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

Abstract

The present invention provides a microneedle comprising surface-modified microspheres containing a hormone, in which in vivo residence duration is enhanced and sustained release effect is strengthened, and a manufacturing method thereof. The microneedle comprising surface-modified microspheres containing a hormone of the present invention is effective when used in a transdermal delivery system for hormone delivery requiring continuous administration, in which in vivo residence duration is enhanced and sustained release effect is excellent.

Description

Technical Field

[0001] This invention relates to microneedles comprising surface-modified microspheres containing hormones and methods for manufacturing the same. More specifically, it relates to microneedles comprising surface-modified microspheres that exhibit enhanced in vivo persistence and superior sustained-release effects, making them suitable for hormone delivery requiring continuous administration, and methods for manufacturing the same. Background Technology

[0002] Hormones generally refer to a group of chemical substances produced by the body's endocrine organs. Although not fundamentally different from neurotransmitters, they are secreted in a wider range of endocrine organs compared to neurotransmitters, which primarily travel through the central nervous system. Therefore, substances that act over a broad range of conditions for a longer period via the bloodstream are called hormones. Hormones produced in various endocrine organs are transported to all organs of the body via the bloodstream, where they perform their respective functions. In particular, hormones are known to be directly related to metabolism, reproduction, and cell proliferation. Therefore, hormones need to be secreted within a normal range in the body, and artificial supplementation is required when levels are insufficient. A representative method of supplementation is injection, but with traditional subcutaneous or intramuscular injections, the short half-life leads to a rapid drop in blood drug concentration after administration. Therefore, maintaining efficacy requires daily administration, which is inconvenient, especially given the characteristics of injectable drugs.

[0003] 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.

[0004] 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.

[0005] 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.

[0006] Therefore, there is a need to develop microneedles containing hormone-modified surface microspheres that enhance in vivo retention and slow-release effects, as well as methods for their manufacture. Summary of the Invention

[0007] Technical issues

[0008] To address the needs of the prior art, the inventors conducted continuous research and surprisingly confirmed that when microneedles are manufactured using microspheres containing leuprolide (a hormone) with a modified surface, the persistence of in vivo residence is enhanced and the sustained-release effect is strengthened, making them suitable for the treatment of diseases requiring the administration of this hormone. Thus, the present invention was completed.

[0009] Therefore, the object of the present invention is to provide microneedles comprising surface-modified microspheres containing hormones.

[0010] Another object of the present invention is to provide a method for manufacturing microneedles comprising surface-modified microspheres containing hormones.

[0011] Another object of the present invention is to provide a microneedle transdermal patch comprising the above-described microneedles.

[0012] Methods for solving problems

[0013] To achieve the objectives of the present invention described above, microneedles comprising surface-modified microspheres containing hormones are provided.

[0014] In this invention, "surface modification" means microspheres having a surface with grooves such as wrinkles or dimples visible on a golf ball.

[0015] 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.

[0016] 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.

[0017] In this invention, the method for manufacturing microspheres can include solvent evaporation, spray drying, sonication, etc., which include steps such as evaporating and solidifying the organic solvent used in manufacturing the microspheres.

[0018] As a spray drying method, in manufacturing biodegradable microspheres, for water-in-oil type microspheres that are a single emulsion, the internal oil phase is manufactured using a non-polar organic solvent that is immiscible with water. This can be achieved by simultaneously dissolving the biodegradable polymer and the drug in the aforementioned non-polar organic solvent. Specifically, the microspheres of the present invention can be manufactured by a method comprising the following steps: i) preparing an oil phase by dissolving a hormone and a surface-active biodegradable polymer in an organic solvent; and ii) spray drying the aforementioned oil phase to obtain surface-modified microspheres. If necessary, the microspheres can be used after washing with a solvent such as ethanol.

