Microneedle structure and composition thereof

Abstract

The present invention relates to a microneedle structure and a composition thereof that can effectively deliver a drug locally or systemically within the body by penetrating the dermis layer through the transdermis without causing damage to the skin by including a biodegradable composition containing a drug and hyaluronidase.

Description

Technology Field

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

[0003] Microneedles are a widely used method for drug delivery systems. They offer the advantage of minimizing pain and improving the speed of therapeutic drug delivery through a mechanism that directly guides drugs into the subcutaneous area. Furthermore, by injecting drugs locally, they allow for effective delivery only to the desired site.

[0004] However, in the case of soluble microneedle structures, limitations in drug application dose have caused problems regarding payload capacity; although various attempts have been made to resolve this, the technology for quantitative drug delivery has not been resolved.

[0005] Meanwhile, most transdermal microneedles are composed of water-soluble polymers, resulting in minimal skin diffusion. Even for drugs with high skin diffusion, drug release within the skin is difficult if the solubility of the microneedles themselves is low. Additionally, while the needle must be strong enough to penetrate the skin, substances that increase needle strength are difficult to dissolve due to skin moisture, which can cause injury. Furthermore, there was a problem in that the drug had to be administered at a higher concentration compared to injectable drugs due to low drug diffusion.

[0006] Therefore, there is an urgent need to develop a form capable of effectively delivering drugs transdermally without causing damage to the skin. Prior art literature

[0008] Republic of Korea Registered Patent 10-2038751 (2019.10.30) The problem to be solved

[0009] The objective of the present invention, derived to solve the problem described above, is to provide a microneedle structure and a composition thereof that can effectively deliver a drug locally or systemically within the body by penetrating the dermis layer and penetrating the skin without causing injury to the skin. means of solving the problem

[0011] To achieve the above objective, a microneedle structure composition according to one embodiment of the present invention comprises a drug and a biodegradable composition, and said biodegradable composition comprises hyaluronidase.

[0012] Here, the hyaluronidase may be included in the biodegradable composition at a concentration of 10 to 1500 IU / mg.

[0013] A microneedle structure for drug delivery according to another embodiment of the present invention comprises a substrate and one or more microneedles disposed on the substrate, wherein the microneedles comprise a drug and a biodegradable composition, and the biodegradable composition comprises hyaluronidase.

[0014] At this time, the above microneedles can increase the transdermal absorption rate of the drug compared to microneedles that do not contain hyaluronidase.

[0015] In addition, the thickness of the above-mentioned material may be 10 to 300 μm.

[0016] Also, the above microneedles may have a length of 100 to 1500 μm. Effects of the invention

[0018] According to one embodiment of the present invention, a microneedle structure and its composition may effectively deliver a drug locally or systemically within the body through the dermis layer by penetrating the skin without causing injury to the skin, by including a biodegradable composition containing a drug and hyaluronidase.

[0019] In addition, by controlling the drug release rate or delivering the appropriate amount of drug to the target site as needed, side effects can be minimized and efficacy maximized. Brief explanation of the drawing

[0021] FIG. 1 is a cross-sectional view schematically showing a microneedle structure according to an embodiment of the present invention. Figure 2 is a graph showing the results according to Experimental Example 1. Figures 3a and 3b are optical microscope images showing the results according to Experimental Example 1. Specific details for implementing the invention

[0022] Hereinafter, the present invention will be described in detail with reference to the attached drawings and embodiments thereof. However, the following embodiments are presented as examples of the present invention, and if it is determined that a detailed description of a technology or configuration well known to those skilled in the art may unnecessarily obscure the essence 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 claims set forth below and the equivalent scope interpreted therefrom.

[0023] Furthermore, the terminology used in this specification is used to appropriately describe preferred embodiments of the present invention, and may vary depending on the intent of the user or operator, or the conventions of the field to which the present invention belongs. Accordingly, the definitions of these terms should be based on the content throughout this specification. Throughout the specification, when a part is described as “comprising” a certain component, unless specifically stated otherwise, this means that it does not exclude other components but may include additional components.

[0024] 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 noted.

