Microneedle containing surface-modified microspheres and manufacturing method thereof

Abstract

To provide a microneedle containing a surface-modified microsphere having improved retention duration in the body and superior sustained-release effects, and suitable for use in treatment of diseases requiring continuous drug administration, and manufacturing method thereof.SOLUTION: A manufacturing method of microneedles containing surface-modified microspheres with an encapsulated drug, the method comprising the steps of: a) dissolving a soluble material in water to form a first solution; b) preparing a surface-modified microsphere containing a drug; c) mixing and homogenizing the first solution and the surface-modified microsphere to form a mixed solution; d) filling an engraved microneedle mold with the mixed solution; and e) drying the filled mixed solution and separating it from the mold.SELECTED DRAWING: Figure 6

Description

Detailed Description of the Invention

[0001] 〔Technical Field〕 The present invention relates to a microneedle containing surface-modified microspheres and a method for manufacturing the same, and more particularly, to a microneedle containing surface-modified microspheres suitable for use in the treatment of diseases that require improved in-vivo retention persistence, excellent sustained-release effects, and continuous drug administration, and a method for manufacturing the same.

[0002] 〔Background Art〕 Transmitting drugs through the skin is used in various fields and forms due to its convenience of use. Such drugs passing through the skin are mainly for transmitting to the systemic circulation system through the skin. In addition, drugs such as atopic treatment agents, acne treatment agents, and skin disease treatment agents are also used for the purpose of transmitting to the organs of the skin itself. Despite such convenience and functionality, due to the structure of the skin, there are many difficulties in transmitting drugs through the skin, and it is not easy to develop drugs that pass through the skin. The stratum corneum of the skin consists of a brick structure composed of keratin-rich keratinocytes and a mortar structure filled with lipids such as ceramides, fatty acids, or waxes between such keratinocytes. Such a structure serves as a barrier and has the characteristic of very low substance permeability. Only low molecular weight components with a molecular weight of 500 Da or less can be transmitted into the skin by a diffusion method, and only substances with excellent lipid affinity can pass through the skin.

[0003] To overcome this, new systems such as microneedles have been developed, and microneedles have the advantage that they can be applied in a patch form without additional equipment and can be easily applied in daily life. Among them, the microneedle patch is a method in which a plurality of microneedles are attached in the patch, and the microneedles project small holes on the surface of the skin to transmit drugs.

[0004] Recently, soluble microneedles based on biodegradable polymers have been developed. After the microneedles penetrate into the skin, they are biodegradable in the body, and a method has been developed in which the active substance is eluted into the skin (Korean Patent Registration No. 10-2234446). In this way, the active substance inserted into the skin by the soluble microneedles has a problem that it is detached from under the skin due to skin elasticity, and the in vivo retention persistence decreases. In the case of sustained-release drugs that require the active substance to exert its medicinal effect over a long period of time, there is a particular need for high in vivo retention persistence.

[0005] Therefore, there is a demand for the development of microneedles that have improved in vivo retention persistence, are excellent in sustained-release effect, and are suitable for use in the treatment of diseases that require continuous drug administration.

[0006] 〔Summary of the Invention〕 〔Problems to be Solved by the Invention〕 Accordingly, as a result of continuous research to meet the requirements in the prior art, the inventors have surprisingly found that in the case of microneedles manufactured using microspheres with a modified surface containing a drug, the in vivo retention persistence is improved, it is excellent in sustained-release effect, and it is suitable for use in the treatment of diseases that require continuous drug administration, and thus the present invention has been completed.

[0007] Therefore, an object of the present invention is to provide a microneedle containing surface-modified microspheres.

[0008] Another object of the present invention is to provide a method for manufacturing a microneedle containing surface-modified microspheres.

[0009] Still another object of the present invention is to provide a microneedle transdermal patch containing the microneedle.

[0010] 〔Means for Solving the Problems〕 To achieve the above object of the present invention, there is provided a microneedle containing surface-modified microspheres containing a drug.

