Microparticle composition for contraceptive microneedles and contraceptive microneedles containing the same

Abstract

To provide a microsphere composition for contraceptive microneedles that is convenient to administer, has excellent skin drug permeability, and enables sustained drug release; to provide contraceptive microneedles containing the same; and to provide contraceptive microneedle patches containing the microneedles.SOLUTION: A microsphere composition for contraceptive microneedles includes one selected from the group consisting of sustained-release estrogen microspheres, sustained-release progesterone microspheres, and mixtures thereof. The sustained-release estrogen microspheres include 400 to 600 pts.wt. of a biodegradable polymer per 100 pts.wt. of estrogen. The sustained-release progesterone microspheres include 700 to 900 pts.wt. of a biodegradable polymer per 100 pts.wt. of progesterone and include hydroxypropyl-β-cyclodextrin at a molar ratio of progesterone:hydroxypropyl-β-cyclodextrin of 1:2 to 1:3.SELECTED DRAWING: Figure 9

Description

Technical Field

[0001] The present invention relates to a microsphere composition for a contraceptive micro needle and a contraceptive micro needle containing the same, and more particularly, to a microsphere composition for a contraceptive micro needle containing sustained-release estrogen microspheres and / or sustained-release progesterone microspheres as active ingredients, and a contraceptive micro needle containing the same.

Background Art

[0002] Contraceptive drugs are mainly used for preventing unwanted pregnancies and are also widely used for dysmenorrhea, regulation of irregular menstrual cycles, polycystic ovary syndrome, menorrhagia, premenstrual syndrome, etc.

[0003] Contraceptive drugs use components of estrogen and / or progesterone and artificially regulate hormone concentrations to suppress ovulation. Contraceptive drugs have been developed up to the fourth generation depending on the presence and type of progesterone, and there are differences in side effects for each generation. The first-generation contraceptive drug is a high-content estrogen single agent, and side effects such as the risk of thrombosis and irregular bleeding are serious, and it has been discontinued from the market. The second-generation contraceptive drug uses levonorgestrel as the main component of progesterone, and side effects such as acne and hirsutism have been reported. Third-generation contraceptive drugs with progesterone as the main component, such as gestoden, desogestrel, and norgestimate, improve the side effects of hirsutism and acne induction of the second-generation contraceptive drug, and there are commercial products such as Melian, Myvlar, and Mercilon.

[0004] When these contraceptive drugs are used as oral contraceptives for contraceptive purposes, it is absolutely necessary to pay attention to taking them in a method of taking one tablet at the same time every day for 21 days and then taking a 7-day break. If this time is not observed, the concentration of the effective active ingredient will be lower than the concentration required for oral contraception, and oral contraception is no longer guaranteed. This means that the user needs to adjust their dosing cycle very carefully and planned (Korean Patent Publication No. 10-2007-0087141).

[0005] Transdermal contraceptives are emerging as an alternative to oral contraceptives, which require such an inconvenient method of administration. Drug absorption through the skin, i.e., transdermal drug delivery, can avoid many undesirable side effects. In particular, it allows the use of pharmacologically active agents with short biological half-lives, and because degradation in the gastrointestinal system is reduced, it offers advantages such as efficacy achieved with a lower total daily dose of the drug, fewer opportunities for over- or under-dosing, a simplified method of administration, and the ability to quickly terminate drug infusion by removing the drug delivery system from the skin surface.

[0006] As an example of a transdermal contraceptive, a transdermal contraceptive delivery system in the form of a polymer patch containing an adhesive polymer matrix has been disclosed (Korean Patent Registration No. 10-0758757). However, polymer patches have an inherent problem in that the skin barrier reduces the skin penetration rate of the active ingredient drug, resulting in insufficient drug delivery efficiency. Furthermore, in order to optimize the efficacy of a contraceptive, the active ingredient hormone must be able to be released in a sustained manner. However, in the case of polymer patches, sustained release requires application for long periods every day, which can cause skin irritation and discomfort when showering in the summer, among other problems.

[0007] Therefore, there is a need to develop a transdermal contraceptive delivery system that is convenient to administer, has excellent skin drug penetration, and allows for sustained release of the active ingredient. [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] Therefore, the inventors, through continuous research to meet the demands of the prior art, developed sustained-release estrogen microparticles and sustained-release progesterone microparticles suitable for the manufacture of contraceptive microneedles. By incorporating these microparticles as active ingredients, they manufactured contraceptive microneedles that offer convenience in administration, excellent skin drug permeability, and sustained drug release, thus completing the present invention.

