KR102183669B1 - Drug delivery carrier for dual drug release - Google Patents

Abstract

The present invention relates to a drug delivery system for dual drug release, and more particularly, a core rod in which a first drug and a first biocompatible polymer are mixed, and a second drug and a second biocompatible polymer are mixed. It relates to a drug delivery system in which drugs are not only sequentially released, but also continuously released by a shell structure.
According to the drug delivery system according to the present invention, it is possible to reduce the number of drug administration by allowing the dual drugs to be released sequentially/continuously, thereby minimizing side effects.

Description

Drug delivery system for dual drug release {DRUG DELIVERY CARRIER FOR DUAL DRUG RELEASE}

The present invention relates to a drug delivery system for dual drug release, and more particularly, a core rod in which a first drug and a first biocompatible polymer are mixed, and a second drug and a second biocompatible polymer are mixed. It relates to a drug delivery system that can be released continuously as well as sequentially by the shell structure.

Recently, research on a drug delivery system based on a core-shell structure is receiving interest. However, since controlling the release patterns of two or more drugs has not yet been specifically studied, achieving effective treatment still has limitations.

On the other hand, in general, the nerve tissue located in the center of the inner retina of the eye is called the macula, and most of the eye cells are gathered here, and the place where the image of the object is formed is the macula, which plays a very important role in vision. An eye disease that causes visual impairment due to various causes of the macular degeneration is called macular degeneration (symptoms), and macular degeneration is known as one of the three major blindness diseases along with glaucoma and diabetic retinopathy. Such macular degeneration affects central vision, making the center of the field of view blurry, central dark spots, dystrophy (a symptom that looks distorted), or loss of vision in a local area, making it difficult to perform sophisticated activities such as reading and driving. , It is a very serious disease that leads to blindness in severe cases.

Currently, in order to treat these macular degeneration and diabetic retinopathy, intraocular lucentis (ingredient name: Ranibizumab), Avastin (ingredient name: Becacizumab), and Ilia (ingredient name: Aflibercept) injection are being performed, and diabetic retinopathy ( For vitreous hemorrhage and macular edema), Lucentis, Avastin, Ilia, as well as Ojudex and Triamsilon injections are performed. However, such a conventional treatment method has a problem that the therapeutic effect due to drug injection is only maintained for less than 1 month, and the therapeutic effect is insufficient with only one type of drug. Therefore, there is a concern that the intraocular drug injection should be repeatedly performed using only the conventional method, increasing the risk of complications such as intraocular bleeding and intraocular infection, thereby reducing the original treatment effect. In addition, for intraocular uveitis treatment, dexamethasone or triamcilone is injected into some of the eyeballs, but the effect is not sustained and treatment is limited, so the treatment is mainly treated with systemic immunosuppressants or systemic steroids. There is a problem.

Under this background, studies on drug delivery systems or complexes for the treatment of ocular diseases such as macular degeneration diabetic retinopathy and uveitis have been actively conducted, but the situation is still insufficient.

Korean Patent Registration No. 10-1809939

In the present invention, drugs are sequentially released by a core rod in which a first drug and a first biocompatible polymer are mixed, and a shell structure in which a second drug and a second biocompatible polymer are mixed. It provides a drug delivery system that can be continuously released.

The present invention includes a core rod in which a first drug and a first biocompatible polymer are mixed; And a shell in which a second drug and a second biocompatible polymer are mixed, wherein the first biocompatible polymer comprises a hydrogel, and is decomposed more rapidly than the second biocompatible polymer. It provides a drug delivery system for dual drug release.

The hydrogel may include one or more selected from the group consisting of collagen, laminin, fibronectin, alginate pluronic, hyaluronic acid, and gelatin.

The second biocompatible polymer is polycaprolactone, polylactic acid, polyglycolic acid, polylactate-co-glycolic acid, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly( It may contain at least one selected from the group consisting of L-lactide co-caprolactone) and poly(L-lactide-co-D-lactide).

In addition, the present invention is a core rod in which the first drug and the first biocompatible polymer are mixed; And a shell in which a second drug and a second biocompatible polymer are mixed, wherein the first biocompatible polymer comprises a hydrogel and is decomposed faster than the second biocompatible polymer. The first drug and the second drug provide a drug delivery system for preventing or treating eye diseases, characterized in that it is selected from an inflammation inhibitor or a VEGF inhibitor.