[0011] In the present invention, "surface modification" means microspheres having a surface on which a dimple structure, wrinkles, or other grooves that can be seen on a golf ball are formed on the surface of the microspheres.

[0012] In the present invention, "microsphere" is a biodegradable microsphere and is a carrier for transmitting drugs and the like into the body. The biodegradable microsphere has a biodegradation period in the living body determined by the degradation mechanism and degradation rate of the biodegradable polymer as the main constituent component, and the release of the drug encapsulated therein is carried out over a certain period according to the biodegradation rate of these polymers in the living body. The average size of the microspheres is not particularly limited, but is a size suitable for use inside a microneedle, and may be approximately 50 μm or less, preferably 10 μm or less.

[0013] In the present invention, the surface-modified microspheres may be in the form of a single emulsion and may be of the oil-in-water (O / W), water-in-oil (W / O), oil-in-oil (O / O), solid-in-oil (S / O), or solid-in-water (S / W) type, preferably the oil-in-water (O / W) type emulsion. in water) type emulsion.

[0014] In the present invention, the method for producing microspheres may use the solvent evaporation method, which includes the step of evaporating and curing the organic solvent used during the production of the microspheres. In addition, other methods such as the spray drying method and the sonication method may also be used.

[0015] When producing biodegradable microspheres by the solvent evaporation method, in the case of water-in-oil (O / W) type microspheres which are a single emulsion, a non-polar organic solvent that does not mix with water is used as the internal oil phase, and a biodegradable polymer and a drug are simultaneously dissolved in the non-polar organic solvent, and this can be rapidly dispersed in an aqueous phase in which a surfactant is dissolved for production. Specifically, the microspheres in the present invention include: i) dissolving a drug and a surfactant biodegradable polymer in an organic solvent to prepare an oil phase; ii) mixing the oil phase with an aqueous phase in which a water-soluble polymer is dissolved to form a water-in-oil emulsion; iii) evaporating the solvent in the water-in-oil emulsion to obtain microspheres with a modified surface. It can be produced by a method including these steps.

[0016] In the present invention, the "drug" is not limited to the scope of the drug as long as it is a drug used for diseases that require continuous drug administration (a sustained release effect is required), but preferably, it is a drug such as an organic compound or an inorganic compound; a biological preparation such as a peptide, protein, antibody, nucleic acid, cell, and gene; a vaccine, hormone, or a mixture thereof, and preferably, it is a poorly water-soluble drug. In the examples of the present invention, tacrolimus was used as an example of the drug.

[0017] Tacrolimus has the structure of Chemical Formula 1, suppresses calcineurin, suppresses the production of inflammatory mediators such as IL-2, and is used for the treatment of moderate-severe atopic dermatitis:

[0018]

Chemical formula

[0019] In the present invention, the surfactant biodegradable polymer may be one that can be naturally biodegraded in the body and thus excreted outside the body. Further, it may have the function of a surfactant capable of emulsifying a poorly water-soluble drug. As the surfactant biodegradable polymer, those derived from nature or those produced synthetically can be used. Twin series, poloxamers, poly(lactic acid-glycolic acid) copolymer (PLGA), poly(D,L-lactic acid) (PDLA), or a copolymer of poly D,L-lactic acid-polycaprolactone can be used. In the present invention, PLGA was used as an example. The surfactant biodegradable polymer may have a weight average molecular weight of 5,000 to 1,000,000.

[0020] The content of the drug and the surfactant biodegradable polymer used is not particularly limited, but a weight ratio of 0.1 to 10:10, 0.5 to 7:10, 3 to 7:10, or preferably 4 to 6:10 can be used. A surface in which desired grooves (dimple structures) are formed in the microspheres can be effectively formed within the above range.

[0021] The organic solvent is not particularly limited, and dichloromethane, methanol, ethanol, chloroform, hexane, ethyl acetate, and mixtures thereof can be used, and preferably dichloromethane is used. The organic solvent is mixed with the mixture of the drug and the surfactant biodegradable polymer at a mixing ratio of 1:10 to 1:30 (w / v). A surface in which desired grooves (dimple structures) are formed in the microspheres can be effectively formed within the above range.