[0019] In this invention, any hormone used for diseases requiring continuous administration (requiring a sustained-release effect) can be used, preferably a hormone that is poorly soluble in water. Specifically, the hormone can be selected from sex hormones, growth hormone, parathyroid hormone, human chorionic gonadotropin, luteinizing hormone, thyroid-stimulating hormone, follicle-stimulating hormone, gonadal-stimulating hormone, pituitary hormones, adrenocorticotropic hormone, insulin, salmon calcitonin, glucagon, estrogen, parathyroid hormone, desogestrel, ethinyl estradiol, testosterone, oxytocin, prolactin, endorphin, chromotropic hormone, thyroxine, triiodothyronine, somatostatin, adrenaline, glucocorticoids, androgens, aldosterone, progesterone, melatonin, angiotensinogen, gastrin, ghrelin, secretin, cholecystokinin, renin, adenosine, gonadotropins, hCG, hPL, leptin, analogues thereof, and mixtures thereof, but is not limited thereto. In an embodiment of the present invention, leuprorelin is used as an example of a hormone.

[0020] Leuprorelin is a type of LHRH (luteinizing hormone-releasing hormone) agonist. LHRH is also known as a GnRH (gonadotropin-releasing hormone), a hypothalamic decapeptide that regulates the reproductive system of vertebrates. This GnRH induces the biosynthesis and release of FSH (follicle-stimulating hormone) and LH (luteinizing hormone), both gonadotropins. LHRH agonists and antagonists have shown efficacy in treating endometriosis, fibroids, polycystic ovary syndrome, breast cancer, ovarian cancer, and endometrial cancer in women; gonadotropin-pituitary desensitization in assisted reproductive technologies; benign prostatic hyperplasia and polymorphism in men; prostate cancer; and precocious puberty in men and women. Currently used LHRH agonists are peptide compounds, and due to their low oral bioavailability, they are generally administered intravenously or subcutaneously. Furthermore, LHRH agonists, as medications for chronic diseases, require long-term administration. Leuprorelin, when administered subcutaneously or intramuscularly, has a short half-life, resulting in a rapid drop in blood concentration after administration, which then disappears within hours. Therefore, maintaining efficacy necessitates daily dosing, a problem exacerbated by the characteristics of injectable formulations.

[0021] In this invention, "Leuprorelin" has the structure of the following chemical formula 1, and is used to treat prostate cancer, breast cancer, endometritis, uterine fibroids, precocious puberty, etc.

[0022]

[0023] In this invention, in order to deliver hormone-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.

[0024] The microneedles of the present invention are soluble, that is, water-soluble and can be dissolved in bodily fluids within the skin.

[0025] 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 hormones. All substances derived from nature or manufactured synthetically can be used as the aforementioned surface-active biodegradable polymer. 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.

[0026] The weight ratio of the hormone to the surface-active biodegradable polymer used is 1:4 to 1:8, preferably 1:4. Within this range, the microspheres can be effectively formed with a surface having the desired grooves (wrinkles). Furthermore, a clear separation can be formed between primary particles, preventing undesirable aggregation of primary particles.

[0027] 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 ratio of the above-mentioned mixture of hormones and surface-active biodegradable polymers to the organic solvent, i.e., the weight ratio of solids in the spray-dried liquid (oil phase), is 0.6 to 1.3% (w / w), preferably 1.3% (w / w). Within this range, microspheres can be effectively formed with a surface having desired grooves (wrinkles). Furthermore, clear separation can be formed between primary particles, preventing undesirable aggregation of primary particles.

[0028] In step i), there is no particular limitation on the dissolution time, and stirring can be carried out as needed to dissolve the hormones and surface-active biodegradable polymers in the solvent.

[0029] In step ii), the spray drying process can use a commonly used spray dryer, such as the EYELA SD-1000 (Japan), Buchi B-290 (Switzerland), YC-500 (China), Nano Spray Dryer B-90 (Switzerland), etc.

[0030] In the spray drying process, the operating conditions of the spray dryer can be determined according to the type of spray dryer and preset values, and can be changed as needed.

[0031] A spray dryer can spray dry an oil phase (spray drying liquid) by adjusting the inlet temperature, outlet temperature, and spray speed. The inlet temperature is 60–80°C, preferably 60°C. It can be adjusted within this range as needed, depending on the type of spray dryer, the type and properties of the components in the solution to be sprayed, and the temperature. The outlet temperature can be 45–95°C. The outlet temperature can also be appropriately adjusted according to the shape of the particles produced and the drying state.