[0009] Therefore, the object of the present invention is to provide a microparticle composition for contraceptive microneedles that offers convenience in drug administration, excellent skin drug permeability, and sustained drug release.

[0010] Another object of the present invention is to provide a contraceptive microneedle that offers convenience in administering the microparticle composition, has excellent skin drug permeability, and enables sustained drug release.

[0011] Another object of the present invention is to provide a contraceptive microneedle patch containing the microneedles. [Means for solving the problem]

[0012] To achieve the objectives of the present invention, the present invention provides a microparticle composition for contraceptive microneedles that offers convenience in drug administration, excellent skin drug permeability, and sustained drug release.

[0013] In this invention, the term "drug" refers to estrogen and progesterone.

[0014] The microparticle composition for contraceptive microneedles in the present invention contains as an active ingredient one selected from the group consisting of sustained-release estrogen microparticles, sustained-release progesterone microparticles, and mixtures thereof.

[0015] In this invention, "sustained-release" means that the release of the drug, estrogen or progesterone, encapsulated in microglobules is controlled. Preferably, it means that 70-80% by weight of the drug is continuously released within 120 hours.

[0016] The sustained-release estrogen microglobulins and sustained-release progesterone microglobulins of the present invention are characterized by the fact that the release of encapsulated estrogen and progesterone in vivo lasts for one week or more, preferably for one week. The sustained-release estrogen microglobulins and sustained-release progesterone microglobulins are characterized by the fact that 70-80% by weight of the encapsulated estrogen and progesterone in vivo is continuously released within 120 hours after entering the environment of use (for example, after administration to the human body).

[0017] In this invention, estrogen is ethinylestradiol (EE).

[0018] In the present invention, progesterone is any of the following: desogestrel (DSG), gestodene, dienogest, levonorgestrel, norgestimate, norethisterone, drospirenone, trimegestone, and dydrogesterone.

[0019] In the present invention, sustained-release estrogen microspheres may contain 400 to 600 parts by weight of biodegradable polymer per 100 parts by weight of estrogen. Most preferably, sustained-release estrogen microspheres contain 100 parts by weight of estrogen and 400 parts by weight of biodegradable polymer. If the estrogen content in the microspheres is within the above range, sustained-release for one week or more is possible.

[0020] The aforementioned biodegradable polymers refer to polymers that do not cause high cytotoxicity or inflammatory responses when administered into the body, and that are broken down within the body.

[0021] In the present invention, the sustained-release estrogen microspheres have a particle size (Dv 90) of 20 μm or less, preferably 15 μm or less. If the particle size (Dv 90) of the microspheres exceeds the above range, the particle size becomes too large and unsuitable for use encapsulated in a microneedle.

[0022] In the present invention, the biodegradable polymer usable in sustained-release estrogen microspheres can be selected from the group consisting of poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) glucose, and mixtures thereof, with poly(lactide-co-glycolide) (PLGA) being the most preferred.

[0023] In this invention, sustained-release estrogen microspheres can be produced by an O / W (oil-in-water) emulsion containing a biodegradable polymer, estrogen, and a solvent, and then agglomerating this emulsion into microspheres using an O / W single-solvent evaporation method. Specifically, an oil phase containing estrogen and a solvent is prepared, and then dispersed in an aqueous phase containing a dissolved surfactant to produce O / W microspheres.

[0024] The solvent can be selected from the group consisting of dichloromethane (DCM), chloroform, acetonatril, dimethyl sulfoxide, dimethylformamide, ethyl acetate, and mixtures thereof, with dichloromethane (DCM) being the most preferred.

[0025] The surfactant can be selected from the group consisting of polyvinyl alcohol (PVA), polysorbate 20, polysorbate 60, polysorbate 80, or mixtures thereof, and most preferably polyvinyl alcohol (PVA) can be used.

[0026] When manufacturing the O / W type emulsion in the present invention, stirring is preferably performed at a speed of 1600 rpm or more for 12 hours or more. If the stirring is performed at a speed of less than 1600 rpm, the particle size (Dv 90) of the microspheres becomes large and they cannot be encapsulated in the micro needles for use.

[0027] The sustained-release estrogen microspheres according to the present invention exhibit a sustained-release property of estrogen for one week or more and have an average particle size suitable for being encapsulated in the micro needles (FIG. 1, FIG. 2).