[0022] In step ii), it includes the mixing of the oil phase and the water phase. The water phase contains a dissolved water-soluble polymer, and the water-soluble polymer can be added for the stabilization of the emulsion during the production process (step iii)) of emulsion-solvent evaporation.

[0023] In the absence of a water-soluble polymer substance, it is possible to obtain results in the form of binding between emulsions or a non-uniform form such as a fibrous form during the process, and the addition can contribute to preventing this. After the production process of emulsion-solvent evaporation, the water-soluble polymer can be removed through a washing process. As the water-soluble polymer, polyvinyl acetate (PVA), polyacrylic acid (PAA), polyvinylpyrrolidone (PVP), polyacrylamide (PAM), polyethylene oxide (PEO), polysorbate (Tween), poloxamer (Poloxamer), etc. can be used. The water-soluble polymer may have a weight average molecular weight of 1,000 to 50,000,000. In the present invention, as an example, PVA was used. The water-soluble polymer can be contained in the aqueous phase at 0.01 to 1% by weight, preferably 0.1 to 0.5% by weight. When used at the concentration of the above conditions, the emulsion is effectively formed.

[0024] The mixing is carried out at a range of 5,000 to 12,000 rpm (1st shear) by mechanical stirring means such as a homogenizer or ultrasonic waves, etc., and most preferably at 12,000 rpm. Mixing in the above range enables the effective formation of a surface on the microspheres where the desired grooves (dimple structure) are generated.

[0025] In the above step iii), evaporation is a process of evaporating the organic solvent of the oil phase formed in the aqueous phase which is the continuous phase. Evaporation is carried out with stirring, and the stirring may include mechanical stirring. At this time, the stirring speed is in the range of 800 to 1,000 rpm (2nd shear), and most preferably at 1,000 rpm. Stirring in the above range appropriately adjusts the evaporation rate and enables the good formation of grooves (dimple structure) on the surface of the microspheres.

[0026] Microspheres are formed through evaporation and exist dispersed in water which is the continuous phase. The microspheres can be easily obtained through filtration. If necessary, further impurity removal processes such as washing, centrifugation processes, and drying processes may be further carried out.

[0027] In the present invention, in order to deliver the surface-modified microspheres containing a drug into the skin, the material of the microneedles must be soluble so that it can disintegrate by the moisture in the skin, and must be biocompatible so that it can be absorbed or decomposed in the body without side effects. After being manufactured with microneedles, it is preferably made of a material with sufficient strength to penetrate the skin.

[0028] The microneedles of the present invention are soluble, that is, water-soluble and can dissolve in body fluids in the skin.

[0029] Examples of the soluble material for forming the microneedles of the present invention include one or more biocompatible materials selected from the group consisting of alginic acid, chitosan, collagen, gelatin, hyaluronic acid, chondroitin (sulfate), dextran (sulfate), fibrin, agarose, pullulan, cellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), vinyl pyrrolidone-vinyl acetate copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyalcohol, cyclodextrin, dextrin, trehalose, glucose, fructose, starch, sucrose, glucose, maltose, lactose, lactulose, fructose, turanose, melibiose, melezitose, dextran, sorbitol, mannitol, and xylitol; derivatives of the above substances; or mixtures thereof. In an example of the present invention, alginic acid and trehalose were mixed and used.

[0030] The microneedles of the present invention may further contain a plasticizer, a surfactant, a preservative, etc.

[0031] As the plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin can be used alone or in combination, but are not limited thereto. As the surfactant, for example, PEG-8 glyceryl isostearate, PEG-10 glyceryl isostearate, PEG-15 glyceryl isostearate, PEG-20 hydrogenated castor oil, PEG-30 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-80 hydrogenated castor oil, ceteth-12, etc. can be used alone or in combination, but are not limited thereto. As the preservative, for example, methyl paraben, ethyl paraben, paraben, (iso)propyl paraben, (iso)butyl chlorobutanol (chlorobutanol), benzalkonium chloride, benzethonium chloride, phenol (p-form), cresol, chlorocresol, dihydroacetic acid, sodium dihydroacetate, sorbic acid, potassium sorbate, sodium sorbate, benzoic acid, sodium benzoate, etc. can be used alone or in combination, but are not limited thereto.