[0032] The spraying speed using a spray dryer can be set at a predetermined rate, ranging from 1 to 12 mL / min. This spraying speed can also be adjusted appropriately depending on the type of spray dryer. The diameter of the nozzle used for spraying varies depending on the type of spray dryer, ranging from 0.1 to 0.7 mm.

[0033] During spray drying, the pressure of the granulating fluid (e.g., air) can be 100 to 150 kPa, and the fluid velocity can be 0.1 to 0.5 m / s. 3 / min, but not limited to this.

[0034] In this invention, in order to deliver hormone-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.

[0035] The microneedles of the present invention are soluble, that is, water-soluble and can be dissolved in bodily fluids within the skin.

[0036] The dissolving material for 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, a mixture of alginic acid and trehalose is used as an example.

[0037] The microneedles of the present invention may further contain plasticizers, surfactants, preservatives, etc.

[0038] 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, paraben, 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.

[0039] 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.

[0040] The structures of the microneedles 10 and the microneedle patch 100 of the present invention are as follows: Figure 6a and Figure 6b 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.

[0041] According to another objective of the present invention, a method for manufacturing the above-described microneedles is provided.

[0042] The above manufacturing method includes:

[0043] a) The step of dissolving the soluble material in water to form a first solution;

[0044] b) Steps for preparing surface-modified microspheres containing drugs;

[0045] c) The step of mixing the first solution with the above-mentioned surface-modified microspheres and homogenizing them to prepare a mixed solution;

[0046] d) The step of filling the above mixed solution into the microneedle negative mold; and

[0047] e) The step of drying the filled mixture and separating it from the mold.

[0048] In the manufacturing method of this invention, the soluble material, drug, surface modifier, and microspheres are the same as defined above.

[0049] In step a), the first solution may further contain plasticizers, surfactants, preservatives, etc. Plasticizers, surfactants, preservatives, etc., are the same as defined above.

[0050] The method for manufacturing surface-modified microspheres in step b) is the same as defined above.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] According to another object of the present invention, a microneedle transdermal patch comprising the above-described microneedles, wherein the microneedles comprise the above-described hormone-containing surface-modified microspheres or drug-containing surface-modified microspheres manufactured by the manufacturing method described above.

[0057] When the hormone mentioned above is leuprorelin, the aforementioned microneedle transdermal patch can be used to treat and improve prostate cancer, breast cancer, endometritis, uterine fibroids, and precocious puberty.

[0058] Invention Effects

[0059] The microneedles of the present invention, which contain surface-modified microspheres containing hormones, exhibit enhanced in vivo retention and excellent sustained-release effect, making them effective for use in transdermal delivery systems for hormone delivery requiring continuous administration. Attached Figure Description

[0060] Figure 1 This is an electron microscope image of the microspheres manufactured in Example 1.

[0061] Figure 2 This is an enlarged electron microscope image of the surface-modified microspheres of formulation LSD5 manufactured in Example 1.

[0062] Figure 3 These are electron microscope images of conventionally manufactured microspheres with smooth surfaces, as shown in Comparative Manufacturing Example 1.

[0063] Figure 4 This is a magnified electron microscope image of microspheres with smooth surfaces of dosage form L6 manufactured in Comparative Manufacturing Example 1.

[0064] Figure 5a The results are obtained by measuring the dispersion stability of the surface-modified leuprolide-containing microspheres of the present invention using LUMiSizer.

[0065] Figure 5b The results were obtained by using the LUMiSizer to determine the dispersion stability of previously smooth-surfaced microspheres containing leuprolide.

[0066] Figure 6a and Figure 6b This is a schematic diagram of an example of the microneedles and microneedle patches of the present invention.

[0067] Figure 7 This is a microscope image of the microneedles of the present invention. Detailed Implementation

[0068] 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.

[0069] Manufacturing Example 1: Manufacturing of Surface-Modified Microspheres Containing Leucoprene

[0070] Microspheres containing leuprolide were manufactured using a spray drying method. Leuprolide acetate was used as the leuprolide, and PLGA was used as the surface-active biodegradable polymer. The manufacturing conditions were carried out according to Tables 1 and 2 below.

