Microneedle structure and composition thereof

Abstract

The present invention relates to a microneedle structure and a composition thereof, the microneedle structure comprising a biodegradable composition containing a medicinal substance and hyaluronidase so that the medicinal substance can be effectively delivered percutaneously, locally or throughout the body, through the dermal layers without injury to the skin.

Description

Microneedle structure and composition thereof

[0001] The present invention relates to a microneedle structure and a composition thereof.

[0002] Microneedles are a widely used drug delivery system. They offer the advantage of minimizing pain and improving therapeutic drug delivery speed through their mechanism of directing drugs to subcutaneous areas. Furthermore, they allow for localized drug injection, effectively targeting the targeted area.

[0003] However, in the case of soluble microneedle structures, the problem of limited loading capacity due to the limitation of drug application capacity has arisen, and various attempts have been made to solve this problem, but the quantitative drug delivery technology has not been solved.

[0004] Meanwhile, most transdermal microneedles are made of water-soluble polymers, resulting in minimal skin diffusion. Even for drugs with high skin diffusion, low solubility within the microneedle itself can hinder drug release through the skin. Furthermore, while penetration requires high needle strength, substances that enhance needle strength have difficulty dissolving in skin moisture, potentially causing injury. Furthermore, low drug diffusion requires higher concentrations compared to injections.

[0005] Therefore, there is an urgent need to develop a form that can effectively deliver drugs transdermally without causing damage to the skin.

[0006] The purpose of the present invention is to solve the above-described problem, and to provide a microneedle structure and composition thereof that can effectively deliver a drug locally or systemically through the dermis layer by percutaneously penetrating the skin without causing damage to the skin.

[0007] To achieve the above purpose, a microneedle structure composition according to one embodiment of the present invention comprises a drug and a biodegradable composition, wherein the biodegradable composition comprises hyaluronidase.

[0008] Here, the hyaluronidase may be included in an amount of 10 to 1500 IU per sheet.

[0009] A drug delivery microneedle structure according to another embodiment of the present invention comprises a substrate and one or more microneedles disposed on the substrate, wherein the microneedles contain a drug and a biodegradable composition, wherein the biodegradable composition contains hyaluronidase.

[0010] At this time, the microneedle can increase the transdermal absorption rate of the drug compared to the microneedle that does not contain hyaluronidase.

[0011] And, the above-mentioned substrate may have a thickness of 10 to 300 μm.

[0012] And, the microneedles may have a length of 100 to 1500 μm.

[0013] According to one embodiment of the present invention, a microneedle structure and its composition can effectively deliver a drug locally or systemically through the dermal layer by percutaneously penetrating the skin without causing damage to the skin by including a biodegradable composition containing a drug and hyaluronidase.

[0014] Additionally, side effects can be minimized and efficacy maximized by controlling the drug release rate or delivering the drug to the target area in the appropriate amount as needed.

[0015] FIG. 1 is a cross-sectional view schematically showing a microneedle structure according to an embodiment of the present invention.

[0016] Figure 2 is a diagram showing the results according to Experimental Example 1.

[0017] Figures 3a and 3b are optical microscope photographs showing the results according to Experimental Example 1.

[0018] Hereinafter, the present invention will be described in detail with reference to the attached drawings, using exemplary embodiments. However, the following exemplary embodiments are provided as illustrative examples of the present invention. If a detailed description of a technology or configuration well known to those skilled in the art is judged to unnecessarily obscure the gist of the present invention, such detailed description may be omitted, and the present invention is not limited thereby. The present invention is capable of various modifications and applications within the scope of the following claims and equivalents interpreted therefrom.

[0019] In addition, the terms used in this specification are terms used to appropriately express preferred embodiments of the present invention, and may vary depending on the intention of the user or operator, or the customs of the field to which the present invention belongs. Therefore, the definitions of these terms should be determined based on the contents throughout this specification. Throughout the specification, when a part is said to "include" a certain component, this does not mean that other components are excluded, but rather that other components may be included, unless specifically stated otherwise.