[0032] The shape of the needle portion of the microneedle according to the present invention may be conical, pyramid-shaped, spherical, single-headed, wedge-shaped, blade-shaped, etc., and these must all be shapes that can penetrate the skin. In one embodiment of the present invention, a microneedle having a structurally stable pyramid-shaped needle portion was adopted.

[0033] The structures of the microneedles 10 and the microneedle patch 100 according to the present invention are illustrated in FIGS. 4a and 4b. The microneedle 10 of the present invention may include a needle part 11 and a matrix layer 12. The needle part 11 has a shape that facilitates penetration into the skin as defined above. The length of the needle part 11 is 500 to 1000 μm, preferably 750 μm. The matrix layer 12 has a thickness of 0.1 to 1 mm, preferably 0.1 to 0.3 mm. The needle part and the matrix layer contain surface-modified microspheres containing a drug. The microneedle patch 100 of the present invention is manufactured by laminating an adhesive layer 20 on one side surface of the matrix layer 12 so that the microneedle patch can be used by being attached to the skin. In the microneedle patch 100, the portion of the adhesive layer other than the portion where the microneedle 10 contacts the adhesive layer 20 is 50% or less of the total area of the adhesive layer. The microneedle patch 100 may also include a protective film 30 on the adhesive layer.

[0034] The present invention further provides a method for manufacturing the microneedle for another purpose.

[0035] The manufacturing method includes a) dissolving a soluble material in water to form a first solution; b) manufacturing surface-modified microspheres containing a drug; c) mixing the first solution and the surface-modified microspheres and homogenizing to make a mixed solution; d) filling the mixed solution into an etched microneedle mold; e) drying the filled mixed solution and separating it from the mold.

[0036] In the manufacturing method of the present invention, the soluble material, the drug, the surface modification, and the microspheres are as defined above.

[0037] In step a), the first solution may further contain a plasticizer, a surfactant, a preservative, etc. The plasticizer, surfactant, preservative, etc. are as defined above.

[0038] The method for manufacturing the surface-modified microspheres in step b) is as defined above.

[0039] In step c), 0.1 to 20 parts by weight of the surface-modified microspheres are mixed with 100 parts by weight of the first solution.

[0040] In the step of preparing the mixed solution, since the surface-modified microspheres containing the drug must be uniformly distributed in the micro-needle, after mixing the first solution and the surface-modified microspheres, they are strongly homogenized by vortexing or the like so that the microspheres in the mixed solution are uniformly dispersed in a stable state.

[0041] The conditions such as the temperature used in the production of the micro-needle are not particularly limited as long as the soluble material and the surface-modified microspheres can be sufficiently dissolved or mixed without being decomposed or deformed.

[0042] In step d), for the step of filling the mixed solution into the micro-needle mold, methods such as applying the mixed solution and then leaving it, injecting the mixed solution using a centrifuge, injecting the mixed solution after evacuating the internal air using a vacuum, injecting the mixed solution by applying pressure, etc. can be used. In step e), drying can be carried out at room temperature, or can be carried out at room temperature to 80 °C using a hot air dryer or the like, but is not limited thereto.

[0043] For still another object of the present invention, there is provided a micro-needle transdermal patch including the micro-needle containing the surface-modified microspheres containing the drug or the micro-needle containing the surface-modified microspheres containing the drug manufactured by the manufacturing method as described above.

[0044] When the drug is tacrolimus, the microneedle transdermal patch can be used for the treatment and improvement of atopic dermatitis and for the treatment and improvement of acne.

[0045] 〔Advantages of the Invention〕 The microneedles containing surface-modified microspheres containing the drug according to the present invention have improved in-vivo retention persistence and excellent sustained-release effects, and are useful for treating diseases that require continuous drug administration.

