Microneedles comprising surface-modified microspheres and methods of making the same

Abstract

The present application provides a microneedle containing surface-modified microspheres with enhanced in vivo residence duration, excellent sustained-release effect, and suitability for use in the treatment of diseases requiring continuous administration, and a manufacturing method thereof. The microneedle containing surface-modified microspheres containing a drug of the present application has enhanced in vivo residence duration, excellent sustained-release effect, and is effective when used in the treatment of diseases requiring continuous administration.

Description

Technical Field

[0001] This invention relates to microneedles comprising surface-modified microspheres and methods for manufacturing the same, and more specifically, to microneedles comprising surface-modified microspheres that exhibit enhanced in vivo persistence and superior sustained-release effects, making them suitable for the treatment of diseases requiring continuous drug delivery, and methods for manufacturing the same. Background Technology

[0002] Drug delivery via the skin is used in various fields and forms due to its convenience. While primarily delivered to the systemic circulation, drugs for allergic dermatitis, acne, and other skin diseases are also used to deliver medications directly to the skin itself. Despite this convenience and functionality, the structure of the skin presents numerous challenges for drug delivery, making the development of transdermal drug delivery systems difficult. The stratum corneum of the skin consists of a brick-like structure of keratin-rich corneocytes and a mortar-like structure of lipids such as ceramides, fatty acids, or waxes filling the spaces between these corneocytes. This structure acts as a barrier, resulting in very poor permeability. Only low-molecular-weight components below 500 Da can be delivered into the skin via diffusion, and only substances with excellent lipid affinity can penetrate the skin.

[0003] To overcome these problems, new systems such as microneedles have been developed. Microneedles are convenient for everyday use because they can be applied as patches without the need for auxiliary equipment. Microneedle patches deliver medication by attaching multiple microneedles to the patch and creating small pores in the skin's surface.

[0004] In recent years, the development of dissolving microneedles based on biodegradable polymers has led to methods where, after the microneedles are inserted into the skin, the active ingredient is dissolved and released into the skin simultaneously through biodegradation (Korean Patent Registration No. 10-2234446). However, the active ingredient inserted into the skin using dissolving microneedles suffers from reduced persistence in the body due to skin elasticity and subsequent detachment from the subcutaneous tissue. High persistence in the body is particularly important for sustained-release drugs that require a long time to exert their effects.

[0005] Therefore, there is a need to develop microneedles with enhanced in vivo persistence and excellent sustained-release effects, suitable for the treatment of diseases requiring continuous drug delivery. Summary of the Invention

[0006] Technical issues

[0007] To address the needs of the prior art, the inventors conducted continuous research and surprisingly confirmed that when microneedles are manufactured using microspheres with modified surfaces containing drugs, the duration of in vivo residence is enhanced, the sustained-release effect is excellent, and they are suitable for the treatment of diseases requiring continuous drug administration, thus completing the present invention.

[0008] Therefore, the object of the present invention is to provide microneedles comprising surface-modified microspheres.

[0009] Another object of the present invention is to provide a method for manufacturing microneedles comprising surface-modified microspheres.

[0010] Another object of the present invention is to provide a microneedle transdermal patch comprising the above-described microneedles.

[0011] Methods for solving problems

[0012] To achieve the objectives of the present invention described above, a microneedle comprising surface-modified microspheres containing a drug is provided.

[0013] In this invention, "surface modification" means a microsphere having a surface with grooves such as dimples and wrinkles visible on a golf ball.

[0014] In this invention, "microspheres" are biodegradable microspheres, serving as carriers for delivering drugs and other substances into the body. The biodegradable microspheres determine their in vivo disappearance period based on the degradation mechanism and rate of the biodegradable polymers that are their main components. Based on the in vivo disappearance rate of these polymers, the drug encapsulated within them is released within a certain timeframe. The average size of the microspheres is not particularly limited, but for suitability for use in microneedles, it can be approximately 50 μm or less, preferably 10 μm or less.

