Dissolving microneedle easily attachable to mucous membrane, and manufacturing method therefor

Abstract

The present disclosure provides a dissolving microneedle comprising: a plurality of needle parts comprising an active ingredient and a biodegradable polymer; and a base layer for supporting the needle parts, wherein each of the needle parts includes a first layer impregnated with the active ingredient and a second layer disposed adjacent to the base layer, and the base layer includes a polymer with bio-adhesiveness, thereby facilitating attachment to a site such as a mucous membrane and providing high strength.

Description

Dissolvable microneedles that are easily attached to the mucosa and a method for manufacturing the same

[0001] The present disclosure relates to a soluble microneedle that is easy to adhere to the mucosa and a method for manufacturing the same.

[0002] When inflammation or cancer occurs in the oral cavity, it is extremely difficult to deliver therapeutic drugs into the oral environment. Existing treatment methods involve applying ointments to the affected area or gargling liquid medications. However, these methods fail to deliver the drug to the affected area for a prolonged period, resulting in minimal therapeutic effects. Consequently, extensive research is currently underway into transdermal drug delivery systems using microneedles.

[0003] Microneedles are typically microscopic structures that penetrate the stratum corneum and deliver drugs into the epidermis and dermis. Microneedles are attached to the skin surface, creating microscopic holes in the epidermis, through which drugs are delivered. Compared to conventional injections, they offer significantly less pain and prevent infection.

[0004] Depending on the drug delivery strategy, microneedles can be divided into solid microneedles, coated microneedles, biodegradable and soluble microneedles, hollow microneedles, and hydrogel forming microneedles.

[0005] Solid microneedles are typically made of silicone, metal, or non-degradable polymers and function simply to physically penetrate the stratum corneum and epidermis, creating channels within the skin. However, the amount of drug delivered into the skin is inconsistent, making it difficult to control. Furthermore, rapid skin recovery after microneedles application can hinder drug delivery.

[0006] Coated microneedles are solid microneedles that are coated with a drug or drug-containing formulation. When inserted into the skin, the drug is uniformly coated on the needle surface, melting with body fluids to deliver the drug. This requires a high level of manufacturing technology because the drug must be quantitatively delivered into the epidermis. Furthermore, the small surface area of ​​the microneedles limits the amount of drug that can be coated, and there is a risk that the coated drug may migrate beyond the epidermis.

[0007] Hollow microneedles have the same structure as a general hypodermic syringe, and are structured to directly deliver liquid drugs into the body through the internal holes of the microneedles after penetrating the skin. This method can deliver a large amount of drugs to the epidermis, but there is a high possibility that the needle hole will be blocked by skin tissue when injecting the drug, and there are problems in that the mechanical strength is relatively low.

[0008] Hydrogel-forming microneedles are a method in which a drug-containing patch is combined with a hydrogel-material microneedles that do not contain a drug, and when applied to the skin, the drug moves through the needle to the epidermis by body fluid. However, there is a problem in that the drug must be attached to the epidermis for a relatively long time to inject the drug, while the mechanical strength is relatively low.

[0009] Conventional microneedles have these limitations, and currently, much research is being conducted on biodegradable / soluble microneedles.

[0010] The present disclosure has been devised to solve the above problems, and according to one aspect of the present disclosure, a microneedle can be provided in which the base portion of the microneedle becomes a gel due to moisture in the oral mucosa, thereby easily attaching to the mucosa without separately attaching a conventional adhesive attachment patch.

[0011] According to one aspect of the present disclosure, a soluble microneedle having sufficient mechanical strength for skin penetration can be provided, which can be inserted into a mucosa such as an oral environment without shape change to deliver an effective substance.

[0012] According to one aspect of the present disclosure, a soluble microneedle that continuously releases a drug for a long period of time can be provided.

[0013] The present disclosure provides a soluble microneedle comprising a plurality of needle portions containing an active ingredient and a biodegradable polymer and a base layer supporting the needle portions, wherein the needle portions include a first layer impregnated with the active ingredient and a second layer disposed adjacent to the base layer, and the base layer includes a polymer having bioadhesive properties.

[0014] In one embodiment according to the present disclosure, when attaching the soluble microneedle to the mucosa, the base layer may include a biodegradable polymer that dissolves before the first layer of the needle portion.

[0015] In one embodiment according to the present disclosure, the first layer of the needle portion comprises chitosan, collagen, gelatin, hyaluronic acid, fibrin, agarose, heparin, chondroitin sulfate albumin, fullulan, cellulose, pectin, starch, glycogen polylysine, polylactic acid (PLA), carboxymethylcellulose (CMC), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polycarbonate. It may include at least one member selected from the group consisting of collagen-acrylate, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, polylactide glycolide (PLGA), and copolymers forming the above polymers.

[0016] In one embodiment according to the present disclosure, the second layer of the needle portion or the base layer may include at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxyalkyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, cellulose polymer, furcelleran, pectin, and a copolymer forming the polymer.