[0046] 〔Brief Description of the Drawings〕 Figures 1a and 1b are electron micrographs of the microspheres produced in Production Example 1.

[0047] Figure 2 is an electron micrograph of microspheres containing tacrolimus surface-modified with the dimple structure of Dosage Form 7 produced to confirm reproducibility.

[0048] Figure 3a shows the results of measuring the dispersion stability of microspheres containing tacrolimus surface-modified with the dimple structure according to the present invention using a LUMiSizer.

[0049] Figure 3b shows the results of measuring the dispersion stability of microspheres containing tacrolimus with a conventional smooth surface structure using a LUMiSizer.

[0050] Figures 4a and 4b are schematic diagrams of an example of the microneedles and microneedle patches according to the present invention.

[0051] Figure 5 is an electron micrograph of the microneedles according to the present invention.

[0052] Figure 6 shows the results of analyzing the content of residual subcutaneous tacrolimus over time after applying the microneedle patch according to the present invention onto the skin of a rat.

[0053] 〔Best Mode for Carrying Out the Invention〕 Hereinafter, the structure and effects of the present invention will be described in more detail based on specific examples to facilitate understanding of the present invention. However, the following examples are merely illustrative for a clearer understanding of the present invention, and the scope of rights of the present invention is not limited by the following examples.

[0054] Production Example 1: Production of Surface-Modified Microspheres Containing Tacrolimus Microspheres containing tacrolimus were produced through the oil-in-water (O / W) emulsion solvent evaporation method. The composition of the dosage form, the oil phase, the water phase, the composition of the solvent, the conditions for the homogenizer, and the mechanical stirrer were carried out as shown in Table 1 below.

[0055] Specifically, dichloromethane (DCM) was added in the volumes shown in Table 1 and Table 2 to 120 mg of tacrolimus and 300 mg of PLGA503H (Evonik Ltd., Germany) and dissolved to produce the oil phase. Then, it was mixed with the water phase of a 0.5 - 1% polyvinyl alcohol (PVA500, OCI Company, Ltd., Korea) solution for 2 minutes under the conditions shown in Table 1 using a homogenizer to form an oil-in-water emulsion. While stirring the oil-in-water emulsion for 3 hours or more under the conditions shown in Table 1 using a mechanical stirrer, the organic solvent was evaporated to form microspheres. In order to remove the remaining PVA and drug particles not captured by the polymer, centrifugation was performed at X820g for 5 minutes, washed 3 times with distilled water, and freeze-dried for 2 days to obtain particles in powder form.

[0056] [Table 1]

[0057] The particle size distribution of each of the produced microspheres containing tacrolimus was measured and shown in Table 2, and the electron micrographs of each microsphere were shown in Figures 1a and 1b.

[0058] [Table 2]

[0059] According to FIGS. 1a and 1b, microspheres containing tacrolimus surface-modified with a dimple structure in dosage forms 4 and 7 can be confirmed, and in dosage forms 1, 2, 3, 5, 6, 8, and 9, it can be confirmed that many microspheres have a conventional smooth surface.

[0060] The reproducibility of dosage form 7 was confirmed. As shown in FIG. 2, microspheres containing tacrolimus surface-modified with a uniform dimple structure were obtained in all four runs. The results of analyzing the content and size by combining all four dosage forms 7 are shown in Table 3.

[0061] [Table 3]