[0028] In the present invention, the sustained-release progesterone microspheres can contain 700 to 900 parts by weight of a biodegradable polymer with respect to 100 parts by weight of progesterone. Most preferably, the sustained-release progesterone microspheres can contain 700 parts by weight of a biodegradable polymer with respect to 100 parts by weight of progesterone.

[0029] In the present invention, the sustained-release progesterone microspheres can further contain hydroxypropyl-β-cyclodextrin (Hydroxypropyl-beta-cyclodextrin; HPβCD) in order to stabilize progesterone. In the sustained-release progesterone microspheres, hydroxypropyl-β-cyclodextrin can be included such that the molar ratio of progesterone:hydroxypropyl-β-cyclodextrin is 1:2 to 1:3.

[0030] If the contents of progesterone and hydroxypropyl-β-cyclodextrin contained in the microspheres are within the above ranges, a sustained-release of progesterone for one week or more is possible.

[0031] The sustained-release progesterone microspheres in the present invention have a particle size (Dv 90) of 20 μm or less, preferably 18 μm or less. If the particle size of the microspheres exceeds the above range, the particle size becomes large and they are not suitable for being encapsulated in the micro needles for use.

[0032] The biodegradable polymers usable in the sustained-release progesterone microspheres of the present invention can be selected from the group consisting of poly(lactide-co-glycolide) (PLGA) with a glycol:lactic ratio of 1:2 to 4, poly(lactide-co-glycolide) glucose, and mixtures thereof, with poly(lactide-co-glycolide) (PLGA) having a glycol:lactic ratio of 1:3 being the most preferred.

[0033] The sustained-release progesterone microspheres in the present invention can be produced by a W / O / W (water / oil / water) double solvent evaporation method. Specifically, a water phase containing hydroxypropyl-β-cyclodextrin dissolved in water is mixed with an oil phase containing a biodegradable polymer, progesterone, and a solvent. This mixture is then dispersed in the water phase containing a dissolved surfactant to produce a W / O / W emulsion, which is then aggregated into microspheres.

[0034] The solvent can be selected from the group consisting of dichloromethane (DCM), chloroform, acetonatril, dimethyl sulfoxide, dimethylformamide, ethyl acetate, and mixtures thereof, with dichloromethane (DCM) being the most preferred.

[0035] During the dispersion process, it is preferable to stir the material at a speed of 1600 rpm or higher for 12 hours or more. If the stirring proceeds at a speed of less than 1600 rpm, the average particle size of the microspheres becomes large, making it impossible to encapsulate and use them in a microneedle.

[0036] The surfactant can be selected from the group consisting of polyvinyl alcohol (PVA), polysorbate 20, polysorbate 60, polysorbate 80, or mixtures thereof, and most preferably polyvinyl alcohol (PVA) can be used.

[0037] The sustained-release progesterone microspheres according to the present invention have a particle size (Dv 90) suitable for use encapsulated in microneedles, while also having pores formed on their surface, resulting in sustained-release progesterone for more than one week (Figures 7 and 8).

[0038] In accordance with another object of the present invention, a contraceptive microneedle comprising the microparticle composition is provided.

[0039] In the present invention, contraceptive microneedles can be manufactured by mixing the microparticle composition, soluble material, stabilizer, and solvent to produce a solution, and then injecting it into a mold for shaping.

[0040] The soluble material in this invention is capable of being naturally biodegraded within the body and excreted from the body, and constitutes the form of a microneedle. Therefore, the microneedle of this invention is water-soluble and dissolves in bodily fluids within the skin. The soluble material can be at least one selected from the group consisting of hyaluronic acid (HA) or its salts, alginic acid (AA) or its salts, chitosan, collagen, gelatin, chondroitin, dextran, 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 (CMC), and mixtures thereof, with hyaluronic acid or its salts being most preferably used.

[0041] In the production of microneedles according to the present invention, the soluble material can be contained in an amount of 20% to 30% by weight relative to the total amount of the solution (100% by weight).

[0042] The above-mentioned stabilizers play a role in contributing to the stability during microneedle manufacturing, and at least one selected from the group consisting of xylitol, trehalose, lactose, sucrose, polyhydric alcohol, cyclodextrin, dextrin, starch, glucose, maltose, lactulose, turanose, melitose, melegitose, sorbitol, and mannitol may be used.

[0043] The stabilizer used in the production of microneedles according to the present invention can be contained in an amount of 3% to 10% by weight relative to the total amount of the solution.