In addition, a core rod in which the first drug and the first biocompatible polymer are mixed; And a shell in which a second drug and a second biocompatible polymer are mixed, wherein the first biocompatible polymer comprises a hydrogel and is decomposed faster than the second biocompatible polymer. One drug contains an inflammation inhibitor, and the second drug provides a drug delivery system for preventing or treating macular degeneration, characterized in that it contains a VEGF inhibitor.

The drug delivery system according to the present invention is a shell structure in which a first drug, a core rod mixed with a first biocompatible polymer, and a second drug and a second biocompatible polymer are mixed, and the first drug and the second drug are sequentially By implementing the second drug to be continuously released at the same time as it is released, the number of times of drug administration may be reduced, thereby minimizing side effects.

In particular, when the drug delivery system according to the present invention is applied for the treatment of eye diseases, a drug such as bevacizumab, which is currently administered for 4 weeks, is continuously secreted at a concentration suitable for the treatment purpose for at least 2 months with only one administration. Since it can increase the therapeutic effect of drugs, it can be used as a core technology for treating eye diseases such as macular degeneration and diabetic retinopathy.

In addition, when treating eye diseases such as macular degeneration, diabetic retinopathy, and macular edema caused by retinal vascular obstruction, steroid drugs such as dexamethasone or drugs such as bevacizumab that inhibit angiogenesis are respectively administered or if there is no effect. Although a method of sequentially injecting two drugs into the eye, respectively, is applied, according to the present invention, since it is possible to sequentially release double drugs, there is an advantage that the same effect can be achieved with one administration.

In addition, since it is possible to adjust the size of the core load-shell and the amount of drugs loaded therein by using 3D printing technology, it can be used for the treatment of other diseases as well as the treatment of eye diseases by changing them as needed. For example, bevacizumab, which is also used as an anticancer treatment, can be used for anticancer treatment.

1 and 2 are schematic diagrams schematically showing a manufacturing process of a drug delivery system having a core rod-shell structure of the present invention.
3 is an image schematically illustrating a process of manufacturing a drug delivery system having a core rod-shell structure using 3D printing technology.
4 is a result of analyzing the drug release rate of the drug delivery system according to an embodiment of the present invention.
5 is a result of comparing the inhibitory effect of angiogenesis by a drug delivery system having a core load-shell structure and a bevacizumab drug through fluorescence images.
FIG. 6 is a result of comparing the remaining amount of bevacizumab in rabbit eyes each injected with a drug delivery system having a core load-shell structure and a bevacizumab drug over time.
7 is a result of comparing the tensile modulus of a biocompatible polymer that can be applied to a drug delivery system having a core load-shell structure according to the present invention.
FIG. 8 is a result of comparing the residual amount of dexamethasone in the rabbit eye to which the drug delivery system of the core load-shell structure and the dexamethasone drug were respectively injected over time.
Figure 9 shows the process of measuring the dose of bevacizumab using ELISA technology.

Hereinafter, the present invention will be described in detail.

The present invention includes a core rod in which a first drug and a first biocompatible polymer are mixed; And it provides a drug delivery system including a shell (Shell) in which the second drug and the second biocompatible polymer are mixed. Here, the first biocompatible polymer may include a hydrogel. In addition, the first biocompatible polymer may be decomposed faster than the second biocompatible polymer.

The biocompatible polymer may be degraded in vivo.

The drug delivery system can control the release rate of the drug by controlling the composition ratio of the biocompatible polymer and the drug.

The core rod may have a form in which a crosslinking agent is further mixed in addition to the first drug and the first biocompatible polymer, and as the crosslinking agent, a material having divalent ions such as calcium chloride, calcium carbonate or sodium chloride, or a mixture thereof may be used. have.

The first biocompatible polymer may be included in an amount of 0.6 to 1.54% by weight based on the total weight of the core rod. If it is less than the above range, there is a problem that the crosslinking of the hydrogel is completely crosslinked by the crosslinking agent, so that injection into the drug delivery system is not possible. There is a problem that it cannot maintain its shape and may leak out.