[0062] <Derivation of Optimal Conditions for the Production of Surface-Modified Microspheres> In order to establish the optimal conditions for producing microspheres containing tacrolimus surface-modified with a dimple structure, the manufacturing conditions of the dosage forms in Table 1 were changed and further manufactured. When manufacturing the microspheres of dosage form 1, the PVA content in the aqueous phase was increased to 1.5%, but there was no effect. When manufacturing the microspheres of dosage form 2, the stirring speed (first shear; 2nd Shear) during evaporation was increased to 1,000 rpm, and microspheres surface-modified with a dimple structure were produced. When manufacturing the microspheres of dosage form 3, the amount of the oil phase solvent (DCM) was reduced to 10 ml, and microspheres surface-modified with a dimple structure were produced. When manufacturing the microspheres of dosage form 5, the stirring speed (secondary shear; 2nd Shear) was increased to 1,000 rpm during the evaporation stage, and microspheres surface-modified with a dimple structure were produced. When manufacturing the microspheres of dosage form 6, the homogenizer mixing speed (first shear; 1st Shear) was increased to 1,000 rpm during the evaporation stage, and microspheres surface-modified with a dimple structure were produced. When the stirring speed (secondary shear; 2nd shear) was reduced to 12,000 rpm during the evaporation step in the production of microspheres for dosage forms 8 and 9, microspheres with a surface-modified dimple structure were produced. When the stirring speed (secondary shear; 2nd shear) was increased to 800-1,000 rpm during the evaporation step in the production of microspheres for dosage forms 8 and 9, microspheres with a surface-modified dimple structure were produced.

[0063] Considering the results of the above manufacturing experiments, the preferred conditions for manufacturing microspheres surface-modified with a dimple structure are mixing of the oil phase and the aqueous phase at 5,000 to 15,000 rpm (1st shear), most preferably at 12,000 rpm, stirring during solvent evaporation at 800 to 1,000 rpm (2nd shear), most preferably at 1,000 rpm, and adding an organic solvent to the mixture of drug and surface-active biodegradable polymer in the oil phase at a ratio of 1:10 to 1:30 (w / v).

[0064] Test Example 1: Analysis of dispersion stability of surface-modified microspheres The dispersion stabilities of the surface-modified (dimple structure) microspheres (formulation 7) containing tacrolimus produced in Production Example 1 and the microspheres with a smooth surface (formulation 9) were measured using a LUMiSizer, and the results are shown in FIGS. 3a and 3b and Table 4, respectively:

[0065] [Table 4]

[0066] It was confirmed that the surface-modified microspheres (dimple structure) according to the present invention have high dispersion stability because the result value of the Instability Index is low.

[0067] Production Example 2: Production of Microneedles Containing Surface-Modified Microspheres The microneedles of Example 1 and Comparative Example 1 containing the surface-modified (dimple structure) microspheres (formulation 7) containing tacrolimus produced in Production Example 1 and the microspheres with a smooth surface (formulation 9) were produced.

[0068] Specifically, after preparing the first solution with 1.0 g of sodium alginate (Sodium alginate, SUNFINE GLOBAL), 1.0 g of trehalose (Trehalose, SUNFINE GLOBAL), and 33 g of H2O, 9.9 g of the first solution was mixed with 0.1 g of the surface-modified microspheres of formulation 7 produced in Production Example 1 or the microspheres with a smooth surface of formulation 9, and vortexed for 5 minutes or more to disperse and homogenize the particles. Then, it was filled into a pyramidal negative etching silicon mold with a depth of 750 μm. After that, the mold was placed in a desiccator, depressurized to -0.04 Mpa, maintained for 30 minutes, and dried at 50 °C for 1 hour and 30 minutes using a hot air dryer. The dried microneedles were recovered using an adhesive tape, and then the ends were cut round using scissors to fit the patch shape (Fig. 4b). An electron micrograph of the completed microneedles was taken and shown in Fig. 5.

[0069] As shown in Fig. 5, it can be confirmed that the micron needles are well formed.

[0070] In addition, the strength of the micron needles of the completed Example 1 was evaluated under the conditions shown in Table 5 using a Texture Analyser, and the results are shown in Table 6:

[0071]

Table 5

[0072]

Table 6

[0073] As shown in Table 6, the strength of the micron needles of Example 1 was 2.02 on average, and it was confirmed that they had sufficient strength for skin penetration.

[0074] Test Example 2: Analysis of the subcutaneous in vivo retention persistence of drugs The hairless back skin of 6-week-old male SD rats was taken and attached to an in-vitro Franz cell permeation tester. After 0.5 minutes had elapsed after applying the micron needle patches of Example 1 and Comparative Example 1 manufactured in Production Example 2 respectively, after removing the micron needle patches, the back skin was taken at sampling times of 0, 1, 12, and 24 hours respectively, the surface was wiped with an alcohol swab, shaken and mixed for extraction with an HPLC mobile phase, the supernatant of the extract was taken, and HPLC quantitative analysis was performed. The results are shown in Table 7 and Fig. 6.

