Microneedles containing hormone-containing surface-modified microspheres and methods for producing the same

Abstract

The present invention provides microneedles containing hormone-containing surface-modified microspheres that have improved retention in the body and enhanced sustained-release effect, and a method for producing the same. The microneedles containing the surface-modified microspheres containing hormones according to the present invention have improved retention in the body and excellent sustained release effects, and are useful for use in transdermal hormone delivery systems that require sustained administration.

Description

Detailed Description of the Invention

[0001] [Technical Field] The present invention relates to a microneedle containing hormone-containing surface-modified microspheres and a method for manufacturing the same, and more particularly to a microneedle containing surface-modified microspheres that have improved retention in the body, have excellent sustained-release effects, and are suitable for hormone delivery that requires continuous administration, and a method for manufacturing the same. [Background technology] Hormones generally refer to chemical substances produced in the endocrine organs of the body. While not fundamentally different from neurotransmitters, hormones are secreted by a wider range of endocrine organs and, unlike neurotransmitters, which primarily travel through the central nervous system, hormones are secreted by a wider range of endocrine organs and have a relatively long-lasting effect over a wider area via the bloodstream. Hormones produced in various endocrine organs are transported via the bloodstream to various organs of the body, where they exert their respective functions. Hormones are known to be directly involved in metabolism, reproduction, and cell proliferation. Therefore, hormones must be secreted within normal limits in the body. However, if hormones are deficient, they must be artificially supplemented. The most common form of replacement therapy is injection. However, conventional subcutaneous or intramuscular injections have a short half-life, which can lead to a rapid decrease in blood levels after administration. Therefore, daily administration is required to maintain efficacy, which is particularly inconvenient due to the nature of injections.

[0002] Due to its convenience, transdermal drug delivery has been used in a variety of fields and forms. While transdermal drugs are primarily used to deliver drugs to the systemic circulation through the skin, drugs for treating atopic dermatitis, acne, and skin diseases are also used to deliver drugs to the skin's own organs. Despite this convenience and functionality, the structure of the skin poses numerous challenges to transdermal drug delivery, making it difficult to develop transdermal drugs. The stratum corneum of the skin is composed of a brick structure of keratin-rich corneocytes and a mortar structure in which the spaces between these corneocytes are filled with lipids such as ceramides, fatty acids, or wax. This structure acts as a barrier, resulting in very low permeability. Only low-molecular-weight compounds (<500 Da) can be delivered into the skin via diffusion, and only substances with excellent lipophilicity can pass through the skin.

[0003] To overcome this, new systems such as microneedles have been developed. Microneedles have the advantage of being applied in the form of a patch without any additional equipment, making them easy to use in daily life. Among them, microneedle patches have multiple microneedles attached to the patch, which deliver drugs by protruding small holes on the surface of the skin.

[0004] Recently, dissolving microneedles based on biodegradable polymers have been developed, and a method has been developed in which the microneedles penetrate the skin and then biodegrade in the body, thereby dissolving the active substance into the skin (Korean Patent Registration No. 10-2234446). The active substance inserted into the skin using dissolving microneedles is prone to detachment from the subcutaneous tissue due to the elasticity of the skin, resulting in a reduced retention time in the body. In the case of sustained-release drugs, which require the active substance to exert its efficacy over a long period of time, a long retention time in the body is particularly important.

[0005] Therefore, there is a need for the development of microneedles containing hormone-containing surface-modified microspheres that have improved retention in the body and enhanced sustained-release effects, and a method for manufacturing the same. Summary of the Invention [Problem to be solved by the invention] As a result of continuous research to meet the demands of the prior art, the inventors have surprisingly found that microneedles manufactured using surface-modified microspheres containing leuprolide, a type of hormone, have improved retention in the body and enhanced sustained-release effects, making them suitable for use in the treatment of diseases requiring the administration of this hormone, thereby completing the present invention.

[0006] It is therefore an object of the present invention to provide microneedles comprising surface-modified microspheres containing hormones.

[0007] Another object of the present invention is to provide a method for producing microneedles containing surface-modified microspheres containing hormones.