[0025] In this invention, to address the difficulty of continuous drug absorption caused by wound healing via epithelial cell migration and the recovery of the skin barrier's ability to prevent external substance penetration within 2 to several hours after a microneedle structure penetrates the skin, depending on the size of the wound, hyaluronidase is used to increase the drug absorption rate of the structure. Hyaluronidase is known to increase the drug diffusion rate by breaking down hyaluronic acid present in the subcutaneous tissue of the human body to increase drug permeability. For example, when a sperm penetrates an egg, hyaluronidase is secreted from the head portion, dissolving the surface surrounding the egg, and the sperm can penetrate through the opening created by the dissolution of a portion of the membrane.

[0026] The drug delivery microneedle structure composition referred to in the present invention comprises a drug and hyaluronidase, and may further comprise one or more selected from a biodegradable polymer, sugars, purified water, and additives.

[0027] 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.

[0028] 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.

[0030] Hereinafter, a microneedle structure composition according to one embodiment of the present invention and a microneedle structure manufactured therefrom will be described in detail.

[0031] The microneedle structure composition includes a drug and a biodegradable composition.

[0032] The drug may refer to a component having medicinal effects and may be, for example, one or more selected from pentoxifyllin, bimatoprost, latanoprost, travoprost, statin, resveratrol, deoxycholic acid, ritocholitic acid, isoproterenol, prostaglandin, polynucleotide, polydeoxynucleotide, lidocaine, donepezil, salicylic acid, EGF, TGF, and BNP. Such drugs may be included in an amount of 7 to 21 parts by weight based on the total weight of the microneedle structure composition.

[0033] The biodegradable composition may include hyaluronidase, which is added to enable the drug to penetrate the muscle layer or capillaries through the dermis to ensure effective drug action within the body; it may be included in the biodegradable composition at a concentration of 10 to 1500 IU / mg. When hyaluronidase is included within the above concentration range, the transdermal absorption rate of the drug may be improved. In this embodiment, by controlling the drug release rate through the content of hyaluronidase or delivering the drug to the target site in the appropriate amount required, side effects can be minimized and efficacy maximized. Additionally, the dosage limit can be improved by enhancing drug delivery efficiency. Meanwhile, although the enzymatic activity of the hyaluronidase included in the biodegradable composition of the present invention may vary depending on the biodegradable composition or the final product, the amount added can be controlled to satisfy the above concentration range.

[0034] Meanwhile, hyaluronidase may be included in an amount of 0.06 to 19 parts by weight relative to the total weight of the microneedle structure.

[0035] For example, the biodegradable composition may include one or more selected from biodegradable polymers, sugars, and additives. This biodegradable composition may be included in an amount of 79 to 93 parts by weight relative to the total weight of the microneedle structure composition. Since a large amount of the biodegradable composition may weaken the strength of the microneedle structure and lower skin permeability, it is desirable to satisfy the aforementioned range to maintain the strength of the microneedle and thereby increase drug delivery efficiency.

[0036] Biodegradable polymers include alginate, carrageenan, gelatin, carboxymethylcellulose (CMC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (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, dextran sulfate, ethylcellulose, collagen, It may include one or more selected from agarose and cyclodextrin, for example, one or more selected from alginate, carrageenan, gelatin, carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), poloxamer, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and ethylcellulose, specifically examples being one or more selected from gelatin, carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), poloxamer, and polyvinylpyrrolidone (PVP). there is.These biodegradable polymers may be included in an amount of 50 to 99 parts by weight per 100 parts by weight of the biodegradable composition.

[0037] 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.

[0038] Sugars are substances added to accelerate the diffusion of drugs 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.

[0039] Sugars may be included in an amount of 7 to 25 parts by weight relative to the total weight of the microneedle structure.

[0040] The additives may include one or more selected from plasticizers, surfactants, preservatives, and anti-inflammatory agents, and these additives may be included in small amounts that do not affect the biodegradable composition, and their content is not significantly limited.

[0041] One or more selected from ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin may be used as plasticizers.

[0042] One or more selected from polysorbate 80, polysorbate 20, polyoxyethylene (POE), and polyoxypropylene glycol (POP) may be used as surfactants.

[0044] Hereinafter, a microneedle structure according to another embodiment of the present invention will be described in detail.

[0045] Referring to FIG. 1, the microneedle structure (100) may include a substrate (10) and microneedles (20).