[0017] In one embodiment according to the present disclosure, the first layer of the needle portion includes fullulan, and the content of fullulan may be included in an amount of 1 to 50 parts by weight of the total weight of the microneedle.

[0018] In one embodiment according to the present disclosure, the base layer or the second layer of the needle portion may include polyvinyl alcohol (PVA), and the content of the polyvinyl alcohol (PVA) may be 1 to 50 parts by weight of the total weight of the microneedle.

[0019] In one embodiment according to the present disclosure, the active ingredient may include at least one active ingredient selected from the group consisting of an antiviral agent, an antifungal agent, an antibiotic, an oral disinfectant, polydeoxyribonucleotide (PDRN), polynucleotide (PN), extracellular matrix (ECM), and epidermal growth factor (EGF).

[0020] In one embodiment according to the present disclosure, the height of the first layer of the needle portion may be 100 to 1000 μm.

[0021] A soluble microneedle, wherein in one embodiment according to the present disclosure, the height ratio of the first layer:second layer of the needle portion is 1:1 to 100:1.

[0022] In one embodiment according to the present disclosure, the width to height ratio of the needle portion may be configured in a ratio of 1:1 to 1:10.

[0023] In one embodiment according to the present disclosure, the strength of the microneedle may be 0.080 N or more.

[0024] The present disclosure provides a method for manufacturing a soluble microneedle, comprising the steps of: preparing a negative mold having a shape of a microneedle; preparing a first solution by dissolving a biodegradable material and an active ingredient in a solvent; preparing a second solution by dissolving a biodegradable polymer having bioadhesiveness in a solvent; injecting the first solution into the negative mold to form a first layer of a needle portion, and sequentially injecting the second solution into a second layer portion and a base portion of the needle portion; and drying the mold into which the solution has been injected.

[0025] In one embodiment according to the present disclosure, the active ingredient may include one or more active ingredients selected from the group consisting of an antiviral agent, an antifungal agent, an antibiotic, an oral disinfectant, a polydeoxyribonucleotide (PDRN), a polynucleotide (PN), an extracellular matrix (ECM), and an epidermal growth factor (EGF).

[0026] In one embodiment according to the present disclosure, the second stage biodegradable material is fullulan, chitosan, collagen, gelatin, hyaluronic acid, fibrin, agarose, heparin, chondroitin sulfate albumin, cellulose, pectin, starch, glycogen polylysine, polylactic acid (PLA), carboxymethylcellulose (CMC), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polycarbonate. It may include at least one member selected from the group consisting of collagen-acrylate, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, polylactide glycolide (PLGA), and copolymers forming the above polymers.

[0027] In one embodiment according to the present disclosure, the biodegradable polymer having bioadhesiveness of the third step may include at least one selected from the group consisting of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose, hydroxyalkyl cellulose, polyvinylpyrrolidone, cellulose polymer, furcelleran, pectin, and copolymers forming the polymer.

[0028] According to one embodiment of the present disclosure, a soluble microneedle and a method for manufacturing the same are configured such that the needle portion is composed of a first layer and a second layer, and thus the first layer impregnated with an active ingredient can be delivered into the dermis within the body.

[0029] A soluble microneedle and a method for manufacturing the same according to one embodiment of the present disclosure can provide a soluble microneedle that is economical and does not cause a foreign body sensation to the recipient, by allowing a biodegradable polymer to form a gel and adhere closely to the oral mucosa without a separate adhesive, thereby allowing the soluble microneedle to adhere closely to skin in a curved and moist environment such as the mucosa.

[0030] The soluble microneedle and the method for manufacturing the same according to one embodiment of the present disclosure have sufficient mechanical strength for skin penetration and can be inserted into a mucous membrane such as an oral environment without shape change to deliver an effective substance.

[0031] The soluble microneedle and the method for manufacturing the same according to one embodiment of the present disclosure can enhance the therapeutic effect by allowing the first layer impregnated with an effective ingredient to slowly release the effective ingredient to the affected area for a long period of time.

[0032] Figure 1 is a schematic diagram of a soluble microneedle according to one embodiment of the present disclosure.

[0033] Figure 2 illustrates a microneedle of Example 1 of the present disclosure.

[0034] Figure 3 shows a microscopic view of the side surface of the microneedle of Example 1 of the present disclosure.

[0035] Figure 4 illustrates the appearance of the microneedle of Example 1 after perforating the pig gum mucosa.

[0036] The advantages and features of the present disclosure, and methods for achieving them, will become clearer with reference to the embodiments described in detail below. However, the present disclosure is not limited to the embodiments disclosed below and may be implemented in various different forms. These embodiments are provided solely to ensure the complete disclosure of the present disclosure and to fully inform those skilled in the art of the present disclosure of the scope of the invention. The present disclosure is defined solely by the scope of the claims.

[0037] Unless otherwise defined, all terms (including technical and scientific terms) used in this specification may be used in a meaning that can be commonly understood by a person of ordinary skill in the art to which this disclosure belongs.

[0038] As used herein, the singular forms of terms may be construed to include the plural forms as well, unless otherwise specified.

