comparative Example 2, the polymer concentration was low in Comparative Example 1 and Comparative Example 2, resulting in insufficient polymer chains during rod preparation, and the rod shape was not maintained after freeze-drying. However, as can be seen from FIG. 1(b), in the case of Example 1, a hydrogel rod was prepared under optimal conditions.

[0050] In order to confirm the mechanical properties of the injectable hydrogel rod of the present invention by adjusting the crosslinking degree, the final concentration of H2O2 used for crosslinking was adjusted to 0.02, 0.04, and 0.08 wt% in Example 1 to adjust the theoretical crosslinking degree to 25, 50, and 100%, as shown in Figure 2(a). Before crosslinking, 300 μL of GPT hydrogel was injected into the plate of a rheometer, and the change in mechanical properties over time due to the progress of crosslinking was measured using a rheometer. As a result, as shown in Figure 2(b), the mechanical properties of the matrix increased to 0.6, 8.1, and 15 kPa, respectively, due to the increase in the theoretical crosslinking degree.

[0051] Experimental Example 2: Evaluation of drug release control by diversifying crosslinking conditions of hydrogel rods

[0052] 2-1. Evaluation of drug release control by adjusting the degree of crosslinking

[0053] Following the evaluation of the adjustment of physical properties by adjusting the crosslinking degree of the injectable hydrogel rod, we proceeded to evaluate the control of bevacizumab release. Hydrogel rods formed according to the degree of crosslinking were cultured in DPBS (37℃, 100 rpm), and DPBS samples containing the released bevacizumab were obtained at the designated time points for 120 days, frozen and stored, and then fresh DPBS solution was added. The obtained samples were quantitatively analyzed using ELISA (Enzyme Linked Immunosorbent Assay) technique, which can specifically quantify bevacizumab, an anti-VEGF agent.

[0054] As shown in Figure 3(a), the results of in vitro drug release from hydrogel rods for 120 days under conditions of H2O2 concentrations of 0.02, 0.04, and 0.08wt%, which allow for the adjustment of the degree of crosslinking, showed that the amount of drug released over time decreased with increasing degree of crosslinking. Specifically, the pharmacological threshold of bevacizumab is known to be about 1μg / mL (IOVS, October 2008, Vol. 49, No. 10), and under the 0.02wt% condition, a very excessive amount above the threshold was released until the first 14 days, under the 0.08wt% condition, a trace amount below the threshold was released, and under the 0.04w% condition, the amount of drug released was approximately 10μg / mL, which satisfied the threshold, and thereafter the amount of drug released was adjusted according to the degree of crosslinking.

[0055] As shown in FIG. 3(b), the cumulative release up to 120 days showed that the initial burst release and release rate decreased in proportion to the degree of crosslinking, with the most suitable release pattern being at 0.04 wt%.

[0056] 2-2. Comparative evaluation of drug release in Examples and Comparative Examples

[0057] The drug release behavior of the hydrogel rod of the embodiment (pre-crosslinked hydrogel rod) and the injectable hydrogel of the comparative example (in situ forming hydrogel) was compared. Using the same conditions of polymer (GPT 20wt%) and crosslinking conditions (H2O20.04wt%), 1500μg of bevacizumab was loaded and the release was evaluated. Referring to (a) and (b) of FIG. 4, the injectable hydrogel of the comparative example was injected into DPBS (37℃, 100rpm) using a well plate insert just before crosslinking to mimic the minimally invasive injection environment in the body, and the hydrogel rod was cultured in DPBS (37℃, 100rpm). Referring to (c) of FIG. 4, the results of evaluation through ELISA after 30 days of cumulative release showed that the injectable hydrogel of the comparative example showed a cumulative release of more than 60% by 30 days after an initial over-release of about 40% by 3 days. This indicates that when the injectable hydrogel is injected, it is diluted with the media solution, resulting in less than the desired degree of crosslinking, which allows the drug to diffuse rapidly into the surrounding medium. On the other hand, the hydrogel rod of the embodiment was used in a crosslinked state, minimizing the initial release to less than 5%, with a cumulative release of about 20% up to 30 days. These results indicate that the hydrogel rod has the advantage of suppressing initial release and providing sustained release over a long period of time.

[0058] As described above, a comparative evaluation was conducted with the non-rod-shaped injectable hydrogel of the comparative example. As a result, it was found that the injectable hydrogel of the comparative example is a material that undergoes a phase transition after minimally invasive injection and releases the loaded drug quickly at an initial stage, whereas the hydrogel rod of the present invention can be injected minimally invasively and can be applied in a form that is crosslinked to a predetermined targeted degree, preventing the loaded drug from being released quickly at an initial stage and demonstrating a sustained release for more than four months.

[0059] Experimental Example 3: Evaluation of long-term efficacy and biological stability of released drugs

[0060] The long-term efficacy and biological stability of the released drug were evaluated through the culture of Human Umbilical Vein Endothelial Cells (HUVECs), which are cells involved in angiogenesis. After culturing HUVECs, 2 × 10 4 After preparing cells / well, the long-term release bevacizumab drug sample, diluted 1:1 in cell culture medium (EBM media containing EGM supplements and 1% P / S), and fresh bevacizumab drug samples of different concentrations were treated to observe cell growth inhibition and safety. Fresh bevacizumab drug sample control groups were prepared by diluting the final concentrations in cell culture medium to 1, 10, and 100 μg / mL.