[0046] The substrate (10) may be formed from a biodegradable material having a certain hardness and strength to support 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, it will be omitted. For example, the substrate (10) preferably has a thickness of 10 to 300 μm, for example, 100 to 200 μm, because if the thickness of the substrate is less than 10 μm, it is thin and easily bends and tears, making it difficult to protect the drug, and if it exceeds 300 μm, it may be difficult to adhere to curved areas when attached to the skin.

[0047] Meanwhile, the substrate (10) may be formed integrally with the microneedle (20) by a mold and may be manufactured with the same components, but is not limited thereto. Additionally, although not shown in the drawing, the substrate (10) may be formed in one or more layers, and in this case, adjacent layers may have different hardness and strength. For example, the hardness and strength may decrease as it approaches the microneedle (20). Accordingly, it may be applicable to a wider variety of body parts and uses.

[0048] One or more microneedles (20) may be placed on the substrate (10) and spaced apart at a certain interval, and unlike conventional injection needles, they can penetrate the skin without causing trauma or pain. For example, the microneedles (20) are formed in a pointed cone shape opposite to the substrate (10) and have a strength of 0.05 N or more, for example 0.05 to 3.04 N, or for example 0.05 to 1.0 N, while satisfying a length of 100 to 1500 μm, so that they can penetrate the stratum corneum of the skin without changing shape and deliver drugs to the muscle layer or capillaries. When the above-described hardness and length range of the microneedles (20) is satisfied, the microneedles (20) can penetrate the skin without changing shape and without causing damage to the skin, and deliver drugs more accurately through the dermis layer to a desired location in the body.

[0049] The microneedle (20) comprises a biodegradable composition and a drug, and the biodegradable composition may include one or more selected from biodegradable polymers, sugars, and additives. The composition is omitted as it overlaps with the above. The microneedle (20) of this embodiment can increase the transdermal absorption rate of the drug compared to a microneedle that does not contain hyaluronidase.

[0050] Meanwhile, although not shown in the drawing, the microneedle (20) may be formed in a single layer or multiple layers, and if formed in multiple layers, the composition of each layer may be the same or different.

[0052] The present invention will be described in more detail below using examples. These examples are solely for the purpose of more specifically explaining the present invention, and it is obvious to those skilled in the art that the scope of the present invention is not limited by them.

[0054] Examples

[0055] Examples 1 to 3. Preparation of microneedle structures

[0056] A biodegradable composition according to an embodiment of the present invention was added to 91.4 g of purified water and stirred. Specifically, 4.5 g of the biodegradable polymer was added and stirred at 500 rpm for 40 minutes, then 2 g of mannitol was added and stirred further. After that, 2 g of PN (sodium polynucleotide) was added and stirred at 700 rpm for 15 minutes, and hyaluronidase was added in the amounts listed in Table 1 to sufficiently dissolve and degas the mixture, after which it was dispensed into a microneedle mold. Then, a microneedle structure was prepared by drying in a pressurized chamber.

[0057] division Example 1 Example 2 Example 3 Hyaluronidase (IU / mg) 10 300 1000

[0059] Examples 4 to 8. Preparation of microneedle structures

[0060] A microneedle structure was prepared in the same manner as in Example 1, except that the components and content or concentrations listed in Table 2 were applied.

[0061] In Table 2, the unit of the content of the components is g.

[0062] division Example 4 Example 5 Example 6 Example 7 Example 8 purified water 91.8 84.3 89.3 90.3 80.8 Biodegradable polymer Polyvinyl alcohol - - - 4 4 Poloxamer - 10 - - - Carboxymethylcellulose 4.5 2 3 2.5 2 gelatin - - 4 - - Polyvinylpyrrolidone - - - - 10 Sugars Mannitol 2 2 2 - - Trehalose - - - 1.5 1.5 hyaluronidase 0.01264 0.01264 0.01264 0.01264 0.01264 drugs PN 1.7 1.7 1.7 1.7 1.7

[0064] Comparative Example 1. Preparation of a microneedle structure

[0065] A microneedle structure was prepared in the same manner as in Example 1, except that hyaluronidase was not included.

[0067] Experimental Example 1. Evaluation of transdermal absorption of a drug

[0068] To determine the degree of transdermal absorption of the drug according to the hyaluronidase content, an experiment was conducted as follows.