[0015] In this invention, the surface-modified microspheres are in the form of a single emulsion, which can be 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), preferably an oil-in-water (O / W) emulsion.

[0016] In this invention, the microspheres can be manufactured using a solvent evaporation method, which includes the steps of evaporating and solidifying the organic solvent used in the manufacture of the microspheres. Alternatively, spray drying and sonication methods can also be used.

[0017] As a solvent evaporation method, in the manufacture of biodegradable microspheres, for oil-in-water (O / W) type microspheres that are a single emulsion, a non-polar organic solvent that is immiscible with water is used as the internal oil phase. This can be achieved by simultaneously dissolving the biodegradable polymer and the drug in the aforementioned non-polar organic solvent and then rapidly dispersing them in an aqueous phase containing a surfactant. Specifically, the microspheres of the present invention can be manufactured by a method comprising the following steps: i) preparing an oil phase by dissolving the drug and the surface-active biodegradable polymer in an organic solvent; ii) mixing the aqueous phase containing the water-soluble polymer with the aforementioned oil phase to form an oil-in-water emulsion; and iii) evaporating the solvent from the aforementioned oil-in-water emulsion to obtain surface-modified microspheres.

[0018] In this invention, "medicine" is not limited to the above-mentioned scope of medicines as long as it is used for diseases requiring continuous administration (requiring sustained-release effect); preferably, it can be a pharmaceutical agent such as an organic or inorganic compound; a biological agent such as a peptide, protein, antibody, nucleic acid, cell, or gene; a vaccine, hormone, or mixture thereof; and preferably, a drug that is poorly soluble in water. In an embodiment of this invention, tacrolimus is used as an example of a medicine.

[0019] Tacrolimus, with the structure of chemical formula 1, is used to treat moderate to severe atopic dermatitis by inhibiting the production of inflammatory mediators such as IL-2 through the inhibition of calcineurin.

[0020]

[0021] In this invention, the surface-active biodegradable polymer can be naturally biodegraded in vivo and thus excreted from the body. Furthermore, it can possess the function of a surfactant capable of emulsifying drugs that are poorly soluble in water. As the aforementioned surface-active biodegradable polymer, all substances derived from nature or manufactured synthetically can be used. Tween series, poloxamer derivatives, polylactic-co-glycolic acid copolymer (PLGA), poly(D,L-lactic acid) (PDLA), or copolymers of poly(D,L-lactic acid) and polycaprolactone can be used. In this invention, PLGA is used as an example. The weight-average molecular weight of the surface-active biodegradable polymer can be from 5,000 to 1,000,000.

[0022] There are no particular restrictions on the content of the drug and the surface-active biodegradable polymer used. By weight ratio, 0.1–10:10, 0.5–7:10, 3–7:10, and preferably 4–6:10 can be used. Within the above range, the microspheres can be effectively formed on a surface with the desired grooves (dent structure).

[0023] There are no particular limitations on the organic solvent; dichloromethane, methanol, ethanol, chloroform, hexane, ethyl acetate, and mixtures thereof can be used, with dichloromethane being preferred. The organic solvent is mixed at a ratio of 1:10 to 1:30 (w / v) relative to the mixture of the aforementioned drug and the surface-active biodegradable polymer. Within this range, the microspheres will effectively form a surface with the desired grooves (indentation structure).

[0024] Step ii) above includes mixing the oil phase and the aqueous phase. The aqueous phase contains dissolved water-soluble polymers, which may be added for the stabilization of the emulsion in the emulsion-solvent evaporation manufacturing process (step iii).