[0039] The numerical ranges used herein include lower and upper limits and all values ​​within that range, increments logically derived from the shape and width of the defined range, all doubly defined values, and all possible combinations of upper and lower limits of numerical ranges defined in different shapes. Unless otherwise specified in the specification of the present disclosure, values ​​outside the defined range that may arise due to experimental error or rounding of values ​​are also included in the defined numerical range.

[0040] The term "includes" as used herein is an open-ended description having the equivalent meaning of expressions such as "comprises," "contains," "has," and "characterizes," and does not exclude additional elements, materials, or processes not listed.

[0041] The term "soluble microneedle" as used herein means a needle-like structure having a length in micrometers, which, when applied to penetrate the skin, dissolves in the body and releases the loaded active ingredient or drug.

[0042] The term "patch" as used herein refers to a formulation that is attached to the skin to deliver a drug into the body.

[0043] The “needle portion” of the microneedle referred to in this specification means the sharp portion that first contacts the skin when the microneedle is inserted into the skin, and refers to portion 30 in Drawing 1 of the present disclosure.

[0044] The “first layer” of the microneedle referred to in this specification means the portion of the needle section where the active ingredient is impregnated, and refers to portion 10 in FIG. 1.

[0045] The term "second layer" of the microneedle as referred to in this specification refers to the portion of the needle portion adjacent to the base layer, and means portion 20 in FIG. 1.

[0046] The term "base" of the microneedle as referred to in this specification means the portion 40 in Drawing 1, which is the portion that turns into a gel and closely adheres to the mucosa when the microneedle is attached to the body.

[0047] Below, the present disclosure's soluble microneedles, which are easily attached to the mucosa, and their manufacturing method will be described in detail. However, these are merely exemplary, and the present disclosure is not limited to the specific embodiments described as examples.

[0048] Currently, the most common method for manufacturing microneedles involves placing a soluble substance in a mold, drying it, and then applying an adhesive, such as a hydrocolloid, to facilitate attachment to the skin. However, these microneedle patches are difficult to adhere to oral lesions, making them difficult to maintain for extended periods.

[0049] Furthermore, the variety of diseases that can occur in the oral cavity is diverse, and their incidence is increasing. The oral cavity's numerous curves and the flow of saliva make it difficult for medications to remain in the body for extended periods of time. Therefore, to enhance the treatment efficacy of oral diseases, research is needed into microneedles that can adhere closely to the mucosal surface and continuously release medication over long periods of time.

[0050] Accordingly, the inventor of the present disclosure has designed a microneedle that is easy to attach to the oral cavity and can efficiently deliver a drug by including an adhesive material that forms a gel with moisture in the oral mucosa at the base of the microneedle without an adhesive patch, rather than a form in which a soluble microneedle is attached to an existing adhesive patch, and that remains in the oral cavity for a long period of time.

[0051] The microneedles of the present disclosure can be used to deliver drugs to any mucosal site within the body, such as intraoral, intravenous, intramuscular, intraarterial, intramedullary, transdermal, subcutaneous, topical sublingual, or rectal.

[0052] In one embodiment of the present disclosure, a soluble microneedle is provided, which comprises a plurality of needle portions including an active ingredient and a biodegradable polymer and a base layer supporting the needle portions, wherein the needle portions include a first layer impregnated with the active ingredient and a second layer disposed adjacent to the base layer, and wherein the base layer includes a polymer having bioadhesive properties.

[0053] Conventional microneedles require a separate attachment of hydrocolloid (adhesive), and even when the adhesive is attached, there is a problem in that it cannot adhere to the oral cavity or curved skin for a long period of time and falls off before the active ingredient is absorbed into the body.

[0054] Since the soluble microneedle of the present disclosure includes a polymer having bioadhesiveness in the base layer, the base layer becomes a gel by moisture of a mucous membrane such as the oral cavity and has adhesiveness, so that it can be closely attached to the mucous membrane.

[0055] Therefore, the soluble microneedle of the present disclosure is economical because it does not require a separate adhesive attachment patch, and it closely attaches to curved skin such as a mucous membrane without an adhesive patch, thereby producing an effect without a foreign body sensation or discomfort.

[0056] In one embodiment of the present disclosure, the soluble microneedle may be provided such that, when attached to a mucosa, the base layer dissolves before the first layer of the needle portion.

[0057] The base layer and the second layer may be made of the same biodegradable polymer. The base layer and the second layer form a gel when attached to the mucosa and adhere closely to the skin. The second layer does not dissolve immediately after contact with the oral mucosa, but maintains a sedimentation rate and can slowly release the active ingredient into the body over a long period of time.

[0058] The biodegradable polymer of the first layer may be formed with a molecular weight that is relatively larger than that of the biodegradable polymer of the second layer. In one embodiment of the present disclosure, the molecular weight of the polymer of the first layer is a polymer having a molecular weight that is relatively larger than that of the polymer of the second layer and the base layer, so that the second layer changes into a gel having adhesiveness like the base when attached to the mucosa, while the first layer slowly dissolves when attached to the mucosa, gradually releasing the active ingredient and maintaining the sedimentation rate.