[0061] Figure 5 (a) shows the results of WST-1 assay, which confirmed that cell growth was inhibited in proportion to the drug concentration, and evaluated the long-term cell growth inhibition by the drug released from the injectable hydrogel of the comparative example and the hydrogel rod of the example. Also, as shown in Figure 5 (b), the Live / Dead assay confirmed that there was almost no toxicity to cells, and the fluorescence image confirmed that cell growth was inhibited compared to the culture medium cell group.

[0062] Through this, the injectable hydrogel of the comparative example showed a rapid release of more than 40% of the loaded drug initially, followed by an excessive release, showing a high inhibition of cell growth initially, whereas the hydrogel rod of the embodiment showed a controlled initial release rate and a sustained release pattern for more than four months, demonstrating medicinal efficacy through long-term inhibition of cell growth.

[0063] Experimental Example 4 - Animal studies and evaluation of intraocular pharmacokinetics

[0064] 4-1. Animal experiment planning

[0065] As shown in Figure 6, using a New Zealand White (NZW) rabbit model, injections were performed on both eyes (two rabbits, total of four eyes) on days 1, 4, 8, 14, 30, 60, 90, and 120. A bevacizumab drug control group, a comparative hydrogel (in situ forming hydrogel), and an example hydrogel rod were injected. To maintain efficacy, the drug must be maintained at a concentration in the vitreous humor and retina, and at the same time, the drug is excreted into the anterior chamber. For evaluation, the animals were sacrificed and the eyes were dissected on a daily basis, and pharmacokinetic analysis of the vitreous, retina, and aqueous humor tissues was performed using ELISA.

[0066] 4-2. Results of intraocular pharmacokinetic evaluation

[0067] After sacrificing the animals and dissecting the eyes every day, pharmacokinetic analysis of the vitreous, retina, and aqueous humor tissues was performed by ELISA. As shown in FIG. 7(a), the initial burst release in the vitreous was significantly decreased in the order of the control group, the comparative hydrogel (in situ forming hydrogel), and the hydrogel rod of the embodiment, and the control group showed the fastest elimination curve. The injectable hydrogel of the comparative embodiment showed a decrease in initial burst release by about 2 times compared to the control group, but a high release amount was maintained due to dilution with tissue fluid during injection, and it could not be sustained for more than 30 days. The hydrogel rod of the embodiment is a pre-crosslinking matrix, and after the initial burst release was suppressed by 7 times compared to the control group and 3 times compared to the comparative hydrogel, it released the drug continuously within a certain range and maintained a drug concentration of about 32 μg / mL on the 120th day, which met the 1 μg / mL or more that is known as the therapeutic threshold of bevacizumab.

[0068] As shown in FIG. 7(b), the initial burst release in the retina was significantly decreased in the order of the control group, the hydrogel of the comparative example (in situ forming hydrogel), and the hydrogel rod of the embodiment, with the control group showing the fastest excretion curve. The hydrogel of the comparative example (in situ forming hydrogel) showed an initial burst release that was reduced by about 4 times compared to the control group, and maintained a low drug concentration until 60 days. It was confirmed that the hydrogel rod of the embodiment showed a burst release that was reduced by 10 times compared to the control group and by about 2 times compared to the hydrogel of the comparative example (in situ forming hydrogel), and was sustained for 120 days, maintaining the drug efficacy at a concentration of about 0.08 μg / g.

[0069] As shown in FIG. 7(c), an initial excessive discharge into the aqueous humor occurred in the control group, and was maintained up to 30 days. The hydrogel of the comparative example (in situ forming hydrogel) showed an initial burst release due to phase transition, resulting in an excessive discharge (~80 μg / mL) similar to that of the control group. The hydrogel rod of the embodiment showed a maximum discharge that was approximately 80 times lower than that of the control group and the hydrogel of the comparative example (in situ forming hydrogel) due to minimization of the initial burst release by pre-crosslinking.

[0070] FIG. 7(d) shows a quantitative table of drug concentration in each tissue.

[0071] As shown in the above results, the injectable hydrogel of the comparative example showed a high initial burst release and was discharged into the surrounding tissues, making it difficult to maintain the efficacy for a long period of time. On the other hand, the hydrogel rod of the embodiment suppressed the initial burst release when injected and showed a sustained release of more than the effective concentration for 4 months, which resulted in a significant reduction in discharge into the surrounding tissues. Based on this, it is possible to overcome problems with side effects such as systemic side-effects caused by excessive discharge and inflammation caused by frequent injections for the purpose of efficacy.

[0072] Experimental Example 5 - Analysis of intraocular morphological stability and safety

[0073] Ultrasound analysis was performed to analyze the morphological stability and safety by day after intraocular hydrogel rod injection. As shown in Figure 8, the daily imaging results showed that the morphology of the hydrogel rod was stably maintained up to 120 days, and that from 60 days, the size began to decrease due to degradation within the body. No inflammatory reaction or side effects occurred within the body up to 120 days, demonstrating safety and morphological stability within the body.