The second biocompatible polymer may be included in an amount of 75 to 90% by weight based on the total weight of the shell. If the amount is less than the above range, there is a problem that the drug delivery system cannot maintain the rod shape during the 3D printing process, and if it is included more than the above range, there is a problem that the printing efficiency of the polymer solution decreases during the printing process.

The decomposition rate of the core rod may be 3 to 14 (days), and the decomposition rate of the shell may be 2 to 24 (months). If it is lower than the above range, there is a problem that the drug injection must be repeatedly performed within a short period of time, and if it is higher than the above range, there is a problem that the drug delivery system having the core load-shell structure must be removed through surgery.

The hydrogel may contain one or more selected from the group consisting of collagen, alginate pluronic, hyaluronic acid, and gelatin.

The second biocompatible polymer is polycaprolactone, polylactic acid, polyglycolic acid, polylactate-co-glycolic acid, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly( It may contain at least one selected from the group consisting of L-lactide co-caprolactone) and poly(L-lactide-co-D-lactide).

The first drug and the second drug may be selected from the group consisting of an inflammation inhibitor, a vascular endothelial growth factor (VEGF) inhibitor, drugs and compounds having an effect equivalent to the drug, and various other drugs. .

The inflammation inhibitor may be selected from the group consisting of dexamethasone, betamethasone, methylprednisolone and ketorolac.

The VEGF-targeted therapeutic agent may be selected from the group consisting of bevacizumab, ranibizumab, and applivalcept.

The drug delivery system has the advantage of being capable of loading all drugs including anticancer agents, and thus can be used as a cancer treatment agent or an eye disease treatment agent.

The cancer treatment may be applied to at least one selected from the group consisting of colon cancer, kidney cancer, uterine cancer, brain cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, liver cancer, or esophageal cancer.

In addition, the present invention, a first drug and a first biocompatible polymer is mixed with a core rod (Core rod); And it provides a drug delivery system for preventing or treating eye diseases, including a shell in which a second drug and a second biocompatible polymer are mixed. The first biocompatible polymer includes a hydrogel, and may be decomposed faster than the second biocompatible polymer. The first drug and the second drug may be selected from an inflammation inhibitor or a VEGF inhibitor.

Specifically, as shown in Figure 1, the drug delivery system according to an embodiment of the present invention is a core rod loaded with a first drug for primary drug treatment of eye diseases and a core rod for secondary drug treatment. It may be configured to include a shell structure loaded with the second drug, and these drugs may be mixed with a biocompatible polymer in an appropriate composition ratio.

By adopting such a configuration, the drug delivery system according to the present invention not only can administer the first treatment drug and the second treatment drug at once, but each of them is appropriately mixed with a biocompatible polymer, resulting in a sustained drug release effect. As can be obtained, it is possible to minimize side effects and maximize the therapeutic effect of the drug by reducing the number of administration of drugs for the treatment of eye diseases.

In the case of the drug delivery system, since the first drug carried on the core rod may be released first and then the second drug may be released, it is possible to treat diseases requiring treatment through complex drug treatment, such as macular degeneration and diabetic retinopathy. It can be usefully used as a drug delivery system.

In particular, the drug delivery system according to the present invention can be freely modified in its configuration according to the type of eye disease for which treatment is intended. As an example, when the eye disease is macular degeneration, the second drug loaded in the shell is a VEGF inhibitor such as avastin (bevacizumab), and the first drug loaded in the core rod is dexamethasone. It may be an inhibitor of inflammation.

On the other hand, when the eye disease is diabetic retinopathy and macular edema due to retinal vessel occlusion, the second drug loaded on the shell and the first drug loaded on the core rod are VEGF inhibitors such as dexamethasone and avastin (bevacizumab), respectively. Can be injected in a patient-specific form.

As the drug, if necessary, Humira (Adalimumab), Remicade (Infliximab), interferon alpha (IFN-α), etc. may be applied to the core rod or shell by replacing the avastin or dexamethasone, but is not limited thereto.