[0075]

Table 7

[0076] As shown in Fig. 6 and Table 7, when using the micron needle patch containing the microspheres with a dimple structure of Example 1 after 24 hours have elapsed, the content of subcutaneous residual tacrolimus is 3.3 μg / cm 2and remained high, but when using the micro-needle patch containing microspheres with a smooth surface of Comparative Example 1, the content of tacrolimus remaining subcutaneously was 0.3 μg / cm 2 and the residual amount was low.

[0077] The inserted microspheres can be removed subcutaneously due to skin elasticity, but the microspheres with a dimple structure of Example 1 do not detach from the subcutaneous layer compared to the microspheres with a smooth surface of Comparative Example 1 due to surface roughness, and it is confirmed that the in vivo retention persistence is high. Therefore, it can be seen that the micro-needle containing the surface-modified microspheres according to the present invention has improved in vivo retention persistence, and as a result, the sustained effect (sustained release effect) of the drug in the microspheres is achieved.

[0078] [Others] (Form 1) A micro-needle containing surface-modified microspheres containing a drug, wherein the surface-modified microspheres are biodegradable microspheres having a surface with a dimple structure or grooves of wrinkles formed thereon, the micro-needle is soluble in the skin and has improved in vivo retention persistence, a micro-needle. (Form 2) The drug is one or more selected from drugs of organic compounds or inorganic compounds, peptides, proteins, antibodies, nucleic acids, cells, genes, vaccines, and mixtures thereof, the micro-needle according to Form 1. (Form 3) The drug is poorly soluble in water, the micro-needle according to Form 2. (Form 4) The average size of the microspheres is 50 μm or less, the micro-needle according to Form 1. (Form 5) The microspheres are manufactured by any one of the solvent evaporation method, the spray drying method, and the ultrasonic crushing method, the micro-needle according to Form 1. (Form 6) The solvent evaporation method is i) Dissolving a drug and a surfactant biodegradable polymer in an organic solvent to prepare an oil phase; ii) Mixing the oil phase with an aqueous phase in which a water-soluble polymer is dissolved to form an oil-in-water emulsion; iii) Evaporating the solvent from the oil-in-water emulsion to obtain microspheres with a modified surface, the micro-needles according to Form 5 comprising these steps. (Form 7) The surfactant biodegradable polymer is any one of the Tween series, poloxamers, poly(lactic-co-glycolic acid) (PLGA), poly(D,L-lactic acid) (PDLA), and poly(D,L-lactic acid)-polycaprolactone copolymers, and the water-soluble polymer is any one of polyvinyl acetate (PVA), polyacrylic acid (PAA), polyvinyl pyrrolidone (PVP), polyacrylamide (PAM), polyethylene oxide (PEO), polysorbate (Tween), and poloxamer (Poloxamer), the micro-needles according to Form 6. (Form 8) In step ii), the mixing is carried out at 5,000 to 12,000 rpm, and in step iii), the evaporation is carried out under stirring at 800 to 1,000 rpm, the micro-needles according to Form 6. (Form 9) The soluble material for forming the microneedles is any one selected from the group consisting of alginic acid, chitosan, collagen, gelatin, hyaluronic acid, chondroitin (sulfate), dextran (sulfate), fibrin, agarose, pullulan, cellulose, polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), vinyl pyrrolidone-vinyl acetate copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyalcohol, cyclodextrin, dextrin, trehalose, glucose, fructose, starch, sucrose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melezitose, dextran, sorbitol, mannitol, xylitol, derivatives thereof, and mixtures thereof, the microneedles according to Form 1. (Form 10) The soluble material for forming the microneedles is a mixture of alginic acid and trehalose, the microneedles according to Form 9. (Form 11) The shape of the needle part of the microneedles is any one of conical, pyramid-shaped, spherical, single-headed, wedge-shaped, and blade-shaped, the microneedles according to Form 1. (Form 12) The length of the needle part of the microneedles is 500 - 1000 μm, the microneedles according to Form 1. (Form 13) A method for manufacturing the microneedles according to Form 1, the method comprising: a) dissolving a soluble material in water to form a first solution; b) manufacturing surface-modified microspheres containing a drug; c) mixing and homogenizing the first solution and the surface-modified microspheres to make a mixed solution; d) filling the mixed solution into an etched microneedle mold; e) drying the filled mixed solution and separating it from the mold. (Form 14) In step c), the method for producing the micro needles according to Form 13, wherein 0.1 to 20 parts by weight of surface-modified microspheres are mixed with 100 parts by weight of the first solution. (Form 15) The method for producing the micro needles according to Form 13, wherein the surface-modified microspheres are biodegradable microspheres having a surface with grooves of a dimple structure, and the drug is tacrolimus. (Form 16) A microneedle transdermal patch comprising microneedles containing surface-modified microspheres containing the drug according to Form 1. (Form 17) The microneedle transdermal patch according to Form 16, wherein the drug is tacrolimus. (Form 18) The microneedle transdermal patch according to Form 17, which is for the treatment and improvement of atopic dermatitis or acne.