[0025] Without water-soluble polymers, the process may result in uneven morphology, such as binding between emulsions or fibrous structures. The addition described above helps prevent this problem. After the emulsion-solvent evaporation manufacturing process, the water-soluble polymers can be removed by a washing process. Water-soluble polymers that can be used include polyvinyl acetate (PVA), polyacrylic acid (PAA), polyvinylpyrrolidone (PVP), polyacrylamide (PAM), polyethylene oxide (PEO), Tween, and poloxamer. The weight-average molecular weight of the water-soluble polymer can be from 1,000 to 50,000,000. In this invention, PVA is used as an example. The content of the water-soluble polymer in the aqueous phase can be from 0.01 to 1% by weight, preferably from 0.1 to 0.5% by weight. When used at the concentrations described above, an emulsion is effectively formed.

[0026] The above mixing is performed using a mechanical stirring mechanism such as a homogenizer or ultrasound at a range of 5,000 to 12,000 rpm (first shear), most preferably 12,000 rpm. Mixing within this range enables the microspheres to effectively form a surface with the desired grooves (dent structure).

[0027] In step iii) above, evaporation is the process of evaporating the organic solvent in the oil phase formed in the aqueous phase, which is a continuous phase. Evaporation can be accompanied by stirring, which may include mechanical stirring, in which case the stirring speed is in the range of 800 to 1,000 rpm (second shear), preferably 1,000 rpm. Stirring within the above range will adjust the evaporation rate appropriately so that grooves (dent structures) are well formed on the surface of the microspheres.

[0028] Microspheres are formed through evaporation and dispersed in the continuous phase of water. These microspheres can be obtained through simple filtration. Further impurity removal processes such as washing, centrifugation, and drying can be performed as needed.

[0029] In this invention, in order to deliver drug-containing surface-modified microspheres into the skin, the material of the microneedles should have solubility that can be broken down by water in the skin, and should have biocompatibility that can be absorbed or decomposed without producing side effects in the body. Preferably, it is made of a material that has the strength to pierce the skin after being made into microneedles.

[0030] The microneedles of the present invention are soluble, that is, they are water-soluble and can be dissolved in bodily fluids within the skin.

[0031] The dissolving material for forming the microneedles of the present invention may comprise: one or more biocompatible materials selected from the group consisting of alginic acid, chitosan, collagen, gelatin, hyaluronic acid, chondroitin (sulfate), dextran (sulfate), fibroin, agarose, amylopectin, cellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), ethylene pyrrolidone-vinyl acetate copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polyols, cyclodextrin, dextrin, trehalose, glucose, fructose, starch, sucrose, maltose, lactose, lactulose, melilothiose, melatotriose, melilothiose, dextran, sorbitol, mannitol, and xylitol; derivatives of the above substances; or mixtures thereof. In an embodiment of the present invention, as an example, a mixture of alginic acid and trehalose is used.

[0032] The microneedles of the present invention may further contain plasticizers, surfactants, preservatives, etc.

[0033] As plasticizers, 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 surfactants, PEG-8 isostearyl ester, PEG-10 isostearyl ester, PEG-15 isostearyl ester, 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, CETEARETH-12, etc., can be used alone or in combination, but are not limited thereto. As preservatives, for example, methylparaben, ethylparaben, parabens, isopropylparaben, chlorobutanol, benzalkonium chloride, benzyl chloride, phenol (p-type), cresol, chlorocresol, dihydroacetic acid, sodium dihydroacetate, sorbic acid, potassium sorbate, sodium sorbate, benzoic acid, sodium benzoate, etc., may be used alone or in combination, but are not limited to these.

[0034] The shape of the needle tip of the microneedle of the present invention can be conical, pyramidal, spear-shaped, short-headed, wedge-shaped, blade-shaped, etc., and they should all have a shape that can penetrate the skin. In one embodiment of the present invention, a microneedle with a structurally stable pyramidal needle tip is selected.