The above modification is determined according to which of the anti-angiogenic effect of VEGF inhibitors such as Avastin and the anti-inflammatory effect of inflammatory inhibitors such as dexamethasone is preferentially applied to the disease. , Preferably, macular degeneration (senile, myopic), diabetic retinopathy (proliferative diabetic retinopathy, diabetic retinal edema), retinal edema including branch or central vein occlusion, retinal edema including branch or central artery occlusion, Non-infectious autoimmune uveitis (including HLAB27, HLA B51, sarcoidosis, Harada's disease, etc.)idiopathic uveitis, non-infectious nonautoimmune uveitis, macular edema due to uveitis, refractory uveitis, tuberculous uveitis, uveitis due to HIV or syphiis May be treated as a disease to be treated, but any eye disease to which the above treatment method is applied may be included without limitation.

When the drug delivery system is applied to prevent or treat macular degeneration, a core rod in which a first biocompatible polymer including a hydrogel and an inflammation inhibitor are mixed; And, it may be composed of a shell structure in which the second biocompatible polymer and the VEGF inhibitor are mixed. At this time, the first biocompatible polymer decomposes faster than the second biocompatible polymer.

The core rod may have a diameter of 235 to 337 μm.

The shell may have a thickness of 50 to 102 μm.

The diameter of the drug delivery system having the core rod-shell structure may have a diameter of 311 to 412 μm. If the diameter is smaller than the above, there is a problem that the intraocular pressure can be increased when the drug delivery system having the core rod-shell structure is injected. If it is formed larger than the above range, it may be dangerous when injecting a drug delivery system having a core load-shell structure and cause discomfort to the patient.

The core rod may be a form in which a crosslinking agent is further mixed in addition to the first drug and the first biocompatible polymer, and a material having divalent ions such as calcium chloride, calcium carbonate or sodium chloride, or a mixture thereof may be used as the crosslinking agent. have.

The first biocompatible polymer may be included in an amount of 0.6 to 1.54% by weight based on the total weight of the core rod.

If it is less than the above range, there is a problem that the crosslinking of the hydrogel is completely crosslinked by the crosslinking agent, so that injection into the drug delivery system is not possible. There is a problem that it cannot maintain its shape and can be counted out.

The second biocompatible polymer may be included in an amount of 75 to 90% by weight based on the total weight of the shell. If it is included less than the above range, there is a problem that the drug delivery system cannot maintain the rod shape during the printing process, and if it is included more than the above range, there is a problem that the printing efficiency of the polymer solution is deteriorated during the printing process.

The decomposition rate of the core rod may be 3 to 7 (days), and the decomposition rate of the shell may be 2 to 24 (months). If it is lower than the above range, there is a problem that drug injection must be repeatedly performed within a short period of time, and if it is higher than the above range, there is a problem that the drug delivery system having the core load-shell structure must be removed through surgery.

Currently, in the treatment of macular degeneration, dexamethasone is administered first to suppress inflammation, and then a drug such as bevacizumab is administered secondarily to suppress angiogenesis, and the administration cycle of bevacizumab (avastin) is known to be 4 weeks.

The drug delivery system according to the present invention can continuously secrete a drug such as bevacizumab, which is known to have an administration cycle of 4 weeks, at a constant concentration for at least 2 months with only one administration, thereby increasing the therapeutic effect of the drug, and also sequentially Since dual drug release is possible, there is an advantage that the first drug and the second drug can be administered at once.

More specifically, in the case of the drug delivery system for the treatment of macular degeneration according to the present invention, the core rod in which the first biocompatible polymer and the inflammation inhibitor are mixed is rapidly released (within about 7 days) at the beginning of the administration, and the second biocompatible polymer and VEGF Shells incorporating are more slowly and continuously released (about 2 months or longer).

By adopting such a configuration, the drug delivery system according to the present invention not only can administer the first treatment drug and the second treatment drug at once, but each of them is appropriately mixed with a biocompatible polymer, resulting in a sustained drug release effect. As can be obtained, it is possible to minimize side effects and maximize the therapeutic effect of the drug by reducing the number of administration of drugs for the treatment of eye diseases.

In addition, the present invention, the first drug and a biocompatible polymer is mixed with a core rod; And it provides a method of manufacturing a drug delivery system using a 3D printing technology, including a shell in which a second drug and a second biocompatible polymer are mixed.