[0044] During the production of the microneedles of the present invention, the microparticle composition can be contained in an amount of 1% to 10% by weight relative to the total solution.

[0045] The solvent in the composition of the present invention is water, preferably purified water (DW), or potassium phosphate buffer (PPB).

[0046] The composition of the present invention may further contain a pH adjuster as needed. The pH adjuster can be any of those commonly used in the manufacture of microneedles, such as NaOH.

[0047] Furthermore, the composition of the present invention may optionally further contain plasticizers, surfactants, preservatives, etc., that are commonly used in the manufacture of microneedles.

[0048] The microneedle of the present invention may include a needle portion that protrudes in one direction and a matrix layer that supports the needle portion. The needle portion has a shape that easily penetrates the skin. The shape of the needle portion of the microneedle of the present invention may be conical, pyramidal, spear-shaped, brachycephalic, wedge-shaped, or blade-shaped, and these must all have a shape that can penetrate the skin. The length of the needle portion is 500 to 1000 μm, preferably 750 μm. The matrix layer has a thickness of 0.1 to 1 mm, preferably 0.1 to 0.3 mm.

[0049] The needle portion of the microneedle of the present invention can be manufactured to separate from the matrix layer when inserted into the skin, if necessary. The matrix layer of the microneedle according to the present invention can also be manufactured from other materials, if necessary. Thus, the microspheres of the present invention can be evenly distributed in the needle portion and the matrix layer, or they can be distributed only in the needle portion.

[0050] The microneedle of the present invention is a soluble microneedle that is degraded in vivo, releasing sustained-release estrogen microparticles and / or sustained-release progesterone microparticles.

[0051] The microneedle of the present invention may contain only sustained-release estrogen microparticles, only sustained-release progesterone microparticles, or both sustained-release estrogen microparticles and sustained-release progesterone microparticles.

[0052] The microneedles of the present invention offer the convenience of drug administration with a single use over a period of one week or more, and because the microneedles penetrate the skin by creating tiny holes, they also have excellent skin drug permeability. Furthermore, the sustained-release microbulbs of the present invention have the advantage of enabling sustained-release drug release over a period of one week or more.

[0053] In accordance with another object of the present invention, a contraceptive microneedle patch comprising the microneedles is provided.

[0054] The contraceptive microneedle patch of the present invention has an adhesive layer laminated on one side of a matrix layer, and the microneedle patch can be used by applying it to the skin. The microneedle patch may also include a protective film on top of the adhesive layer.

[0055] The contraceptive microneedle patch of the present invention allows for sustained drug release for more than one week even with short-term application of less than three hours, making it useful as a female contraceptive. [Effects of the Invention]

[0056] The microparticle composition for contraceptive microneedles according to the present invention stably encapsulates the drug, exhibits sustained-release of the drug for more than one week, and has a particle size (Dv 90) suitable for use when encapsulated in a microneedle.

[0057] The contraceptive microneedle according to the present invention offers the convenience of medication administration with single use over a period of one week or more, excellent skin drug permeability, can be worn for a short period of time, and allows for sustained drug release for one week or more.

[0058] The contraceptive microneedle patch according to the present invention allows for sustained drug release for more than one week even with short-term application, making it useful as a female contraceptive. [Brief explanation of the drawing]

[0059] [Figure 1] This is an electron microscope image of ethinylestradiol granules produced in Production Example 1. [Figure 2] This graph shows the results of the dissolution (release) test of ethinylestradiol microparticles produced in Production Example 1. [Figure 3] This is an electron microscope image of desogestrel granules produced in Production Example 2. [Figure 4] This graph shows the dissolution test results for desogestrel microspheres produced in Production Example 2. [Figure 5]This graph shows the results of a stability analysis of desogestrel with a stabilizer. [Figure 6] This graph shows the results of stability analysis based on the molar ratio of desogestrel to stabilizer in microparticles. [Figure 7] This is an electron microscope image of desogestrel granules produced in Production Example 4. [Figure 8] This graph shows the dissolution test results for desogestrel microglobules produced in Manufacturing Example 4. [Figure 9] These are electron microscope images of ethinylestradiol granules from Example 2 and desogestrel granules from Example 3. [Figure 10] These are photographs of the microneedles and their needle portions from Examples 4-6. [Modes for carrying out the invention]

[0060] To aid in understanding the present invention, the structure and effects of the present invention will be described in more detail below through specific examples. However, the following examples are provided as illustrations to make the present invention clearer, and the scope of the present invention is not limited by these examples.