[0035] The structures of the microneedles 10 and the microneedle patch 100 of the present invention are as follows: Figure 4a and Figure 4b As illustrated, the microneedle 10 of the present invention may include a needle head 11 and a pad 12. The needle head 11 has a shape that facilitates skin penetration as defined above. The length of the needle head 11 is 500 to 1000 μm, preferably 750 μm. The thickness of the pad 12 is 0.1 to 1 mm, preferably 0.1 to 0.3 mm. The needle head and the pad contain surface-modified microspheres containing a drug. The microneedle patch 100 of the present invention is manufactured in such a way that an adhesive layer 20 is laminated on one side of the pad 12, thereby enabling the microneedle patch to be adhered to the skin for use. 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 less than 50% of the total area of ​​the adhesive layer. The microneedle patch 100 may also include a protective film 30 on the adhesive layer.

[0036] According to another objective of the present invention, a method for manufacturing the above-described microneedles is provided.

[0037] The above manufacturing method includes:

[0038] a) The step of dissolving the soluble material in water to form a first solution;

[0039] b) Steps for preparing surface-modified microspheres containing drugs;

[0040] c) The step of mixing the first solution with the above-mentioned surface-modified microspheres and homogenizing them to prepare a mixed solution;

[0041] d) The step of filling the above mixed solution into the microneedle negative mold; and

[0042] e) The step of drying the filled mixture and separating it from the mold.

[0043] In the manufacturing method of this invention, the soluble material, drug, surface modifier, and microspheres are the same as defined above.

[0044] In step a), the first solution may further contain plasticizers, surfactants, preservatives, etc. Plasticizers, surfactants, preservatives, etc., are the same as defined above.

[0045] The method for manufacturing surface-modified microspheres in step b) is the same as defined above.

[0046] In step c), 0.1 to 20 parts by weight of surface-modified microspheres are mixed relative to 100 parts by weight of the first solution.

[0047] In the process of preparing the mixed solution, since the surface-modified microspheres containing the drug need to be uniformly distributed within the microneedles, after mixing the first solution with the surface-modified microspheres, they are homogenized by strong methods such as eddy mixing to ensure that the microspheres are uniformly dispersed in a stable state in the mixed solution.

[0048] There are no particular restrictions on the temperature and other conditions used in the manufacture of the aforementioned microneedles, as long as the soluble material or surface-modified microspheres can be fully dissolved or mixed without decomposition or deformation.

[0049] In step d), the step of filling the mixed solution into the microneedle mold can be performed by the following methods: coating the mixed solution and then letting it stand; injecting the mixed solution using a centrifuge; injecting the mixed solution by extracting the internal air through a vacuum; or injecting the mixed solution by applying pressure, etc.

[0050] In step e), drying can be carried out at room temperature, or at room temperature to 80°C using a hot air dryer, but is not limited to these methods.

[0051] According to another object of the present invention, a microneedle transdermal patch comprising the microneedles described above, wherein the microneedles comprise the drug-containing surface-modified microspheres described above or drug-containing surface-modified microspheres manufactured by the manufacturing method described above.

[0052] When the aforementioned drug is tacrolimus, the aforementioned microneedle transdermal patch can be used for the treatment and improvement of allergic dermatitis and acne.

[0053] Invention Effects

[0054] The microneedles of the present invention, comprising surface-modified microspheres containing drugs, exhibit enhanced in vivo retention and excellent sustained-release effect, making them effective for the treatment of diseases requiring continuous drug administration. Attached Figure Description

[0055] Figure 1a and Figure 1b This is an electron microscope image of the microspheres manufactured in Example 1.

[0056] Figure 2 This is an electron microscope image of tacrolimus-containing microspheres of dosage form 7, which were surface-modified with a concave structure and manufactured to confirm reproducibility.

[0057] Figure 3a The results were obtained by measuring the dispersion stability of the tacrolimus-containing microspheres with surface modification and concave structure according to the present invention using LUMiSizer.

[0058] Figure 3b The results are obtained by using the LUMiSizer to determine the dispersion stability of tacrolimus-containing microspheres with previously smooth surface structures.

[0059] Figure 4a and Figure 4b This is a schematic diagram of an example of the microneedles and microneedle patches of the present invention.