[0008] It is yet another object of the present invention to provide a microneedle transdermal patch comprising the microneedles. [Means for solving the problem] In order to achieve the above-mentioned object of the present invention, a microneedle containing surface-modified microspheres containing hormones is provided.

[0009] In the present invention, "surface modified" refers to microspheres having surfaces on which wrinkles or grooves such as dimple structures that can be seen on golf balls are formed.

[0010] In the present invention, "microspheres" refer to biodegradable microspheres, which are carriers for delivering drugs and other substances into the body. The period of biodegradable microspheres' elimination in vivo is determined by the degradation mechanism and degradation rate of the biodegradable polymers that are their main constituents. The release of encapsulated drugs occurs over a certain period of time depending on the elimination rate of these polymers in vivo. The average size of the microspheres is not particularly limited, but should be a size suitable for insertion into a microneedle, and may be approximately 50 μm or less, preferably 10 μm or less.

[0011] In the present invention, the surface-modified microspheres may be in the form of a single emulsion, which may be oil-in-water (O / W; oil in water), water-in-oil (W / O; water in oil), oil-in-oil (O / O; oil in oil), S / O (solid in oil), or S / W (soil in water), and are preferably oil-in-water (O / W; oil in water) emulsions.

[0012] In the present invention, the microspheres may be prepared by a solvent evaporation method, which includes a step of volatilizing an organic solvent used in preparing the microspheres and hardening them, a spray drying method, an ultrasonic crushing method, or the like.

[0013] When preparing biodegradable microspheres using the spray-drying method, oil-in-water microspheres, which are single emulsions, can be prepared by using a water-immiscible nonpolar organic solvent as the internal oil phase and simultaneously dissolving a biodegradable polymer and a drug in the nonpolar organic solvent. Specifically, the microspheres of the present invention can be prepared by a method comprising the steps of: i) dissolving a hormone and a surface-active biodegradable polymer in an organic solvent to prepare an oil phase; and ii) spray-drying the oil phase to obtain surface-modified microspheres. If necessary, the microspheres can be used after washing with a solvent such as ethanol.

[0014] In the present invention, any hormone can be used as long as it is used for diseases requiring continuous hormone administration (requiring sustained release effect), and preferably it is a hormone that is poorly soluble in water. Specifically, the hormone may be selected from, but is not limited to, sex hormones, growth hormone, parathyroid hormone, human chorionic gonadotropin, luteinizing hormone, thyroid-stimulating hormone, follicle-stimulating hormone, gonadotropin, pituitary hormone, adrenocorticotropic hormone, insulin, salmon calcitonin, glucagon, estrogen, parathyroid, desogestrel, ethinylestradiol, testosterone, oxytocin, prolactin, endorphins, pigment-stimulating hormone, thyroxine, triiodothyronine, somatostatin, adrenaline, glucocorticoids, androgens, aldosterone, progesterone, melatonin, angiotensinogen, gastrin, somatostatin, ghrelin, secretin, cholecystokinin, renin, adenosine, gonadotropins, hCG, hPL, leptin, analogs thereof, and mixtures thereof. In the examples of the present invention, leuprolide is used as an example of a hormone.

[0015] Leuprolide is a type of LHRH (luteinizing hormone-releasing hormone) agonist. LHRH, also known as GnRH (gonadotropin-releasing hormone), is a hypothalamic decapeptide that regulates the reproductive system in vertebrates. The action of GnRH induces the synthesis and release of the gonadotropins FSH (follicle-stimulating hormone) and LH (luteinizing hormone). LHRH agonists and antagonists have been shown to be effective in treating endometriosis, fibroids, polycystic ovary syndrome, breast cancer, ovarian cancer, and endometrial cancer in women; gonadotropin-induced pituitary prolapse during medically assisted reproductive protocols; benign prostate gland polymorphism and prostate cancer in men; and precocious puberty in men and women. Currently used LHRH agonists are peptide compounds that generally must be administered intravenously or subcutaneously due to their low oral bioavailability. Furthermore, LHRH agonists must be administered long-term as medications for chronic diseases. Leuprolide has a short half-life when administered subcutaneously or intramuscularly, resulting in a rapid decrease in blood concentration and disappearance within a few hours. This means that it must be administered daily to maintain its efficacy, which is particularly inconvenient due to the nature of the injection.