[0059] As an embodiment of the present disclosure, the molecular weight of the biodegradable polymer included in the first layer may be, as a lower limit, 10,000 Da or more, 20,000 Da or more, 25,000 Da or more, 30,000 Da or more, 35,000 Da or more, 40,000 Da or more, 45,000 Da or more, or 500,000 Da or more, and as an upper limit, 800,000 Da or less, 750,000 Da or less, 700,000 Da or less, 650,000 Da or less, 600,000 Da or less, 550,000 Da or less, or 750,000 Da or less, but is not necessarily limited thereto. More preferably, it can be 10,000 to 800,000 Da or 20,000 to 700,000 Da, and even more preferably, it can be 50,000 to 200,000 Da. Since the molecular weight of the biodegradable polymer of the first layer satisfies the above range, the dissolution and decomposition speed of the biodegradable polymer is slow, and as a result, the effect of slowly releasing the active ingredient over a long period of time can be exhibited. In other words, there is an effect of preventing rapid release of the active ingredient from the first layer of the microneedle, and delivering the active ingredient to the affected area at a constant concentration for a long period of time. The molecular weight of the biodegradable polymer included in the second layer and the base layer may be, as a lower limit, 3,000 Da or more, 4,000 Da or more, 5,000 Da or more, 6,000 Da or more, 7,000 Da or more, 8,000 Da or more, 9,000 Da or more, or 10,000 Da or more, and as an upper limit, may be, but is not necessarily limited to, 200,000 Da or less, 150,000 Da or less, or 100,000 Da or less. Specifically, it may be 3,000 Da to 500,000 Da, 3,000 Da to 300,000 Da, or 3,000 Da to 200,000 Da, and more preferably, 5,000 Da to 100,000 Da, but is not necessarily limited thereto.Since the molecular weight of the biodegradable polymer included in the second layer and the base layer satisfies the above range, the second layer and the base layer dissolve in body moisture such as mucous membranes and change into a gel form, and this gel form has the advantage of being able to stably attach to curved affected areas such as mucous membranes without a separate adhesive. Accordingly, it can be attached closely to curved skin such as mucous membranes without a foreign body sensation even without an adhesive patch, and can provide a stable therapeutic effect for a long time.

[0060] This differs from typical microneedles. Typical microneedle patches are designed to have excellent solubility by lowering the molecular weight of the biodegradable polymer impregnated in the needle portion, which is the active ingredient, as the adhesive hydrocolloid quickly detaches from the mucosa. In other words, while conventional dissolvable microneedles increase solubility to ensure rapid absorption before the patch detaches from the mucosa, one embodiment of the present disclosure is designed to slowly release the active ingredient to the affected area over a long period of time, thereby reducing the number of microneedle attachments while simultaneously enhancing the therapeutic effect.

[0061] In one embodiment of the present disclosure, the microneedle portion may include a biodegradable polymer, and the first layer may further include an additive that can improve the stability of the active ingredient or a viscosity-controlling agent or surfactant.

[0062] In one embodiment of the present disclosure, the first layer of the needle portion comprises chitosan, collagen, gelatin, hyaluronic acid, fibrin, agarose, heparin, chondroitin sulfate albumin, fullulan, cellulose, pectin, starch, glycogen polylysine, polylactic acid (PLA), carboxymethylcellulose (CMC), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polycarbonate. It may include at least one selected from the group consisting of collagen acrylate, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, polylactide glycolide (PLGA), and copolymers forming the above polymers, but is not limited thereto.

[0063] In one embodiment of the present disclosure, the second layer of the needle portion or the base portion may include at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxyalkyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, cellulose polymer, furcelleran, pectin, and copolymers forming the polymer, but is not limited thereto.

[0064] In addition to the above-described mechanism, the microneedles of the present disclosure may further include a solubilizer, plasticizer, surfactant, preservative, anti-inflammatory agent, etc., depending on the intended use. Various ingredients known in the art may be appropriately selected and used.

[0065] In one embodiment of the present disclosure, the first layer of the needle portion includes fullulan, and the content of fullulan may be 0.1 to 70 parts by weight of the total weight of the microneedle, and specifically, may include 1 to 50 parts by weight. The molecular weight of fullulan may be 50,000 to 200,000 Da.

[0066] In one embodiment of the present disclosure, the base layer or the second layer of the needle portion may include polyvinyl alcohol (PVA), and the content of the polyvinyl alcohol (PVA) may be included in an amount of 0.1 to 70 parts by weight based on the total weight of the microneedle. More specifically, the content may be included in an amount of 1 to 50 parts by weight. The molecular weight of the polyvinyl alcohol (PVA) may be 5,000 to 200,000 Da.