[0060] Figure 5 This is an electron microscope image of the microneedles of the present invention.

[0061] Figure 6 The results are from the analysis of the subcutaneous tacrolimus content over time after the microneedle patch of the present invention was applied to the skin of rats. Detailed Implementation

[0062] The following specific embodiments are provided to illustrate the structure and effects of the present invention in more detail to aid in understanding. However, these embodiments are merely illustrative to provide a clearer understanding of the invention, and the scope of the claims is not limited to these embodiments.

[0063] Manufacturing Example 1: Manufacturing of Surface-Modified Microspheres Containing Tacrolimus

[0064] Tacrolimus-containing microspheres were manufactured using an oil-in-water (O / W) emulsion solvent evaporation method. The dosage form composition, oil phase, aqueous phase, solvent composition, homogenizer, and mechanical stirrer conditions were performed according to Table 1 below.

[0065] Specifically, 120 mg of tacrolimus and 300 mg of PLGA 503H (Evonik, Germany) were dissolved in dichloromethane at the volumes shown in Tables 1 and 2 to prepare an oil phase. This oil phase was then mixed with an aqueous phase of 0.5–1% polyvinyl alcohol (PVA 500, OCI, Korea) solution for 2 minutes using a homogenizer under the conditions shown in Table 1 to form an oil-in-water emulsion. The oil-in-water emulsion was stirred using a mechanical stirrer for at least 3 hours under the conditions shown in Table 1 to evaporate the organic solvent and form microspheres. To remove residual PVA and drug particles not captured by the polymer, the microspheres were centrifuged at 820 g for 5 minutes, washed three times with distilled water, and freeze-dried for 2 days to obtain powdered particles.

[0066] [Table 1]

[0067]

[0068] The particle size distribution of each tacrolimus-containing microsphere was determined and is shown in Table 2. Electron micrographs of each microsphere are shown below. Figure 1a and Figure 1b As shown.

[0069] [Table 2]

[0070] Dv10(μm) 1.13 1.2 1.14 1 1.15 1.69 1.21 0.196 0.191 Dv50(μm) 3.06 3.15 7.06 6.77 4.62 6.84 5.96 5.81 4.34 Dv90(μm) 6.46 7.39 14.8 12.6 10.4 11.11 10.6 20.5 13.4 Span value 1.741 1.96 1.94 1.71 2.00 1.38 1.57 3.50 2.86 Yield (%) 69 64 55.4 69.9 38.5 51.0 59.8 37.6 45.7

[0071] according to Figure 1a and Figure 1b In formulations 4 and 7, tacrolimus-containing microspheres with surface-modified dimple structures were identified, while in formulations 1, 2, 3, 5, 6, 8, and 9, most microspheres had the previously smooth surface.

[0072] For dosage form 7, reproducibility was confirmed, such as Figure 2 As shown, tacrolimus-containing microspheres with a uniform indentation structure were obtained in all four trials. The dosage form 7 from all four trials was collected for content and size analysis, and the results are shown in Table 3.

[0073] [Table 3]

[0074]

[0075] <Derivation of Optimal Conditions for Manufacturing Surface-Modified Microspheres>

[0076] To establish optimal conditions for manufacturing tacrolimus-containing microspheres with a surface-modified concave structure, additional manufacturing was conducted by modifying the manufacturing conditions for the dosage forms listed in Table 1. In manufacturing microspheres of dosage form 1, the PVA content in the aqueous phase was increased to 1.5%, but no effect was observed. In manufacturing microspheres of dosage form 2, the stirring speed (second shear) during evaporation was increased to 1,000 rpm, resulting in microspheres with a surface-modified concave structure. In manufacturing microspheres of dosage form 3, the amount of solvent (DCM) in the oil phase was reduced to 10 ml, resulting in microspheres with a surface-modified concave structure. In manufacturing microspheres of dosage form 5, stirring was increased during the evaporation step... Manufacturing was performed with the speed (second shear) increased to 1,000 rpm, resulting in the production of microspheres with a surface-modified concave structure. When manufacturing microspheres of dosage form 6, the homogenizer mixing speed (first shear) was reduced to 12,000 rpm, resulting in the production of microspheres with a surface-modified concave structure. When manufacturing microspheres of dosage forms 8 and 9, the stirring speed (second shear) was increased to 800-1,000 rpm during the evaporation step, resulting in the production of microspheres with a surface-modified concave structure.