[0016] In the present invention, "leuprolide" has the structure of the following chemical formula 1 and is used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, precocious puberty, etc.

[0017] [ka]

[0018] In order to deliver the hormone-containing surface-modified microspheres into the skin in the present invention, the material of the microneedles must be soluble so that they can be broken down by the moisture in the skin, and must be biocompatible so that they can be absorbed or decomposed in the body without side effects.It is preferable that the material be strong enough to puncture the skin after being made into microneedles.

[0019] The microneedles of the present invention are soluble, that is, water-soluble and dissolve in body fluids.

[0020] In the present invention, the surface-active biodegradable polymer may be one that can be naturally biodegraded in the body and excreted from the body. It may also have the function of a surfactant capable of emulsifying hormones. The surface-active biodegradable polymer may be any of those derived from nature or produced synthetically. Twin-type polymers, poloxamers, polylactic acid-glycolic acid copolymer (PLGA) or poly(D,L-lactic acid) (PDLA), and poly(D,L-lactic acid-polycaprolactone) copolymers may be used. In the present invention, PLGA is used as an example. The surface-active biodegradable polymer may have a weight-average molecular weight of 5,000 to 1,000,000.

[0021] The weight ratio of the hormone to the surface-active biodegradable polymer used is 1:4 to 1:8, preferably 1:4. This range effectively allows the microspheres to have a surface with the desired grooves (wrinkles). Furthermore, clear separation is achieved between primary particles, preventing undesired aggregation of the primary particles.

[0022] The organic solvent is not particularly limited, and dichloromethane, methanol, ethanol, chloroform, hexane, ethyl acetate, and mixtures thereof can be used. Dichloromethane is preferred. The ratio of the hormone and surfactant biodegradable polymer mixture to the organic solvent, i.e., the solids weight ratio in the spray-dried liquid (oil phase), is 0.6 to 1.3% (w / w), preferably 1.3% (w / w). This range allows the microspheres to effectively form surfaces with the desired grooves (wrinkles). Furthermore, clear separation between primary particles can be achieved, preventing undesired aggregation of the primary particles.

[0023] In step i), the dissolution time is not particularly limited, and stirring can be carried out as necessary so that the hormone and the surface-active biodegradable polymer are dissolved in the solvent.

[0024] In step ii), the spray drying process can be carried out using a conventional commercial spray dryer, and known commercial spray dryers include EYELA SD-1000 (Japan), Buchi B-290 (Switzerland), YC-500 (China), and Nano Spray Dryer B-90 (Switzerland).

[0025] In the spray drying step, the operating conditions of the spray dryer may be determined by preset values ​​depending on the type of spray dryer, but may be changed as needed.

[0026] The spray dryer can spray-dry the oil phase (spray-dried liquid) by adjusting the inlet temperature, outlet temperature, and injection speed. The inlet temperature is 60 to 80°C, preferably 60°C. It can be adjusted within the above range as needed depending on the type of spray dryer, the type and properties of the components in the solution to be spray-dried, the temperature, etc. The outlet temperature may be 45 to 95°C. The outlet temperature can also be appropriately adjusted depending on the morphology and drying condition of the particles to be produced.

[0027] Injection into the spray dryer can be carried out at a predetermined rate, which may be 1 to 12 mL / min. The injection rate can also be appropriately adjusted depending on the type of spray dryer. The diameter of the nozzle for injection varies depending on the type of spray dryer, but may be in the range of 0.1 to 0.7 mm.

[0028] During spray drying, the pressure of the fluid (e.g., air) used for atomization may be 100 to 150 kPa, and the velocity of the fluid flow may be 0.1 to 0.5 m / s. 3 / min, but is not limited to this.

[0029] In order to deliver the hormone-containing surface-modified microspheres into the skin in the present invention, the material of the microneedles must be soluble enough to be broken down by the moisture in the skin, and must be biocompatible enough to be absorbed or decomposed in the body without side effects. It is also preferable that the material be strong enough to penetrate the skin after being manufactured into microneedles.