[0067] In one embodiment of the present disclosure, the active ingredient impregnated in the first layer may include at least one active ingredient selected from the group consisting of an antiviral agent, an antifungal agent, an antibiotic, an oral disinfectant, polydeoxyribonucleotide (PDRN), a polynucleotide (PN), an extracellular matrix (ECM), and an epidermal growth factor (EGF).

[0068] Specifically, the antibiotic may include one or more antibiotics selected from the group consisting of penicillin antibiotics, cephalosporin antibiotics, macrolide antibiotics, lincosamide antibiotics, tetracycline antibiotics, and metronidazole.

[0069] Specifically, the antiviral agent may include at least one selected from the group consisting of sodium azulene sulfonate, cetylpyridinium chloride, acyclovir, triamcinolone acetonide, beclomethasone dipropionate (BMDP), betamethasone valerate, triamcinolone, triamcinolone acetonide, dexamethasone, fluocinolone acetonide, fluocinonide, flumethasone, hydrocortisone, prednisolone, and prednisone.

[0070] Specifically, the antifungal agent may be an azole-based, arylamine-based, polyene-based, or echinocandin-based antifungal agent, and the oral disinfectant may include chlorhexidine gluconate, cetylpyridinium chloride, benzethonium chloride, eucalyptol, methyl salicylate, thymol, chlorhexidine gluconate, or the like.

[0071] More specifically, the active ingredient used in the present disclosure may be epidermal growth factor (EGF). The active ingredient is not limited thereto, and may be used as a drug, vaccine, nutrient, or cosmetic, depending on the intended use.

[0072] The microneedle of the present disclosure can be designed to have a height range of the first layer of the needle portion that varies depending on the skin thickness, age, gender, race, and degree of obesity of each body part. The shape of the needle portion can be a cone shape or a polyhedral shape.

[0073] In one embodiment of the present disclosure, the height of the first layer may be, as a lower limit, 50 μm or more, 60 μm or more, 70 μm or more, 80 μm or more, 90 μm or more, or 100 μm or more, and as an upper limit, 2,000 μm or less, 1,900 μm or less, 1,800 μm or less, 1,700 μm or less, 1,600 μm or less, 1,500 μm or less, 1,400 μm or less, 1,300 μm or less, 1,100 μm or less, or 1,000 μm or less, but is not necessarily limited thereto. Specifically, the height may be in the range of 50 to 2,000 μm or 70 to 1,500 μm. More preferably, the height may be in the range of 100 to 1,000 μm.

[0074] The height ratio of the first layer:second layer of the above needle portion may be, but is not necessarily limited to, a ratio of 1:1 to 100:1, 1:1 to 80:1, or 1:1 to 70:1. Depending on the thickness of the second layer, the first layer impregnated with the active ingredient may perforate deeper into the dermis of the skin, and this may be appropriately designed to maximize the drug effect depending on the skin thickness of each body part. Therefore, the height ratio of the first layer:second layer is not limited to the above range, and a person skilled in the art may appropriately select and design the ratio of the first layer:second layer depending on the perforation depth, the material of the drug, etc.

[0075] In one embodiment of the present disclosure, the width can be adjusted according to the height of the needle portion. The width-to-height ratio of the needle portion may be 1:1 to 20, 1:1 to 1:18, 1:1 to 1:16, 1:1 to 1:14, or 1:1 to 1:12, and more specifically, may be 1:1 to 10, but is not necessarily limited thereto. If the needle portion exceeds a ratio of 1:1 to 20, the needle may break or bend when piercing the skin, preventing smooth drug delivery within the body.

[0076] In one embodiment of the present disclosure, the compressive strength of the soluble microneedle may be 0.080 N or more.

[0077] The above compressive strength refers to the force resisted by the micro needle by applying compression of 0.325 mm at a speed of 0.5 mm / s after fixing the compressive strength jig so that it can extrude one micro needle using a UTM (Universal Testing Machine).

[0078] Specifically, under the above conditions, the compressive strength of the soluble microneedle may be 0.080 N or more, 0.090 N or more, 0.01 N or more, 0.02 N or more, or 0.030 N or more, and more preferably 0.031 N or more, 0.032 N or more, or 0.033 N or more. Since the microneedle is characterized by painless skin penetration, the microneedle must have sufficient strength to penetrate the stratum corneum and epidermis layer of 10-20 μm. Since the microneedle of the present disclosure has a strength greater than the compressive strength of the above range, when puncturing the mucosa to inject the active ingredient, the active ingredient can be effectively delivered into the skin without breaking or bending.

[0079] One embodiment of the present disclosure can provide a method for manufacturing a soluble microneedle, including the steps of: preparing a negative mold having a shape of a microneedle; preparing a first solution by dissolving a biodegradable material and an active ingredient in a solvent; preparing a second solution by dissolving a biodegradable polymer having bioadhesiveness in a solvent; forming a first layer of a needle portion by injecting the first solution into the negative mold, and sequentially injecting the second solution into a second layer portion and a base portion of the needle portion; and drying the mold into which the solution has been injected.