In addition, the present invention, the use of the drug delivery system for the treatment of eye diseases; A composition for treating eye diseases comprising the drug delivery system; And administering a therapeutically effective amount of the drug delivery system to the individual.

The term "treatment" used in the present invention refers to all actions in which symptoms for eye diseases are improved or advantageously changed by administration of the drug delivery system according to the present invention.

In the present invention, "individual" means a subject in need of treatment of a disease,

More specifically, it means mammals such as human or non-human primates, mice, dogs, cats, horses and cattle.

The drug delivery system carrying the double-drug of the present invention can be administered parenterally during clinical administration and can be used in the form of a professional pharmaceutical formulation. Parenteral administration may mean administration through a route other than oral administration such as rectal, intravenous, peritoneal, muscle, arterial, transdermal, nasal, inhalation, ocular and subcutaneous. When the drug delivery system carrying the double-drug of the present invention is used as a pharmaceutical product, it may further contain one or more active ingredients exhibiting the same or similar function.

That is, the drug delivery system carrying the dual-drug of the present invention can actually be administered in various parenteral formulations.When formulated, a diluent such as a commonly used filler, extender, binder, wetting agent, disintegrant, or surfactant, or It is formulated using excipients. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for the suppository, Witepsol, Macrogol, Tween 61, cacao butter, liurinji, glycerogelatin, and the like may be used.

In addition, the drug delivery system carrying the double-drug of the present invention may be used in combination with various carriers allowed as drugs such as physiological saline or organic solvents, and glucose, sucrose or dex in order to increase stability or absorption. Carbohydrates such as tran, antioxidants such as Ascorbic acid or Glutathione, chelating agents, small molecule proteins or other stabilizers may be used as pharmaceuticals.

The effective dose of the drug delivery system carrying the double-drug of the present invention may be 0.01 to 100 mg/kg, and preferably 0.1 to 10 mg/kg. In the pharmaceutical composition of the present invention, the total effective amount of the drug delivery system carrying the dual-drug of the present invention can be administered to a patient as a single dose, and multiple doses are administered for a long period of time. It can also be administered by a fractionated treatment protocol. Since the concentration is determined by taking into account various factors such as the patient's age and health condition, as well as the route of administration and the number of treatments of the drug, the effective dosage of the patient is determined. It will be possible to determine an appropriate effective dosage according to the specific use as a pharmaceutical composition of a drug delivery system carrying a double-drug of.

Hereinafter, the present invention will be described in more detail through examples. Objects, features, and advantages of the present invention will be easily understood through the following examples. The present invention is not limited to the embodiments described herein, but may be embodied in other forms. The embodiments introduced herein are provided in order to sufficiently convey the spirit of the present invention to those of ordinary skill in the art. Therefore, the present invention should not be limited by the following examples.

Example: Preparation of drug delivery system for dual drug release

The drug delivery system of the core rod-shell structure was prepared using polycaprolactone (PCL; Mw = 43000; Polysciences, Inc) as a shell component and sodium alginate (Sigma-Aldrich) as a core component. .

PCL was dissolved at 40% using a dichloromethane solvent, and bevacizumab was added at various concentrations (10 to 30% by weight of PCL). Alginate is dissolved in 6% using distilled water as a solvent, and then 30 mM calcium chloride to which dexamethasone of various concentrations (1800 ~ 3150% based on the weight of alginate) is added is mixed in a ratio of 1:4 to form a semi-solid state. Made material PCL (+bevacizumab) as a shell and Pluronic as a sacrificial core were prepared using 3D printing technology using a co-axial nozzle. The coaxial nozzle was used in the range of 19/14 gauge to 28/20 gauge, and air pressure of 5 to 200 KPa was used to print the shell, and air pressure of 400 to 600 KPa was used to print the sacrificial core. Then, laminar flow was applied to the printed structure for more than 30 minutes to completely remove dichloromethane, and then phosphate buffer saline (PBS) was injected to remove the pluronic, and the place was semi-solid. Alginate (+ dexamethasone) was injected to prepare a drug delivery system having a core load-shell structure loaded with two drugs. Alginate was injected using a 27-32 gauge needle.