[0074] The hydrogel of the comparative example was diluted with surrounding tissue fluids before complete phase transition after injection, making it difficult to maintain its shape, and there was a risk of side effects due to adhesion with surrounding tissues during the phase transition. However, the hydrogel rod of the example was confirmed to be injected in the form of a crosslinked rod and to exhibit a stable shape and safety in the body for four months.

[0075] As described above, certain parts of the present invention have been described in detail, but it is obvious to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the claims and their equivalents.

Claims

1. a rod-shaped hydrogel matrix made of a polymer substituted with a phenol derivative, in which the phenol derivatives introduced into the side chains of the polymer are bonded to each other and crosslinked; a drug loaded within the hydrogel matrix; An injectable hydrogel rod comprising:

2. The hydrogel rod according to claim 1, characterized in that the hydrogel rod exhibits sustained release characteristics for three months or more by controlling the initial release rate to 10% or less.

3. The hydrogel rod of claim 1, wherein the polymer is one or more polymers selected from the group consisting of gelatin, chitosan, heparin, cellulose, dextran, dextran sulfate, chondroitin sulfate, keratan sulfate, dermatan sulfate, alginic acid, collagen, albumin, fibronectin, laminin, elastin, vitronectin, hyaluronic acid, fibrinogen, and hyperbranched polymers.

4. The body-injectable hydrogel rod according to claim 1, wherein the phenol derivative is one or more selected from the group consisting of hydroxyphenylpropionic acid, 4-hydroxyphenylacetic acid, tyrosine, tyramine, tetronic acid tyramine, and PEG-tyramine.

5. The injectable hydrogel rod of claim 1, wherein the drug is one or more drugs selected from a protein therapeutic preparation that can be injected into the eye, a chemical drug, a small molecule therapeutic agent, a gene, a cell, or a cell-derived substance.

6. The hydrogel rod according to claim 1, wherein the hydrogel is formed into a rod-shaped hydrogel matrix by adjusting the concentrations of polymers, enzymes and hydrogen peroxide.

7. The hydrogel rod according to claim 1, wherein the hydrogel matrix has a cross-linking degree of 20 to 100%.

8. An implant material that can be injected into the body, comprising the hydrogel rod according to claim 1.

9. The implant material according to claim 8, wherein the implant material is applied to any one selected from the group consisting of inside the eyeball, extraocular body space, subcutaneous tissue, and inside other organs.

10. An ocular injectable implant material comprising the hydrogel rod of claim 1.

11. A drug delivery device comprising the hydrogel rod of claim 1.

12. preparing a mold having rod-shaped holes; preparing a solution in which a phenol derivative-substituted polymer, a drug, and an enzyme are dissolved; sequentially injecting the dissolving solution and hydrogen peroxide into the holes in the mold, and then crosslinking the hydrogel; separating the crosslinked hydrogel from the mold; and freeze-drying the separated hydrogel to prepare a hydrogel rod. The method for producing a hydrogel rod for injection into the body is characterized in that the mixing ratio of the polymer in which a phenol derivative is substituted, the enzyme, and hydrogen peroxide is 10:0.1-0.5:0.1-0.5 by volume.

13. The method for producing an injectable hydrogel rod according to claim 12, wherein the step of crosslinking the hydrogel comprises crosslinking one or more phenol groups introduced into the side chains of the polymer by binding to each other through an enzymatic crosslinking reaction between an enzyme and hydrogen peroxide.

14. The method for producing a hydrogel rod to be injected into the body according to claim 12, wherein the enzyme comprises one or more selected from the group consisting of horseradish peroxidase, glutathione peroxidase, haloperoxidase, myeloperoxidase, catalase, heme protein, peroxide, peroxiredoxin, animal heme-dependent peroxidase, thyroid peroxidase, vanadium bromoperoxidase, lactoperoxidase, tyrosinase, and catechol oxidase.

15. The method for producing a hydrogel rod to be injected into the body according to claim 12, characterized in that the polymer is one or more polymers selected from the group consisting of gelatin, chitosan, heparin, cellulose, dextran, dextran sulfate, chondroitin sulfate, keratan sulfate, dermatan sulfate, alginic acid, collagen, albumin, fibronectin, laminin, elastin, vitronectin, hyaluronic acid, fibrinogen, and hyperbranched polymers.

16. The method for producing a hydrogel rod for injection into the body according to claim 12, wherein the content of the hydrogen peroxide is 0.02 to 0.08 wt %.

17. The method for producing a hydrogel rod for injection into the body according to claim 12, wherein the content of the polymer is 10 to 30 wt %.

18. 13. The method of claim 12, wherein the gelatin is dissolved at a temperature of 30 to 40° C. in the separating step.

19. The method for producing a hydrogel rod to be injected into the body according to claim 12, characterized in that the freeze-drying is carried out at a temperature of -70 to -85°C for 12 to 24 hours.

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