[0030] The microneedles of the present invention are soluble, i.e., water-soluble, so that they dissolve in body fluids within the skin.

[0031] The dissolvable material for the microneedles of the present invention may 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), vinylpyrrolidone-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, and xylitol; derivatives of the above substances; or mixtures thereof. In the examples of the present invention, a mixture of alginic acid and trehalose was used as an example.

[0032] The microneedles of the present invention may further contain a plasticizer, a surfactant, a preservative, and the like.

[0033] Examples of the plasticizer include, but are not limited to, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin, which can be used alone or in combination. Examples of the surfactant include, but are not limited to, 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, and ceteareth-12, which can be used alone or in combination. Examples of preservatives that can be used alone or in combination include, but are not limited to, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, parahydroxybenzoic acid, (iso)propyl parahydroxybenzoate, (iso)butylchlorobutanol (chlorobutol), benzalkonium chloride, benzethonium chloride, phenol (p-isomer), cresol, chlorocresol, dihydroacetic acid, sodium dihydroacetate, sorbic acid, potassium sorbate, sodium sorbate, benzoic acid, and sodium benzoate.

[0034] The shape of the needle portion of the microneedle according to the present invention may be conical, pyramidal, spherical, single-headed, wedge-shaped, blade-shaped, etc., but these shapes must all be capable of penetrating the skin. In one embodiment of the present invention, a microneedle having a structurally stable pyramidal needle portion is adopted.

[0035] The structures of a microneedle 10 and a microneedle patch 100 according to the present invention are illustrated in Figures 6a and 6b. The microneedle 10 of the present invention may include a needle portion 11 and a matrix layer 12. The needle portion 11 has a shape that allows easy penetration into the skin, as defined above. The length of the needle portion 11 is 500 to 1000 µm, preferably 750 µm. The thickness of the matrix layer 12 is 0.1 to 1 mm, preferably 0.1 to 0.3 mm. Surface-modified microspheres containing a drug are embedded in the needle portion and the matrix layer. The microneedle patch 100 of the present invention is manufactured by laminating an adhesive layer 20 on one side of the matrix layer 12 so that the microneedle patch can be 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 accounts for 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.

[0036] According to a further object of the present invention, there is provided a method for producing the microneedle.

[0037] The manufacturing method includes: a) dissolving a soluble material in water to form a first solution; b) preparing drug-containing surface-modified microspheres; c) mixing and homogenizing the first solution with the surface-modified microspheres to form a mixed solution; d) filling the mixed solution into an engraved microneedle mold; e) drying the filled mixed solution and separating it from the mold.

[0038] In the manufacturing method of the present invention, the soluble material, drug, surface modification, and microspheres are as defined above.

[0039] In step a), the first solution may further comprise a plasticizer, a surfactant, a preservative, etc. The plasticizer, surfactant, preservative, etc. are as defined above.

[0040] The method for producing the surface-modified microspheres of step b) is as defined above.

[0041] In step c), 0.1 to 20 parts by weight of surface-modified microspheres are mixed with 100 parts by weight of the first solution.

[0042] In the step of preparing the mixed solution, the drug-containing surface-modified microspheres must be uniformly distributed within the microneedles. After mixing the first solution with the surface-modified microspheres, the mixture is vigorously homogenized using a vortex or the like to ensure that the microspheres in the mixed solution are uniformly dispersed in a stable state.

[0043] The conditions such as temperature used in the production of the microneedles are not particularly limited as long as they can sufficiently dissolve and mix the soluble material and the surface-modified microspheres without decomposing or deforming them.

[0044] In step d), the step of filling the microneedle mold with the mixed solution can be carried out by applying the mixed solution and then leaving it, by injecting the mixed solution using a centrifuge, by using a vacuum to remove the air inside and then injecting the mixed solution, or by applying pressure and injecting the mixed solution.

[0045] In step e), the drying can be performed at room temperature or at room temperature to 80° C. using a hot air dryer, but is not limited thereto.

[0046] According to yet another object of the present invention, there is provided a microneedle transdermal patch comprising microneedles containing surface-modified microspheres containing the hormone or microneedles containing surface-modified microspheres containing the hormone produced by the above-mentioned production method.