[0080] The solvent of the first solution is determined by the active ingredient and the biodegradable polymer, and the active ingredient and the biodegradable polymer may be dissolved in a hydrophilic solvent. The hydrophilic solvent may be water, ionized water, distilled water, or purified water, and specifically, distilled water.

[0081] In one embodiment of the present disclosure, the active ingredient included in the first solution may include one or more active ingredients selected from the group consisting of an antiviral agent, an antifungal agent, an antibiotic, an oral disinfectant, polydeoxyribonucleotide (PDRN), polynucleotide (PN), extracellular matrix (ECM), and epidermal growth factor (EGF), but is not limited thereto.

[0082] In one embodiment of the present disclosure, the biodegradable material of the first solution is chitosan, collagen, gelatin, hyaluronic acid, fibrin, agarose, heparin, chondroitin (sulfate) albumin, fullulan, cellulose, pectin, starch, glycogen polylysine, polylactic acid (PLA), carboxymethylcellulose (CMC), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polycarbonate. It may include at least one or two or more selected from the group consisting of collagen-acrylate, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, polylactide glycolide (PLGA), and copolymers forming the above polymers.

[0083] In the present disclosure, the biodegradable material of the first solution may be included in an amount of 0.1 to 20 parts by weight relative to the weight of the entire solution.

[0084] Specifically, the biodegradable material may be included in an amount of 0.1 parts by weight or more, 0.5 parts by weight or more, 1.0 parts by weight or more, 2.0 parts by weight or more, 3.0 parts by weight or more, 4.0 parts by weight or more, or 5.0 parts by weight or more, as a lower limit, and 15 parts by weight or less, 14 parts by weight or less, 13 parts by weight or less, 12 parts by weight or less, 11 parts by weight or less, or 10 parts by weight or less, as an upper limit, but is not necessarily limited thereto. More specifically, it may be included in an amount of 0.1 to 10 parts by weight, or 1 to 10 parts by weight.

[0085] When the first solution contains fullerene, distilled water may be used as the solvent of the first solution as a hydrophilic solvent.

[0086] The water-soluble additive in the first solution may further include at least one selected from the group consisting of xanthan gum, fucoidan, carrageenan, carbopol, sucrose, maltose, lactose, cellobiose, hyaluronic acid, and cyclodextrin.

[0087] The first solution may additionally contain a surfactant to facilitate interaction between the active ingredient and the biodegradable polymer. Any surfactant known to those skilled in the art that can be added to drugs may be used without limitation. Specifically, the first solution may include at least one selected from the group consisting of sodium lauryl sulfate, sorbitan, polyglycerin ester, lecithin, saponin, and sugar ester.

[0088] The above additive may be included in an amount of 1 to 20 parts by weight relative to the weight of the first solution. More specifically, it may be included in an amount of 1 to 10 parts by weight.

[0089] In one embodiment of the present disclosure, the biodegradable polymer having bioadhesive properties of the second solution may include at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxyalkyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol (PVA), cellulose polymer, furcelleran, pectin, and copolymers forming the polymer, but is not limited thereto.

[0090] The biodegradable material of the second solution may be included in an amount of 0.1 parts by weight or more, 0.5 parts by weight or more, 1.0 parts by weight or more, 2.0 parts by weight or more, 3.0 parts by weight or more, 4.0 parts by weight or more, or 5.0 parts by weight or more, as a lower limit, relative to the weight of the entire second solution. The amount may be included in an amount of 20 parts by weight or less, 18 parts by weight or less, 16 parts by weight or less, 14 parts by weight or less, 12 parts by weight or less, or 10 parts by weight or less, but is not necessarily limited thereto. Specifically, the amount may be included in an amount of 0.1 to 20 parts by weight, and more specifically, the amount may be included in an amount of 1 to 10 parts by weight.

[0091] When polyvinyl alcohol (PVA), a water-soluble polymer, is used as the water-soluble compound contained in the second solution, the solvent of the second solution may be water or a mixed solution of water and alkyl alcohol as the hydrophilic solvent. More specifically, water may be used as the solvent.

[0092] The above solution may further include solubilizers, plasticizers, surfactants, preservatives, anti-inflammatory agents, and the like, depending on the intended use. Various ingredients known in the art may be appropriately selected and used. The above additives may be included in an amount of 1 to 20 parts by weight relative to the total weight of the solution. More specifically, they may be included in an amount of 1 to 10 parts by weight.

[0093] To facilitate understanding of the present invention, the following detailed description will be given through examples and other means. However, the embodiments of the present invention are not limited to the embodiments described herein and may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more fully explain the present invention to those of ordinary skill in the art, and are provided solely to sufficiently convey the spirit of the present invention to those skilled in the art.

[0094]

[0095] <Example 1: Manufacturing of soluble microneedles>

[0096] A first solution to be injected into the needle portion of the negative mold was prepared by dissolving 4% concentration of fullulan, a biodegradable polymer, and 1 ppm of EGF (epidermal growth factor), an active ingredient, in distilled water. A second solution was prepared by dissolving 4% concentration of polyvinyl alcohol (PVA) in water.