[0020] Throughout this specification, '%' used to indicate the concentration of a particular substance is %(w / w) for solid / solid, %(w / v) for solid / liquid, and %(v / v) for liquid / liquid, unless otherwise stated.

[0021] In the present invention, after a microneedle structure pierces the skin, depending on the size of the wound, wound healing by epithelial cell migration and recovery of the ability to prevent penetration of foreign substances by recovering the skin barrier progress within 2 to several hours, making it difficult to continuously absorb the drug. In order to solve this problem, hyaluronidase was used to increase the drug absorption rate of the structure and improve the drug absorption rate. Hyaluronidase is known to increase the drug permeability and diffusion rate by decomposing hyaluronic acid present under the skin in the human body. For example, when a sperm penetrates an egg, hyaluronidase is secreted from the head and melts the surface surrounding the egg, allowing it to penetrate through the area where a portion of the membrane is melted and a hole is created.

[0022] The drug delivery microneedle structure composition referred to in the present invention includes a drug and hyaluronidase, and may further include one or more selected from a biodegradable polymer, a sugar, purified water, and an additive.

[0023] The biodegradable composition referred to in the present invention comprises hyaluronidase and may further comprise one or more selected from biodegradable polymers, sugars, and additives.

[0024] The drug delivery microneedle structure referred to in the present invention may include a state in which all or part of the purified water in the drug delivery microneedle structure composition has been evaporated.

[0025] The one sheet referred to in the present invention may be the entire composition of a microneedle structure for drug delivery or the entire microneedle structure for drug delivery.

[0026]

[0027] Hereinafter, a microneedle structure composition according to one embodiment of the present invention and a microneedle structure manufactured therefrom are described in detail.

[0028] The microneedle structure composition comprises a drug and a biodegradable composition.

[0029] The drug may refer to a component having a medicinal effect, and may be, for example, a chemical pharmaceutical comprising at least one of pentoxifylline, bimatoprost, latanoprost, travoprost, a statin, resveratrol, deoxycholic acid, lithocholic acid, isoproterenol, a prostaglandin, a polynucleotide, a polydeoxynucleotide, lidocaine, donepezil, and salicylic acid, a growth factor comprising at least one of EGF, TGF, and BMP, and one or more selected from peptides and proteins. Such a drug may be included in an amount of 1 to 21 parts by weight based on the total weight of the microneedle structure composition.

[0030] The biodegradable composition may contain hyaluronidase. Hyaluronidase is added to enable the drug to penetrate through the dermis layer into the muscle layer or capillaries to effectively take effect in the body. The hyaluronidase may be contained in an amount of 10 to 1500 IU (International Unit) per sheet. When hyaluronidase is contained in the above concentration range, the transdermal absorption rate of the drug may be improved. In the present embodiment, the release rate of the drug may be controlled through the content of hyaluronidase, or the drug may be delivered to the target site in an appropriate amount as needed, thereby minimizing side effects and maximizing efficacy. In addition, the drug delivery efficiency may be improved, thereby improving the dosage limit. Meanwhile, the hyaluronidase contained in the biodegradable composition of the present invention may have different enzyme titers depending on the biodegradable composition or the final product, but the amount administered may be controlled to satisfy the above concentration range.

[0031] For example, the biodegradable composition may include one or more selected from a biodegradable polymer, a sugar, and an additive. The biodegradable composition may be included in an amount of 79 to 99 parts by weight based on the total weight of the microneedle structure composition. This is because if a large amount of the biodegradable composition is included, the strength of the microneedle structure may be weakened, thereby reducing skin permeability. Therefore, it is desirable to maintain the strength of the microneedle within the above-mentioned range, thereby increasing drug delivery efficiency.