[0047] When the hormone is leuprolide, it can be used in the microneedle transdermal patch for the treatment and improvement of prostate cancer, breast cancer, endometriosis, uterine fibroids, and precocious puberty. [Effects of the Invention] The microneedles containing the surface-modified hormone-containing microspheres according to the present invention have improved retention in the body and excellent sustained release effects, making them useful for transdermal hormone delivery systems that require sustained administration. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an electron microscope photograph of the microspheres produced in Production Example 1.

[0048] FIG. 2 is an enlarged electron microscope photograph of the surface-modified microspheres of dosage form LSD5 produced in Production Example 1.

[0049] FIG. 3 is an electron microscope photograph of the conventional microspheres having a smooth surface produced in Comparative Production Example 1.

[0050] FIG. 4 is an enlarged electron microscope photograph of the microspheres having a smooth surface of dosage form L6 produced in Comparative Production Example 1.

[0051] FIG. 5a shows the dispersion stability of surface-modified leuprolide-containing microspheres according to the present invention measured using a LUMiSizer.

[0052] Figure 5b shows the dispersion stability of leuprolide-containing microspheres with conventional smooth surfaces measured using a LUMiSizer.

[0053] 6a and 6b are schematic diagrams of an example of a microneedle and a microneedle patch according to the present invention.

[0054] FIG. 7 is an electron microscope photograph of a microneedle according to the present invention. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the configuration 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 examples for a clearer understanding of the present invention, and the scope of the present invention is not limited to the following examples.

[0055] [Production Example 1: Production of surface-modified microspheres containing leuprolide] Microspheres containing leuprolide were produced using the spray drying method. Leuprolide acetate was used as the leuprolide, and PLGA was used as the surface-active biodegradable polymer. The production conditions were as shown in Tables 1 and 2 below.

[0056] Specifically, a mixed solvent of dichloromethane and methanol was added to leuprolide acetate (ANYGEN) and PLGA503H (Evonik Ltd., Germany) in the volumes shown in Tables 1 and 2, and the mixture was stirred for 30 minutes to dissolve. The oil phase (spray-dried solution) was then prepared. The spray-dried solution was then spray-dried under the conditions shown in Tables 1 and 2, with an injection rate of 6.5 mL / min, a pressure of 130 kPa, and an air flow rate of 0.3 m. 3 Dry powder microspheres were obtained using a spray dryer (EYELA SD-1000, Japan) at 1000 rpm / min. Ethanol (99.5%) was added to the microspheres and vortexed for 5 minutes to wash them.

[0057] [Table 1]

[0058] [Table 2]

[0059] The particle size distribution of each of the prepared microspheres containing leuprolide acetate was measured and is shown in Table 3, and electron micrographs of each microsphere are shown in Figures 1 and 2 (except for formulation LSD8, which was not possible to photograph by electron microscopy due to severe aggregation).

[0060] [Table 3]

[0061] According to Figure 1 and Table 3, in dosage forms LSD1 to LSD5, there was no aggregation between particles, and microspheres containing leuprolide acetate that were surface-modified with a wrinkled structure (grooves) were confirmed, but in dosage forms LSD6 to LSD8, aggregation of microsphere particles was confirmed to have occurred.

[0062] <Derivation of optimal conditions for manufacturing surface-modified microspheres> Comparing dosage forms LSD2, LSD3 and LSD8, it can be seen that as the amount of solvent increases, microspheres without aggregation are formed. To produce microspheres with a surface-modified wrinkled structure (grooves) without aggregation between particles, the solid content in the spray-drying liquid (oil phase) is 0.6-1.3% (w / w), preferably 1.3% (w / w).

[0063] Comparing dosage forms LSD4, LSD3 and LSD7, it was found that as the weight ratio of drug (hormone):polymer (PLGA) decreased, microspheres without aggregation were formed. To produce microspheres with a surface-modified wrinkled structure (grooves) without interparticle aggregation, the appropriate weight ratio of drug (hormone):polymer (PLGA) is 1:4 to 1:8, preferably 1:4.