[0097] A needle-shaped negative mold was prepared, and using a Musashi equipment (precision dispensing equipment), a first solution was first injected into the needle portion of the negative mold to form a first layer, and a second solution was then injected into the needle portion to form a second layer. Next, the second solution was injected into the base portion, and then dried to produce soluble microneedles.

[0098] Referring to the schematic diagram of Fig. 1 of the above embodiment, it can be confirmed that the first solution and the second solution are sequentially injected into the needle portion of the soluble microneedle, and the second solution is injected into the base portion.

[0099] <Comparative Example 1>

[0100] After dissolving 4% of the biodegradable polymer fullulan and 1 ppm of EGF in distilled water, the solution was injected into the needle portion and base portion of the negative mold and then dried to manufacture microneedles.

[0101] Comparative Example 2

[0102] Polyvinyl alcohol (PVA) 4% and EGF 1 ppm were dissolved in distilled water and prepared using the same method as in Comparative Example 1.

[0103] <Comparative Example 3>

[0104] A comparative experiment was conducted with the commercially available Acropass Needle Patch from Laphas Co., Ltd., compared to the present invention.

[0105] Experimental Example 1: Microneedle mucosal adhesion experiment.

[0106] In order to test the solubility and mucosal adhesion of microneedles in the skin, the above-mentioned manufacturing examples 1 and comparative examples 1 and 2, and the existing commercially available needle patch (comparative example 3) were attached to the pig gum skin to conduct a solubility test.

[0107] As a result of the mucosal adhesion experiment, it was confirmed that the needle patches of Example 1 of the present disclosure and Comparative Example 1, which are microneedles composed only of fullulan, closely adhered to the pig gum mucosa, while the needle patches of Comparative Examples 2 and 3, which are microneedles composed only of polyvinyl alcohol (PVA), did not adhere to the pig gum mucosa.

[0108] It can be confirmed that Comparative Examples 2 and 3 are difficult to attach to the affected area of ​​the oral cavity and cannot be used for oral use without a separate adhesive, and even if attached using an adhesive, the adhesive of the existing hydrocolloid has the problem of causing irritation or damage to the skin.

[0109] That is, as a result of the mucosal adhesion experiment, one embodiment of the present disclosure can provide a soluble microneedle that does not damage the adhesive surface of the skin by forming a gel with a bioadhesive material in the moisture of the mucosa and closely adhering to the mucosa without an adhesive for attaching to the existing microneedle.

[0110] Experimental Example 2: Microneedle solubility measurement experiment.

[0111] Next, the dissolution time was measured by checking the point at which the microneedles were completely dissolved every 5 minutes after being attached to the pig gum skin. Comparative Examples 1 and 3 did not attach to the pig gum mucosa, so physical contact was maintained to confirm solubility.

[0112] Attachment Example 1 Comparative Example 1 (Not attached, enjoyed) Comparative Example 2 Comparative Example 3 (Needle Patch) (Not attached, enjoyed) 150 min 60 min 5 min 20 min 245 min 65 min 10 min 25 min 350 min 60 min 5 min 30 min Result (average) 50 min 65 min 10 min 30 min

[0113] Referring to Table 1 above, it can be confirmed that the time required for Example 1 of the present disclosure to be closely attached to the pig gum mucosa and for the needle portion to be completely dissolved is up to 50 minutes.

[0114] On the other hand, Comparative Example 2 adhered closely to the gum mucosa, but the needle part was measured to be completely dissolved in a short time of up to 10 minutes. Dissolvable microneedles have excellent dosing properties because they are dissolved by body fluids after skin administration, but require a long time of more than 30 minutes for the drug to be completely delivered. In cases where dissolution occurs quickly, as in Comparative Example 2, the problem arises of having to attach the same microneedles multiple times.

[0115] Through this experiment, it was confirmed that the embodiment of the present disclosure can be closely attached to a mucous membrane such as the oral cavity for a relatively long period of time, and has the effect of continuously releasing a drug for a long period of time, thereby increasing the treatment efficiency.

[0116] Additionally, since the entire first layer of the micro needle is inserted into the skin and dissolved, the effect of allowing virtually all of the effective ingredients to penetrate into the body is achieved.

[0117]

[0118] Experimental Example 3: Measurement of soluble microneedle strength (compressive yield stress)

[0119] In order to measure the compressive yield strength of the soluble microneedle, a UTM (Universal Testing Machine) was used to fix the compressive strength jig so that one microneedle could be extruded, and then 0.325 mm of compression was applied at a speed of 0.5 mm / s to measure the force resisted by the microneedle.

[0120] Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 (Hyaluronic Acid Base) 10.383 N 0.397 N 0.080 N 0.074 N 20.381 N 0.374 N 0.079 N 0.077 N 30.374 N 0.394 N 0.074 N 0.079 N Average 0.380 N 0.388 N 0.077 N 0.076 N

[0121] Referring to Table 2 above, the strength of the embodiment of the present disclosure was measured at 0.380 N, while the strength of Comparative Example 3, an existing commercially available needle patch, was measured at an average of 0.076 N, and that of Comparative Example 2 was measured at an average of 0.077 N. Comparative Example 1 has a relatively high strength, but has the problem of being difficult to attach to the mucosa.