[0032] The biodegradable polymer is a polysaccharide including at least one of alginate, carrageenan, gelatin, carboxymethyl cellulose (CMC), and aloe polysaccharide (APS), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinylacetate (PVAc), polyethylene glycol (PEG), polypropylene glycol (PPG), polyethylene oxide (PEO), polypropylene oxide (PPO), polylactic acid (PLA), polylactide (PL), polyglycolic acid (PGA), polycaprolactone (PCL), hydroxypropyl methylcellulose (HPMC), chondroitin sulfate, dextrin, dextran, At least one selected from dextran sulfate, ethylcellulose, collagen, agarose, cyclodextrin, heparosan, and sodium chondroitin sulfate, for example, at least one selected from alginate, carrageenan, gelatin, carboxymethyl cellulose (CMC), polyvinyl alcohol (PVA), poloxamer, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and ethylcellulose, specific examples thereof include gelatin, carboxymethyl cellulose (CMC,The biodegradable composition may include at least one selected from among polyvinyl alcohol (PVA), carboxymethyl cellulose (CMC), poloxamer, and polyvinyl pyrrolidone (PVP). The biodegradable polymer may be included in an amount of 50 to 99 parts by weight per 100 parts by weight of the biodegradable composition.

[0033] The biodegradable polymer may be included in an amount of 40 to 85 parts by weight relative to the total weight of the microneedle structure.

[0034] Sugars are substances added to accelerate drug diffusion, and may include one or more selected from mannitol, glucose, sucrose, maltose, sucrose, trehalose, and lactose. These sugars may be included in an amount of 7.5 to 32 parts by weight per 100 parts by weight of the biodegradable composition.

[0035] The sugar may be included in an amount of 7 to 25 parts by weight relative to the total weight of the microneedle structure.

[0036] The additive may include one or more selected from among a plasticizer, a surfactant, a preservative, and an anti-inflammatory agent. Such additive may be included in a small amount as long as it does not affect the biodegradable composition, and the content thereof is not significantly limited.

[0037] As a plasticizer, one or more selected from ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin can be used.

[0038] As the surfactant, one or more selected from polysorbate 80, polysorbate 20, polyoxyethylene (POE), and polyoxypropylene glycol (POP) may be used.

[0039]

[0040] Hereinafter, a microneedle structure according to another embodiment of the present invention will be described in detail.

[0041] Referring to FIG. 1, the microneedle structure (100) may include a substrate (10) and microneedles (20).

[0042] The substrate (10) may be formed of a biodegradable material having a certain hardness and strength so as to be capable of supporting one or more microneedles (20). For example, the substrate (10) may include a biodegradable polymer, and since the biodegradable polymer has been described in detail above, a detailed description thereof will be omitted. For example, the substrate (10) preferably has a thickness of 10 to 300 μm, for example, 100 to 200 μm. If the thickness of the substrate is less than 10 μm, it may be difficult to protect the drug because it is too thin and may easily bend and tear, and if it exceeds 300 μm, it may be difficult to adhere to a curved area when adhered to the skin.

[0043] Meanwhile, the substrate (10) may be formed integrally with the microneedles (20) by a mold, and may also be manufactured from the same components, but is not limited thereto. Furthermore, although not illustrated in the drawing, the substrate (10) may be formed of one or more layers, in which case adjacent layers may have different hardness and strength. For example, the hardness and strength may decrease as they approach the microneedles (20). Accordingly, the substrate (10) may be applicable to a wider range of body parts and purposes.

[0044] The microneedle (20) can be arranged one or more times on the substrate (10) at a certain interval, and unlike conventional injection needles, can penetrate the skin without causing trauma or pain. For example, the microneedle (20) is formed in a cone shape that is sharp in the opposite direction to the substrate (10), and preferably has a strength of 0.05 N or more, for example, 0.05 to 3.04 N, or another example, 0.05 to 1.0 N, while satisfying a length of 100 to 1500 μm so that the microneedle (20) can penetrate the stratum corneum of the skin without changing its shape and deliver the drug to the muscle layer or capillaries. When the hardness and length range of the microneedle (20) described above are satisfied, the microneedle (20) can more accurately deliver the drug to the desired location in the body through the dermis layer by penetrating the skin without changing its shape and without causing damage to the skin.