[0064] Comparing dosage forms LSD5 and LSD3 with dosage form LSD6, it can be seen that when the inlet temperature of the spray dryer is reduced, agglomerated microspheres are formed. To produce microspheres with no agglomeration between particles and surface-modified with a wrinkled structure (grooves), the inlet temperature is 60°C to 80°C, preferably 60°C.

[0065] Comparative Preparation Example 1: Preparation of smooth-surfaced microspheres containing leuprolide Leuprolide-containing microspheres with smooth surfaces were prepared using an oil-in-water (O / W) emulsion solvent evaporation method. The formulation composition, oil phase, water phase, solvent composition, homogenizer, and mechanical stirrer conditions are shown in Table 4 below.

[0066] Specifically, 100 mg of leuprolide acetate and 600 mg of PLGA503H (Evonik Ltd., Germany) were dissolved in a mixture of 11.2 g of dichloromethane and 2.9 g of methanol to prepare an oil phase. This was then mixed with 400 mL of 0.5% polyvinyl alcohol (PVA500, OCI Company, Ltd., Korea) solution in an aqueous phase at 10,000 rpm for 2 minutes to form an oil-in-water emulsion. The oil-in-water emulsion was stirred at 1,000 rpm for 3 hours using a mechanical stirrer to evaporate the organic solvent, forming microspheres. To remove remaining PVA and drug particles not trapped by the polymer, the emulsion was centrifuged at 200 g for 5 minutes and then lyophilized to obtain powder-form microspheres. Photographs of the microspheres are shown in Figures 3 and 4.

[0067] [Table 4]

[0068] [Test Example 1: Analysis of dispersion stability of surface-modified microspheres] The dispersion stability of the surface-modified (wrinkled groove structure) microspheres (LSD5) and the smooth surface microspheres (dosage form L6) prepared in Preparation Example 1 was measured using LUMiSizer, and the results are shown in Figure 5a and Figure 5b and Table 5, respectively:

[0069] [Table 5]

[0070] The surface-modified microspheres according to the present invention have a low Instability Index value, which confirms their high dispersion stability.

[0071] [Production Example 2: Production of microneedles containing surface-modified microspheres] Microneedles of Example 1 and Comparative Example 1 were prepared, respectively, containing surface-modified (wrinkled groove) microspheres (formulation LSD5) containing leuprolide acetate prepared in Preparation Example 1 and smooth-surfaced microspheres (formulation L6) prepared in Comparative Preparation Example 1.

[0072] Specifically, a first solution was prepared using 1.0 g of sodium alginate (SUNFINE GLOBAL), 1.0 g of trehalose (SUNFINE GLOBAL), and 33 g of HO. 9.9 g of the first solution was mixed with 0.1 g of the surface-modified microspheres of dosage form LSD5 prepared in Preparation Example 1 or the smooth-surfaced microspheres of dosage form L6. The mixture was vortexed for at least 5 minutes to disperse and homogenize the particles, and then filled into a 750 μm deep pyramidal recessed silicon mold. The mold was then placed in a desiccator, vacuumed to -0.04 MPa for 30 minutes, and then dried in a hot air oven at 35°C for 2 hours and 10 minutes. The dried microneedles were collected using adhesive tape, and the ends were rounded with scissors to fit the patch shape (Figure 6b). A micrograph of the completed microneedles was taken and is shown in Figure 7.

[0073] As shown in FIG. 7, it can be seen that the microneedles were well formed.

[0074] In addition, the strength of the completed microneedles of Example 1 was evaluated using texture analyzers under the conditions in Table 6, and the results are shown in Table 7.

[0075] [Table 6]

[0076] [Table 7]

[0077] As shown in Table 7, the strength of the microneedles of Example 1 was 3.45 on average, which confirms that they have sufficient strength to penetrate the skin.

[0078] [Test Example 2: Analysis of drug retention in the subcutaneous tissue] The hairless dorsal skin of an 8-week-old male SD (Sprague-Dawley) rat was removed and placed in an in-vitro Franz cell permeation tester (Phoenix DB-6, Teledyne, US, 400 rpm, 37°C). After 0.5 minutes had passed since the microneedle patches of Example 1 and Comparative Example 1 prepared in Preparation Example 2 were applied, the microneedle patches were removed, and the dorsal skin was sampled at sampling times of 0, 1, and 24 hours, respectively. The surface was wiped with alcohol cotton and subjected to shaking and mixed extraction in an HPLC mobile phase. The supernatant of the extract was collected and quantitatively analyzed by HPLC. The results are shown in Table 8.