[0071] Specifically, a mixed solvent of dichloromethane and methanol was added to leuprolide acetate (Anygen Co., Ltd.) and PLGA 503H (Evonik, Germany) according to the volumes shown in Tables 1 and 2, and stirred for 30 minutes to dissolve, thereby preparing the oil phase (spray-dried solution). The solution was then sprayed under the conditions shown in Tables 1 and 2 at a spray rate of 6.5 mL / min, a pressure of 130 kPa, and an air flow rate of 0.3 m / min. 3 Dry powder microspheres were obtained from a spray-dried solution using a spray dryer (EYELA SD-1000, Japan) at a flow rate of [unspecified value]. The microspheres were washed by adding 99.5% ethanol and vortexing for 5 minutes.

[0072] [Table 1]

[0073]

[0074] [Table 2]

[0075] Inlet temperature 60～80℃ Outlet temperature 45～95℃ Feeding rate 6.5 mL / min Air pressure (Pressure air atomizing) 130kPa Air flow rate <![CDATA[0.3m 3 / min]]> Nozzle size 0.4mm

[0076] The particle size distribution of each manufactured microsphere containing leuprolide acetate was determined and is shown in Table 3. Electron micrographs of each microsphere are shown below. Figure 1 and Figure 2 As shown (except for formulation LSD8, which exhibited such severe aggregation that electron micrographs could not be taken).

[0077] [Table 3]

[0078]

[0079] *ND: Microsphere particles excessively aggregate and fall outside the measurement range of the equipment.

[0080] according to Figure 1 According to Table 3, no interparticle aggregation occurred in formulations LSD1 to LSD5, and microspheres containing leuprolide acetate with a wrinkled structure (groove) surface modification were confirmed. However, in formulations LSD6 to LSD8, aggregation of microsphere particles was confirmed.

[0081] <Derivation of Optimal Conditions for Manufacturing Surface-Modified Microspheres>

[0082] Comparing formulations LSD2, LSD3 and LSD8, microspheres without aggregation are formed when the solvent content is increased. In order to manufacture microspheres without interparticle aggregation and with surface modification by a wrinkled structure (groove), the solid content ratio in the spray-dried liquid (oil phase) is 0.6 to 1.3% (w / w), preferably 1.3% (w / w).

[0083] Comparing dosage forms LSD4, LSD3 and LSD7, when the drug (hormone):polymer (PLGA) weight ratio decreases, non-agglomerated microspheres are formed. In order to manufacture microspheres without interparticle aggregation and with surface modification by a wrinkled structure (groove), the suitable drug (hormone):polymer (PLGA) weight ratio is 1:4 to 1:8, preferably 1:4.

[0084] Comparing formulations LSD5, LSD3 and LSD6, microspheres without aggregation are formed when the inlet temperature of the spray dryer decreases. In order to manufacture microspheres without interparticle aggregation and with surface modification by a wrinkled structure (groove), the inlet temperature is 60°C to 80°C, preferably 60°C.

[0085] Comparative Manufacturing Example 1: Manufacturing of Microspheres with Smooth Surfaces Containing Leucoprene

[0086] Microspheres containing leuprolide with a smooth surface were manufactured by solvent evaporation of an oil-in-water (O / W) emulsion. The dosage form composition, oil phase, aqueous phase, solvent composition, homogenizer, and mechanical stirrer conditions were performed according to Table 4 below.

[0087] Specifically, 100 mg of leuprorelin acetate and 600 mg of PLGA 503H (Evonik, Germany) were dissolved in a mixed solvent of 11.2 g of dichloromethane and 2.9 g of methanol to prepare an oil phase. This oil phase was then homogenized at 10,000 rpm with 400 ml of an aqueous phase containing 0.5% polyvinyl alcohol (PVA500, OCI, Korea) 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, thereby forming microspheres. To remove residual PVA and drug particles not trapped by the polymer, the microspheres were centrifuged at 200 g for 5 minutes, followed by freeze-drying to obtain powdered microspheres. (Image of microspheres follows.) Figure 3 and Figure 4 As shown.