Experimental Example 1: Analysis of drug release behavior 1

Using the same method as in Example 1, after preparing a drug delivery system having the structure as shown in FIG. 4A, after putting the drug delivery system in PBS, the PBS from which the drug was released was recovered for each time period, and this was performed with Elisa and high performance liquid chromatography. The drug release rate was analyzed through high-performance liquid chromatography (HPLC) and the results are shown in FIG. 4B. As a result of the experiment, it was confirmed that in the drug delivery system according to the present invention, the first drug (dexamethasone) constituting the core rod was rapidly released, and the second drug (bevacizumab) constituting the shell was slowly and continuously released. In addition, it was confirmed through Groups 1, 2, and 3 that when the first drug (dexamethasone) and the second drug (bevacizumab) were released at the same time, they did not affect each other.

Experimental Example 2: Analysis of angiogenesis inhibitory effect

The inhibitory effect of angiogenesis by the core rod-shell structured drug delivery vehicle (rod group) and bevacizumab drug (Ava group) was compared through fluorescence images, and the results are shown in FIG. 5. A core rod-shell structured drug delivery system and bevacizumab were treated in a rat model in which angiogenesis in the eye was induced through the first laser treatment, and 2 weeks later, the second laser treatment was performed again. The angiogenesis in the rat's eye was re-induced and the course was monitored for 2 weeks. The extraction of the eyes of the rats was performed 2 weeks after treatment with the drug delivery system of the core rod-shell structure and the drug bevacizumab and 2 weeks after the second laser treatment, and the extracted eyes were analyzed through marker expression. The formation of new blood vessels could be confirmed through the expression of Isolectin, and leukocytes could be identified through the expression of CD45. Two weeks after treatment with the drug, it was confirmed that both the drug bevacizumab (5a) and the drug delivery system of the core rod-shell structure (5b) inhibited the formation of angiogenesis, and a small number of drug delivery systems of the core load-shell structure Leukocytes were identified. In addition, it was confirmed that two weeks after the second laser treatment, treatment with the drug delivery system having a core load-shell structure was more effective than the treatment with the drug bevacizumab.

Experimental Example 3: Analysis of drug release behavior 2

After injecting the drug bevacizumab (avastin) and a drug delivery system having a core rod-shell structure (Example) into the rabbit eye, respectively, the release rate of the drug in the eye was analyzed, and the results are shown in FIG. 6. As shown in FIG. 6, it was confirmed that a larger amount of bevacizumab was continuously detected through a drug delivery system having a core load-shell structure.

Experimental Example 4: Analysis of physical properties of biocompatible polymers

The physical properties of the biocompatible polymer constituting the shell of the drug delivery system of the present invention were analyzed and the results are shown in FIG. 7. As shown in FIG. 7, since different types of polymers have different physical properties, a biocompatible polymer may be selected according to the purpose to be implemented.

Experimental Example 5: Analysis of drug release behavior 3

After injecting the drug dexamethasone and the drug carrier (Example) having a core rod-shell structure into the rabbit eye, respectively, the release rate of the drug in the eye was analyzed, and the results are shown in FIG. 8. As shown in FIG. 8, it was confirmed that dexamethasone was detected for a longer time through the drug delivery system having a core load-shell structure.

Experimental Example 6: Method of measuring the dose of bevacizumab

The process of measuring the dose of bevacizumab loaded on the drug delivery system of the present invention is shown in FIG. 9A. Through the process of FIG. 9A, the amount of bevacizumab loaded for each sample can be confirmed (FIG. 9B), and the amount of bevacizumab released for each time can be confirmed (FIG. 9C).

The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not limiting.

Claims (5)

A core rod in which dexamethasone and alginate are mixed; And a shell in which bevacizumab and polycaprolactone are mixed,
The alginate is characterized in that faster decomposition than the polycaprolactone, a drug delivery system for dual drug release.
delete delete A core rod in which dexamethasone and alginate are mixed; And a shell in which bevacizumab and polycaprolactone are mixed,
The alginate is decomposed faster than the polycaprolactone, a drug delivery system for preventing or treating eye diseases.
A core rod in which dexamethasone and alginate are mixed; And a shell in which bevacizumab and polycaprolactone are mixed,
The alginate decomposes faster than the polycaprolactone,
Drug delivery system for the prevention or treatment of macular degeneration.

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