[0045] The microneedle (20) comprises a biodegradable composition and a drug, and the biodegradable composition may comprise one or more selected from a biodegradable polymer, a sugar, and an additive. The composition is omitted as it overlaps with the above description. The microneedle (20) of the present embodiment can increase the transdermal absorption rate of the drug compared to microneedles that do not contain hyaluronidase.

[0046] Meanwhile, although not shown in the drawing, the microneedle (20) may be formed in a single layer or multiple layers, and when formed in multiple layers, the composition of each layer may be the same or different.

[0047]

[0048] Hereinafter, the present invention will be described in more detail using examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples.

[0049]

[0050] Example

[0051] Examples 1 to 3. Manufacturing of microneedle structures

[0052] A biodegradable composition according to an embodiment of the present invention was added to 91.8 g of purified water and stirred. Specifically, 4.5 g of a biodegradable polymer was added and stirred at 500 rpm for 40 minutes, then 2 g of mannitol was added and stirred further. Thereafter, 2 g of PN (sodium polynucleotide) was added and stirred at 700 rpm for 15 minutes, and hyaluronidase was added in the amount shown in Table 1, sufficiently dissolved, degassed, and dispensed into a microneedle mold. Then, the mixture was dried in a pressurized chamber to produce a microneedle structure.

[0053] In Table 1, the content of hyaluronidase is the concentration of hyaluronidase per patch of the microneedle structure. Here, the patch may refer to one sheet of the microneedle structure.

[0054] Example 1 Example 2 Example 3 Hyaluronidase (IU / patch) 10300 1000

[0055]

[0056] Examples 4 to 8. Manufacturing of microneedle structures

[0057] A microneedle structure was manufactured in the same manner as in Example 1, except that the ingredients and contents or concentrations described in Table 2 were applied.

[0058] In Table 2, the content of hyaluronidase is the concentration of hyaluronidase per patch of microneedle structure, and the unit of components excluding hyaluronidase is g.

[0059] Classification Example 4 Example 5 Example 6 Example 7 Example 8 Purified water 91.884.389.390.380.8 Biodegradable polymer Polyvinyl alcohol---44 Poloxamer-10---Carboxymethylcellulose 4.5232.52 Gelatin--4--Polyvinylpyrrolidone----10 Saccharide Mannitol 222--Trehalose---1.51.5 Hyaluronidase (IU / patch) 10001000100010001000 Drug PN 1.71.71.71.71.7

[0060]

[0061] Comparative Example 1. Manufacturing of Microneedle Structures

[0062] A microneedle structure was manufactured in the same manner as in Example 1, except that hyaluronidase was not included.

[0063]

[0064] Experimental Example 1. Evaluation of percutaneous absorption of drugs

[0065] To determine the degree of percutaneous absorption of drugs according to the content of hyaluronidase, the following experiment was conducted.

[0066] A magnetic bar was inserted into the cell, and 5 mL of pH 7.4 PBS was injected through the sampling zone, then stirred at 600 rpm and heated to 32±1℃. Once the temperature was sufficiently heated, the micropig skin with the microneedle structure attached to the top of the receptor, followed by the gasket, was placed in that order, and the upper part of the inserted Franz Cell was fixed so as not to move. As time passed, the drug coming out of the microneedle structure penetrated the skin and mixed with the pH 7.4 PBS. After sampling the drug-permeated solution with a syringe at a desired time point, the cell was filled with pH 7.4 PBS in the amount of the sampled solution with a syringe again, and this was repeated at time points (0.5, 1, 2, 4, 6, and 8 h). Here, the time points are shown as 1 for 0.5 h, 2 for 1 h, 3 for 2 h, 4 for 4 h, 5 for 6 h, and 6 for 8 h. Samples collected at each time point were tested using a UV / VIS Spectrophotometer (JASCO, V-730) to evaluate the content of drugs that had penetrated the skin through the microneedle structure. 1.5 mL of the sample was placed in a quartz cell and the absorbance was measured at 260 nm using a spectrophotometer. The results are shown in Figs. 2, 3a, and 3b.