[0088] [Table 4]

[0089]

[0090] Experimental Example 1: Dispersion Stability Analysis of Surface-Modified Microspheres

[0091] The dispersion stability of surface-modified (wrinkled groove structure) microspheres (LSD5) and smooth-surface microspheres (dosage form L6) manufactured in Example 1 was determined using the LUMiSizer, and the results are as follows: Figure 5a and Figure 5b And as shown in Table 5:

[0092] [Table 5]

[0093]

[0094] The surface-modified microspheres of the present invention have a low instability index, thus confirming high dispersion stability.

[0095] Manufacturing Example 2: Fabrication of Microneedles Containing Surface-Modified Microspheres

[0096] Microneedles of Examples 1 and Comparative Example 1 were manufactured, including surface-modified (wrinkled groove) microspheres containing leuprolide acetate (dosage form LSD5) manufactured in Manufacturing Example 1 and smooth-surface microspheres (dosage form L6) manufactured in Comparative Manufacturing Example 1.

[0097] 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 LSD5 or smooth-surfaced microspheres of formulation L6 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 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 35°C for 2 hours and 10 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 6b Electron microscope images of the completed microneedles are shown below. Figure 7 .

[0098] like Figure 7 As shown, microneedles can be confirmed to have formed well.

[0099] In addition, the strength of the completed microneedles of Example 1 was evaluated using texture analyzers under the conditions shown in Table 6, and the results are shown in Table 7:

[0100] [Table 6]

[0101]

[0102] [Table 7]

[0103]

[0104] As shown in Table 7, it can be confirmed that the microneedles of Example 1 have an average strength of 3.45, which is sufficient to penetrate the skin.

[0105] Experimental Example 2: Analysis of the duration of drug retention in the subcutaneous and in vivo

[0106] Hairless dosal skoin skin was taken from 8-week-old male Sprague-Dawley rats and fixed in an in-vitro Franz cell permeation test (Phoenix DB-6, Teledyne, US, 400 rpm, 37°C drying). The microneedle patches of Example 1 and Comparative Example 1 prepared in Manufacturing Example 2 were attached. After 0.5 minutes, the microneedle patches were removed. Then, dosal skin was taken at sampling times of 0, 1, and 24 hours. The surface was wiped with an alcohol swab and extracted by shaking and mixing using the HPLC mobile phase. The supernatant of the extract was taken for HPLC quantitative analysis. The results are shown in Table 8.

[0107] [Table 8]

[0108] initial 100.0 100.0 1hr 30.9 16.3 24hr 25.2 3.3

[0109] As shown in Table 8, after 24 hours, when using the microneedle patch containing surface-modified microspheres of Example 1, the subcutaneous residue of leuprorelin was 25.2% relative to the initial residue, which was high. However, when using the microneedle patch containing microspheres with a smooth surface of Comparative Example 1, the subcutaneous residue of leuprorelin was 3.3% relative to the initial residue, which was very low.

[0110] 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 hormone within the microspheres.

[0111] [Symbol Explanation]

[0112] 10: Microneedles

[0113] 11: Needle head

[0114] 12: Subbase

[0115] 20: Adhesive layer

[0116] 30: Protective film

[0117] 100: Microneedle Patch

Claims

1. A microneedle comprising surface-modified microspheres encapsulated with leuprolide, The surface-modified microspheres are biodegradable microspheres with a wrinkled surface. The surface-modified microspheres are manufactured by a spray drying method including the following steps: i) The step of preparing the oil phase by dissolving leuprolide and a surface-active biodegradable polymer in an organic solvent; and ii) The step of spray drying the oil phase to obtain surface-modified microspheres. The solid content ratio of leuprolide and surfactant biodegradable polymer in the oil phase is 0.6-1.3% (w / w), the weight ratio of leuprolide to surfactant biodegradable polymer is 1:4 to 1:8, and the inlet temperature of the spray dryer is 60℃-80℃. The surface-modified microspheres have an average size of less than 10 μm. The surface-active biodegradable polymer is polylactic-co-glycolic acid copolymer (PLGA). 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 soluble material forming the microneedle is a mixture of alginate and trehalose.

3. 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.

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

5. A microneedle transdermal patch comprising the microneedles of claim 1, wherein the microneedles comprise surface-modified microspheres encapsulated with leuprolide.

6. The microneedle transdermal patch according to claim 5 is used to treat and improve prostate cancer, breast cancer, endometritis, uterine fibroids, and precocious puberty.

Images