[0079] 〔Description of symbols〕 10 Microneedles 11 Needle part 12 Matrix layer 20 Adhesive layer 30 Protective film 100 Microneedle patch

Brief description of the drawings

[0080]

Fig. 1a

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Fig. 6

Claims

1. A method for manufacturing a microneedle comprising surface-modified microspheres encapsulating a drug, the method comprising: a) dissolving a soluble material in water to form a first solution; b) manufacturing surface-modified microspheres containing a drug; c) mixing and homogenizing the first solution and the surface-modified microspheres to form a mixed solution; d) filling the mixed solution into a microneedle mold with intaglio; e) drying the filled mixed solution and separating it from the mold, wherein the soluble material is any one selected from alginic acid, hyaluronic acid, dextran, cellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), sodium carboxymethyl cellulose, polyalcohol, cyclodextrin, dextrin, trehalose, sucrose, lactose, mannitol, xylitol, and mixtures thereof; In step b), the surface-modified microspheres are manufactured by a method comprising: i) dissolving a drug and a surfactant biodegradable polymer in an organic solvent to prepare an oil phase; ii) mixing the oil phase with an aqueous phase in which a water-soluble polymer is dissolved to form a water-in-oil emulsion; iii) evaporating the solvent from the water-in-oil emulsion under stirring at 800 to 1,000 rpm to obtain surface-modified microspheres; the surfactant biodegradable polymer is a poly(lactic-co-glycolic acid) copolymer (PLGA); the water-soluble polymer is polyvinyl acetate (PVA); the surface-modified microspheres are biodegradable microspheres having a surface with a dimple structure; the microneedle is soluble in the skin and has improved in-vivo retention persistence.

2. The method for manufacturing a microneedle comprising surface-modified microspheres encapsulating a drug according to claim 1, wherein in step ii), the mixing is performed at 5,000 to 12,000 rpm.

3. The method for manufacturing a microneedle comprising surface-modified microspheres encapsulating a drug according to claim 1, wherein in step i), the organic solvent is mixed with the mixture of the drug and the surfactant biodegradable polymer at a mixing ratio of 1:10 to 1:30 (w / v).

4. In step c), 0.1 to 20 parts by weight of the surface-modified microspheres are mixed with 100 parts by weight of the first solution, the method for producing a microneedle comprising surface-modified microspheres encapsulating the drug according to claim 1.

5. The method for producing a microneedle comprising surface-modified microspheres encapsulating the drug according to claim 1, wherein the soluble material is a mixture of alginic acid and trehalose.

6. The method for producing a microneedle comprising surface-modified microspheres encapsulating the drug according to claim 1, wherein the drug is tacrolimus.

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