[0061] Manufacturing Example 1: Sustained-release ethinylestradiol granules <Production of microspheres> Ethinylestradiol (EE) and PLGA 503H (Evonik Ltd., Germany) were added to 10 ml of dichloromethane (DCM) in the volumes shown in Table 1, and the mixture was dissolved by mixing and sonication for 30 minutes to produce an oil phase. 100 ml of polyvinyl alcohol solution (5% PVA in DW) was stirred at the stirring speed (rpm) shown in Table 1, while the oil phase was dropped into the polyvinyl alcohol solution at a rate of 2 ml / min using a syringe pump. Stirring was continued for 12 hours to allow the DCM to volatilize and produce microspheres. The produced microspheres were then precipitated using a centrifuge (2000 rpm, 10 min). After filtering the precipitated microspheres (0.2 μm PVDF membrane filter), the washing process using DW was repeated twice, and then the mixture was dried at room temperature for 12 hours to complete the production of microspheres.

[0062] [Table 1]

[0063] <Yield, inclusion rate, and inclusion efficiency of microglobules> Drugs encapsulated in microspheres produced using an HLPC (Agilent 1200 HPLC system) were analyzed, and the yield, loading, and encapsulation efficiency of the microspheres were calculated using the following formulas, as shown in Table 2.

[0064] Yield: Actual yield / Theoretical yield * 100 (%) Inclusion rate: Amount of encapsulated drug / Weight of microglobules * 100 (%) Encapsulation efficiency: Actual drug encapsulation rate / Theoretical drug encapsulation rate * 100 (%)

[0065] [Table 2]

[0066] In the case of the microspheres in Comparative Example 4, the encapsulation efficiency (approximately 10.13%) was low, making it unsuitable. It can be confirmed that the encapsulation efficiency decreases when the amount of ethinylestradiol (EE) mixed in is high.

[0067] <Particle morphology and particle size of microspheres> The particle morphology of the microspheres was observed using a SEM (Ultra Plus, Carl Zeiss), and the resulting photographs are shown in Figure 1. All of the microspheres exhibited a spherical particle morphology.

[0068] Furthermore, the particle sizes of the microspheres, namely Dv 10, Dv 50, and Dv 90, were measured (wet measurement) using the Mastersizer 3000E equipment and are shown in Table 3.

[0069] [Table 3]

[0070] In the case of the microspheres in Comparative Example 1, the particle size (Dv 90) was large at 36.57 ± 2.62 μm, making them unsuitable for use in microneedles. It was confirmed that stirring during microsphere production at 1600 rpm or higher resulted in a particle size (Dv 90) of around 10 μm, which is a desirable size for mounting on microneedles.

[0071] <Dissolution Test - Sustained-Release Test> The granules produced as described above were subjected to the following dissolution tests to analyze their sustained-release properties.

[0072] After placing 40 ml of 0.5% Tween 80 (in PBS, pH 7.4, 1X) eluate into a 50 ml conical tube in a shaking bath (37°C, 50 rpm), microglobules were weighed to achieve an ethinylestradiol (EE) concentration of 1000 μg, and the elution was evaluated by adding them to the eluate.

[0073] Before sampling, the spheres were precipitated using a centrifuge (1500 rpm, 5 min). 10 ml of the upper layer was sampled, analyzed by HPLC, and 10 ml was replenished with the eluate. Sampling times were set to 4, 8, 16, 24, 48, 72, 96, and 120 hours.

[0074] The kinetics were calculated by substituting the elution time and elution rate results (up to elution rate of less than 60%) into the following formula:

number

[0075] The test results are shown in Figure 2 and Tables 4 and 5.

[0076] [Table 4]

[0077] [Table 5]

[0078] According to Table 4 and Figure 2, a lower PLGA ratio resulted in a faster dissolution rate. The microparticles from Example 1 and Example 2 showed drug release of approximately 77.7% to 81% after 120 hours, and were judged to be suitable for sustained-release over one week.

[0079] According to Table 5, the elution pattern showed a slow-release pattern and was fitted to Higuchi or Korsmeyer-peppaskinetics.

[0080] From the analysis results described above, it can be seen that the sustained-release estrogen granules of the present invention are suitable when mixed with 400 to 600 parts by weight of biodegradable polymer per 100 parts by weight of estrogen, and when stirred at a speed of 1600 rpm or more for 12 hours or more during manufacturing.