[0077] Based on the manufacturing experiment results described above, the preferred conditions for manufacturing microspheres with surface modification using a concave structure are as follows: the mixing of the oil phase and the aqueous phase is carried out at a range of 5,000 to 15,000 rpm (first shear), most preferably 12,000 rpm; the stirring during solvent evaporation is carried out at a range of 800 to 1,000 rpm (second shear), most preferably 1,000 rpm; and in the oil phase, the organic solvent is added at a ratio of 1:10 to 1:30 (w / v) relative to the mixture of the drug and the surface-active biodegradable polymer.

[0078] Experimental Example 1: Dispersion Stability Analysis of Surface-Modified Microspheres

[0079] The dispersion stability of surface-modified (indented structure) microspheres (dosage form 7) and smooth-surface microspheres (dosage form 9) containing tacrolimus, manufactured in Example 1, was determined using the LUMiSizer. The results are as follows: Figure 3a and Figure 3b And as shown in Table 4:

[0080] [Table 4]

[0081] Form 7 0.234 11.63 2,991 Dosage Form 9 0.261 11.62 3,002

[0082] The surface-modified microspheres (dent structure) of the present invention have a low instability index, thus confirming high dispersion stability.

[0083] Manufacturing Example 2: Fabrication of Microneedles Containing Surface-Modified Microspheres

[0084] Microneedles were manufactured in Examples 1 and Comparative Example 1, respectively, comprising surface-modified (dented structure) microspheres (dosage form 7) containing tacrolimus and smooth-surfaced microspheres (dosage form 9) manufactured in Example 1.

[0085] Specifically, a first solution was prepared by mixing 1.0 g of sodium alginate (Sunfine Global Co., Ltd.), 1.0 g of trehalose (Sunfine Global Co., Ltd.), and 33 g of H2O. Then, 9.9 g of the first solution was mixed with 0.1 g of surface-modified microspheres of dosage form 7 or smooth-surfaced microspheres of dosage form 9 prepared in Manufacturing Example 1, and vortexed for at least 5 minutes to disperse and homogenize the particles. This mixture was then filled into a pyramidal-shaped silicone mold with a depth of 750 μm. The mold was then placed in a desiccator, depressurized to -0.04 MPa and maintained for 30 minutes, and then dried in a hot air dryer at 50°C for 1 hour and 30 minutes. After drying, the microneedles were collected using adhesive tape, and the edges were cut into a circle using scissors to conform to the shape of the patch. Figure 4b Electron microscope images of the completed microneedles are shown below. Figure 5 .

[0086] like Figure 5 As shown, microneedles can be confirmed to have formed well.

[0087] In addition, the strength of the completed microneedles of Example 1 was evaluated using texture analyzers under the conditions shown in Table 5, and the results are shown in Table 6:

[0088] Table 5]

[0089]

[0090] [Table 6]

[0091]

[0092] As shown in Table 6, it can be confirmed that the strength of the microneedles in Example 1 is an average of 2.02, which is sufficient to penetrate the skin.