[0122] Referring to FIG. 4, it can be confirmed that the microneedle according to Example 1 perforated the pig gum mucosa. Accordingly, it can be confirmed that the soluble microneedle of the example of the present disclosure has sufficient mechanical strength to be inserted into the skin without bending, thereby completely supplying the effective substance into the body.

[0123] While the embodiments of the present invention have been described above with reference to the attached drawings, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without altering the technical concept or essential features thereof. Therefore, the embodiments described above should be understood to be illustrative in all respects and not restrictive.

[0124] (Explanation of symbols)

[0125] 1: Soluble microneedles

[0126] 10: First layer

[0127] 20: Second layer

[0128] 30: Needle part

[0129] 40: Base layer

Claims

1. A soluble microneedle comprising a plurality of needle portions containing an active ingredient and a biodegradable polymer and a base layer supporting the needle portions, The above needle portion includes a first layer impregnated with an effective ingredient and a second layer disposed adjacent to the base layer, The base layer is a soluble microneedle comprising a polymer having bioadhesive properties.

2. In paragraph 1, A soluble microneedle, wherein when the soluble microneedle is attached to the mucosa, the base layer dissolves before the first layer of the needle portion.

3. In paragraph 1, The first layer of the above needle portion is made of chitosan, collagen, gelatin, hyaluronic acid, fibrin, agarose, heparin, chondroitin sulfate albumin, fullulan, cellulose, pectin, starch, glycogen polylysine, polylactic acid (PLA), carboxymethylcellulose (CMC), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polycarbonate. A soluble microneedle comprising at least one member selected from the group consisting of collagen-acrylate, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, polylactide glycolide (PLGA), and copolymers forming the above polymers.

4. In paragraph 1 A soluble microneedle, wherein the second layer of the needle portion or the base layer comprises at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxyalkyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, cellulose polymer, furcelleran, pectin, and a copolymer forming the polymer.

5. In paragraph 1, The first layer of the above needle portion contains fullulan, A soluble microneedle, wherein the content of fullulan is 1 to 50 parts by weight of the total weight of the microneedle.

6. In paragraph 1, The second layer of the base layer or the needle portion contains polyvinyl alcohol (PVA), A soluble microneedle, wherein the content of the polyvinyl alcohol (PVA) is 1 to 50 parts by weight of the total weight of the microneedle.

7. In paragraph 1, A soluble microneedle comprising at least one active ingredient selected from the group consisting of an antiviral agent, an antifungal agent, an antibiotic, an oral disinfectant, polydeoxyribonucleotide (PDRN), polynucleotide (PN), extracellular matrix (ECM), and epidermal growth factor (EGF).

8. In paragraph 1, A soluble microneedle, wherein the height of the first layer of the needle portion is 100 to 10,000 μm.

9. A soluble microneedle having a height ratio of the first layer: second layer of the needle portion of 1:1 to 100:

1.

10. In paragraph 1, A soluble microneedle having a width to height ratio of the needle portion of 1:1 to 1:

10.

11. In paragraph 1, A soluble microneedle having a compressive strength of 0.080 N or more.

12. Step of preparing a microneedle shape engraving mold; A step of preparing a first solution by dissolving a biodegradable material and an active ingredient in a solvent; A step of preparing a second solution by dissolving a biodegradable polymer having bioadhesive properties in a solvent; A step of forming a first layer of a needle part by injecting the first solution into a negative mold, and sequentially injecting the second solution into the second layer part of the needle part and the base part; A method for manufacturing a soluble microneedle, comprising the step of drying a mold into which the solution is injected.

13. In paragraph 12, A method for manufacturing a soluble microneedle, wherein the above active ingredient comprises at least one active ingredient selected from the group consisting of an antiviral agent, an antifungal agent, an antibiotic, an oral disinfectant, polydeoxyribonucleotide (PDRN), polynucleotide (PN), extracellular matrix (ECM), and epidermal growth factor (EGF).

14. In paragraph 12, The biodegradable materials of the second stage above are fullulan, chitosan, collagen, gelatin, hyaluronic acid, fibrin, agarose, heparin, chondroitin (sulfate) albumin, cellulose, pectin, starch, glycogen polylysine, polylactic acid (PLA), carboxymethylcellulose (CMC), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polycarbonate. A method for manufacturing a soluble microneedle, comprising at least one member selected from the group consisting of collagen-acrylate, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, polylactide glycolide (PLGA), and copolymers forming the above polymers.

15. In paragraph 12, A method for manufacturing a soluble microneedle, wherein the biodegradable polymer having bioadhesiveness in the third step comprises at least one selected from the group consisting of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose, hydroxyalkyl cellulose, polyvinylpyrrolidone, cellulose polymer, furcelleran, pectin, and copolymers forming the polymer.

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