[0069] A magnetic bar was inserted into the cell, and 5 mL of pH 7.4 PBS was injected through the sampling zone. The cell was then heated to 32 ± 1°C while stirring at 600 rpm. Once the temperature was sufficiently heated, a micropig skin with a microneedle structure attached to the top of the receptor and a gasket were placed on top, and the upper part of the inserted Franz Cell was fixed to prevent movement. As time passed, the drug released from the microneedle structure permeated the skin and mixed with the pH 7.4 PBS. At desired time points, the solution containing the drug was sampled using a syringe, and the cell was refilled with pH 7.4 PBS equal to the volume of the sampled solution using a syringe. This process was repeated at time points (0.5, 1, 2, 4, 6, 8 h). Here, the time points are indicated as 1 at 0.5 h, 2 at 1 h, 3 at 2 h, 4 at 4 h, 5 at 6 h, and 6 at 8 h. Samples collected at each time point were subjected to confirmation testing using a UV / VIS Spectrophotometer (JASCO, V-730) to evaluate the content of the drug that 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 Figures 2, 3a, and 3b.

[0070] Referring to FIGS. 2, FIGS. 3a, and FIGS. 3b, it was confirmed that the drug release over time in Examples 1 to 3 containing hyaluronidase appeared somewhat faster than in Comparative Example 1, which did not contain hyaluronidase. When comparing the absorbance after 8 hours, it was confirmed that Example 2, containing 300 IU / mg of hyaluronidase, showed a difference of about 2.5 compared to Comparative Example 1, which did not contain hyaluronidase, and Example 3, containing 1000 IU / mg of hyaluronidase, showed a difference of about 3.5.

[0071] Therefore, it was found that the drug release rate can be controlled or the appropriate amount of drug delivered to the target site can be achieved through the hyaluronidase content.

[0073] Experimental Example 2. Evaluation of the strength of the microneedle structure

[0074] Examples 4 to 6 were taken in a size of 10 mm X 10 mm X 10 mm and their strength was measured according to the KSL 1601 test method, and the results are shown in Table 3.

[0075] The device used was the Instron 5582 from Instron.

[0076] division Force(N) 1 2 3 average standard Example 4 0.34992 0.13243 0.09545 0.192600 ≥0.05N Example 5 0.59086 0.30034 0.65175 0.514317 Example 6 0.28469 0.17751 0.10872 0.190307

[0077] Referring to Table 3, the average strength values ​​of Examples 4 to 6 were all confirmed to be greater than the reference value of 0.05 N. Therefore, it was found that the microneedles could reach the dermis layer without changing shape or causing damage to the skin.

[0079] 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 by those skilled in the art using the basic concept of the present invention as defined in the following claims also fall within the scope of the present invention.

[0080] All technical terms used in this invention, unless otherwise defined, are used in the sense generally understood by those skilled in the art in the relevant field of this invention. The contents of all publications cited as references in this specification are incorporated into this invention. Explanation of the symbols

[0082] 100: Microneedle structure 10: Entry 20: Microneedle

Claims

Claim 1 A microneedle structure composition for drug delivery comprising a drug; and a biodegradable composition; wherein the biodegradable composition comprises hyaluronidase. Claim 2 A drug delivery microneedle structure composition according to claim 1, wherein the hyaluronidase is included in the biodegradable composition at a concentration of 10 to 1500 IU / mg. Claim 3 A microneedle structure composition for drug delivery according to claim 1, wherein the biodegradable composition comprises one or more selected from biodegradable polymers, sugars, and additives. Claim 4 A microneedle structure composition for drug delivery according to claim 3, wherein the biodegradable polymer is included in an amount of 50 to 99 parts by weight per 100 parts by weight of the biodegradable composition. Claim 5 A microneedle structure for drug delivery comprising: a substrate; and one or more microneedles disposed on the substrate; wherein the microneedles comprise a drug and a biodegradable composition, and the biodegradable composition comprises hyaluronidase. Claim 6 A drug delivery microneedle structure according to claim 5, wherein the microneedle has a higher transdermal absorption rate of the drug compared to a microneedle that does not contain hyaluronidase. Claim 7 The drug delivery microneedle structure according to claim 5, wherein the microneedles have a height of 100 to 1500 μm. Claim 8 In claim 5, the drug delivery microneedle structure is a drug delivery microneedle structure having a strength of 0.05 N or more.

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