[0093] Experimental Example 2: Analysis of the duration of drug retention in the subcutaneous and in vivo

[0094] Hairless dorsal skin was taken from 6-week-old male SD rats and fixed in an in-vitro Franz cell permeation tester. Microneedle patches, prepared in Manufacturing Example 2 and Comparative Example 1 respectively, were attached. After 0.5 minutes, the microneedle patches were removed. Dorsal skin samples were then taken at 0, 1, 12, and 24 hours. The surface was wiped with an alcohol swab, and extraction was performed using HPLC mobile phase with shaking. The supernatant of the extract was used for HPLC quantitative analysis. The results are shown in Table 7. Figure 6 As shown.

[0095] [Table 7]

[0096]

[0097] like Figure 6 As shown in Table 7, after 24 hours, the subcutaneous tacrolimus residue was 3.3 μg / cm³ when using the microneedle patch containing microspheres with an indented structure as described in Example 1. 2 While there was significant residue, in the case of the microneedle patch containing microspheres with a smooth surface (Comparative Example 1), the subcutaneous tacrolimus residue was 0.3 μg / cm³. 2 Low residue level.

[0098] The inserted microspheres can be removed from the subcutaneous tissue due to skin elasticity, but it was confirmed that the microspheres with the concave structure of Example 1, due to their surface roughness, did not detach from the subcutaneous tissue compared to the smooth-surfaced microspheres of Comparative Example 1, thus exhibiting high persistence in vivo. Therefore, it can be seen that the persistence of microneedles containing the surface-modified microspheres of the present invention in vivo is enhanced, resulting in sustained efficacy (sustained-release effect) of the drug within the microspheres.

[0099] [Symbol Explanation]

[0100] 10: Microneedling

[0101] 11: Needle head

[0102] 12: Subbase

[0103] 20: Adhesive layer

[0104] 30: Protective film

[0105] 100: Microneedle Patch

Claims

1. A microneedle comprising surface-modified microspheres containing a drug, The surface-modified microspheres are biodegradable microspheres with a surface having formed indentations. The surface-modified microspheres are manufactured by a solvent evaporation method, which includes: i) The step of preparing an oil phase by dissolving the drug and the surface-active biodegradable polymer in an organic solvent; ii) the step of mixing the aqueous phase containing the water-soluble polymer with the oil phase to form an oil-in-water emulsion; and iii) the step of evaporating the solvent from the oil-in-water emulsion under stirring at 800 to 1,000 rpm to obtain surface-modified microspheres. In step ii), mixing is carried out at 5,000 to 15,000 rpm. In the oil phase, an organic solvent is added at a w / v ratio of 1:10 to 1:30 relative to the mixture of the drug and the surfactant biodegradable polymer. The surfactant biodegradable polymer is polylactic-co-glycolic acid copolymer (PLGA). The water-soluble polymer is polyvinyl alcohol (PVA). The drug in question is tacrolimus. The organic solvent is dichloromethane, chloroform, or a mixture thereof. The content of the drug and the surface-active biodegradable polymer is 3-7:10 by weight. The content of the water-soluble polymer in the aqueous phase is 0.01% to 1% by weight. The soluble material forming the microneedles is selected from any one of the group consisting of alginate, hyaluronic acid, dextran, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), sodium carboxymethyl cellulose, trehalose, and mixtures thereof. The microneedles are soluble in the skin and have enhanced persistence in vivo.

2. The microneedle according to claim 1, wherein the average size of the microsphere is less than 50 μm.

3. In step ii), the mixing is carried out at 5,000 to 12,000 rpm, according to the microneedle of claim 1.

4. The microneedle according to claim 1, wherein the soluble material forming the microneedle is a mixture of alginate and trehalose.

5. The microneedle according to claim 1, wherein the shape of the needle head is any one of conical, pyramidal, spear-shaped, short-headed, wedge-shaped, or blade-shaped.

6. The microneedle according to claim 1, wherein the length of the needle tip is 500 to 1000 μm.

7. A microneedle transdermal patch comprising the microneedles of claim 1, wherein the microneedles comprise surface-modified microspheres containing a drug.

8. The microneedle transdermal patch according to claim 7, used for the treatment and improvement of allergic dermatitis or acne.

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