[0079] [Table 8]

[0080] As shown in Table 8, when the microneedle patch containing the surface-modified microspheres of Example 1 was used, the amount of leuprolide remaining in the subcutaneous tissue after 24 hours was 25.2% higher than the initial amount, whereas when the microneedle patch containing the smooth-surfaced microspheres of Comparative Example 1 was used, the amount of leuprolide remaining in the subcutaneous tissue was only 3.3% lower than the initial amount.

[0081] The inserted microspheres can be removed from the subcutaneous tissue due to the elasticity of the skin, but the surface-modified microspheres of Example 1 do not detach from the subcutaneous tissue due to their surface roughness, as compared to the smooth-surfaced microspheres of Comparative Example 1, demonstrating a longer retention time in the body. Therefore, it can be seen that the microneedles containing the surface-modified microspheres of the present invention have improved retention time in the body, and as a result, a sustained effect (sustained release effect) of the hormones in the microspheres is achieved. [Brief explanation of the drawings]

[0082] [Figure 1] FIG. 1 is an electron microscope photograph of the microspheres produced in Production Example 1. [Figure 2] FIG. 2 is an enlarged electron microscope photograph of the surface-modified microspheres of dosage form LSD5 produced in Production Example 1. [Figure 3] FIG. 3 is an electron microscope photograph of the conventional microspheres having a smooth surface produced in Comparative Production Example 1. [Figure 4] FIG. 4 is an enlarged electron microscope photograph of the microspheres having a smooth surface of dosage form L6 produced in Comparative Production Example 1. [Figure 5a] FIG. 5a shows the dispersion stability of surface-modified leuprolide-containing microspheres according to the present invention measured using a LUMiSizer. [Figure 5b] Figure 5b shows the dispersion stability of leuprolide-containing microspheres with conventional smooth surfaces measured using a LUMiSizer. [Figure 6a]FIG. 6a is a schematic diagram of an example of a microneedle and microneedle patch according to the present invention. [Figure 6b] FIG. 6b is a schematic diagram of an example of a microneedle and microneedle patch according to the present invention. [Figure 7] FIG. 7 is an electron microscope photograph of a microneedle according to the present invention. [Explanation of symbols]

[0083] 10 Microneedles 11 Needle section 12 Matrix layer 20 adhesive layer 30 Protective Film 100 Microneedle Patches

Claims

1. A method for producing a microneedle comprising surface-modified microspheres having leuprolide encapsulated therein, the method comprising: a) dissolving a soluble material in water to form a first solution; b) preparing surface-modified microspheres containing leuprolide; c) mixing and homogenizing the first solution and the surface-modified microspheres to form a mixed solution; d) filling the mixed solution into an engraved microneedle mold; e) drying the filled mixed solution and separating it from the mold; the dissolvable material forming the microneedles in step a) is any one selected from the group consisting of alginic acid, hyaluronic acid, dextran, cellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), sodium carboxymethylcellulose, polyalcohol, cyclodextrin, dextrin, trehalose, sucrose, lactose, mannitol, xylitol, and mixtures thereof; Step b) is carried out by a spray drying method, comprising the steps of: i) dissolving leuprolide and a surface-active biodegradable polymer in an organic solvent to prepare an oil phase; and ii) spray-drying the oil phase to obtain surface-modified microspheres; the surface-active biodegradable polymer is polylactic acid-co-glycolic acid (PLGA); The oil phase has a solid content of 0.6 to 1.3% (w / w), a weight ratio of leuprolide to surfactant biodegradable polymer is 1:4 to 1:8, and the inlet temperature of the spray dryer is 60°C to 80°C; the surface-modified microspheres are biodegradable microspheres having wrinkled surfaces; The microneedles are soluble in the skin and have improved retention of leuprolide in the body compared to when the surface-modified microspheres are not included.

2. The method for producing microneedles according to claim 1, wherein 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.

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