[0067] Referring to FIGS. 2, 3a, and 3b, it was confirmed that the drug release over time was somewhat faster in Examples 1 to 3 containing hyaluronidase than in Comparative Example 1 not containing hyaluronidase. When the absorbance was compared after 8 hours, it was confirmed that Example 2 containing 300 IU of hyaluronidase per sheet showed a difference of about 2.5, and Example 3 containing 1000 IU of hyaluronidase per sheet showed a difference of about 3.5 compared to Comparative Example 1 not containing hyaluronidase.

[0068] Therefore, it was found that the release rate of the drug can be controlled through the content of hyaluronidase or the drug can be delivered to the target site in an appropriate amount as needed.

[0069]

[0070] Experimental Example 2. Strength Evaluation of Microneedle Structures

[0071] Examples 4 to 6 were taken in a size of 10 mm X 10 mm X 10 mm and the strength was measured according to the KSL 1601 test method, and the results are shown in Table 3.

[0072] The device used was Instron 5582 from Instron.

[0073] Classification Force (N) 123 Average Standard Example 40.3 49 9 20.1 32 43 0.0 95 45 0.1 92 60 0 ≥ 0.05 N Example 50.5 9 0 86 0.3 00 34 0.6 5 17 5 0.5 1 43 17 Example 60.2 8 46 9 0.1 7 5 10.1 0 87 20.1 90 307

[0074] Referring to Table 3, the average strength values ​​of Examples 4 to 6 were all confirmed to be above the reference value of 0.05 N. Therefore, it was confirmed that the microneedles could reach the dermal layer without causing damage to the skin and without changing their shape.

[0075]

[0076] Although exemplary embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concept of the present invention defined in the following claims also fall within the scope of the present invention.

[0077] All technical terms used in this invention, unless otherwise defined, have the same meaning as commonly understood by those skilled in the art. The contents of all publications cited herein as references are incorporated herein by reference.

[0078]

[0079] Description of the symbol

[0080] 100: Microneedle structure

[0081] 10: Description

[0082] 20: Microneedle

Claims

1. Drugs; and biodegradable composition; Including, The above biodegradable composition is a microneedle structure composition for drug delivery, comprising hyaluronidase.

2. In claim 1, A drug delivery microneedle structure composition, wherein the hyaluronidase is contained in an amount of 10 to 1500 IU per sheet.

3. In claim 1, A drug delivery microneedle structure composition, wherein the biodegradable composition comprises at least one selected from a biodegradable polymer, a sugar, and an additive.

4. In claim 3, A drug delivery microneedle structure composition, wherein the biodegradable polymer is contained in an amount of 50 to 99 parts by weight per 100 parts by weight of the biodegradable composition.

5. Description; and One or more microneedles disposed on the above substrate; Including, A drug delivery microneedle structure, wherein the microneedle comprises a drug and a biodegradable composition, wherein the biodegradable composition comprises hyaluronidase.

6. In claim 5, The above microneedle is a microneedle structure for drug delivery, which has a higher transdermal absorption rate of the drug compared to microneedles that do not contain hyaluronidase.

7. In claim 5, The above microneedle is a microneedle structure for drug delivery, having a height of 100 to 1500 μm.

8. In claim 5, The above drug delivery microneedle structure is a drug delivery microneedle structure having a strength of 0.05 N or more.

Images