[0081] Manufacturing Example 2: Derivation of Manufacturing Conditions for Desogestrel Microspheres <Production of microspheres> Desogestrel (DSG) and PLGA 503H (Evonik Ltd., Germany) were added to 10 ml of dichloromethane (DCM) in the volumes shown in Table 6, and the mixture was dissolved by mixing and sonication for 30 minutes to produce an oil phase. 100 ml of polyvinyl alcohol solution (5% PVA in DW) was added to the oil phase at a rate of 2 ml / min using a syringe pump while stirring at the stirring speed (rpm) shown in Table 6. Stirring was continued for 12 hours to allow the DCM to volatilize and produce microspheres. Subsequently, the produced microspheres were precipitated using a centrifuge (2000 rpm, 10 min). After filtering the precipitated microspheres (0.2 μm PVDF membrane filter), the washing process using DW was repeated twice, and then the microspheres were dried at room temperature for 12 hours to complete the production of microspheres.

[0082] [Table 6]

[0083] <Yield, inclusion rate, and inclusion efficiency of microglobules> Drugs encapsulated in microspheres produced using an HLPC system (Agilent 1200 HPLC system) were analyzed, and the yield, encapsulation rate, and encapsulation efficiency of the microspheres were calculated using the above formula and are shown in Table 7.

[0084] [Table 7]

[0085] <Particle morphology and particle size of microspheres> The particle morphology of the microspheres was observed using a SEM (Ultra Plus, Carl Zeiss), and the results are shown in Figure 3. All of the microspheres exhibited a spherical particle morphology.

[0086] Furthermore, the particle sizes of the microspheres, namely Dv 10, Dv 50, and Dv 90, were measured (wet measurement) using the Mastersizer 3000E equipment and are shown in Table 8.

[0087] [Table 8]

[0088] In the case of the microspheres in Comparative Examples 4 and 5, the particle size Dv 90 was large at approximately 55 μm, making them unsuitable for use in microneedles. It was confirmed that the size of the microspheres becomes too large when the amount of biodegradable polymer mixed is large. Furthermore, it was confirmed that stirring during microsphere production at 1600 rpm or higher results in a Dv 90 of around 10 μm, which is a desirable size for mounting on microneedles.

[0089] <Dissolution Test - Sustained-Release Test> The microspheres produced as described above were subjected to dissolution tests using the same method as in Production Example 1, and their sustained-release properties were analyzed. The test results are shown in Figure 4 and Table 9.

[0090] [Table 9]

[0091] According to Table 9 and Figure 4, the microgranules of Comparative Examples 4 to 6 showed a drug release rate of approximately 44% or less after 120 hours, making them unsuitable for sustained-release over one week, and requiring improvement in the stability of the drug (DSG).

[0092] Manufacturing Example 3: Production of desogestrel granules with different stabilizers <Selection of stabilizers> To select stabilizers suitable for the production of desogestrel microspheres with enhanced stability, microsphere compositions containing stabilizers were prepared with the compositions shown in Table 10, and their stability was tested in thin film form.

[0093] [Table 10]

[0094] Specifically, the ethanol solution obtained by dissolving the DSG drug with each stabilizer was mixed with the DCM solution obtained by dissolving PLGA, and then dried using a nitrogen evaporator to produce a film (thickness 50-100 μm).

[0095] The manufactured films were subjected to stability analysis immediately after manufacturing and again while stored in a constant temperature and humidity stability chamber at 30°C and 65% under accelerated conditions for 8 weeks.

[0096] Specifically, for the stability analysis, the entire volume of each film sample was added to 5 ml of a dilution solvent (a 1:1 mixed solvent of Phosphate buffer solution pH 3.5 and 78% Acetonitrile), mixed by shaking, and then quantitative analysis of DSG was performed using the HPLC method under the conditions shown in Table 11 below. The results are shown in Table 12 and Figure 5.

[0097] [Table 11]

[0098] [Table 12]

[0099] As shown in Table 12 and Figure 5, when hydroxypropyl-β-cyclodextrin (HPβCD) is used as a stabilizer, it can be confirmed that DSG denaturation is prevented and stability is ensured after 8 weeks of storage under moderately accelerated conditions.

[0100] <Manufacturing and mixing ratio of stabilizer-containing microbulbs> As shown in Table 13, HPβCD was added to 2 ml of DW and dissolved by mixing and sonication for 30 minutes to prepare the aqueous phase. Desogestrel (DSG) and PLGA 503H (Evonik Ltd., Germany) were added to 10 ml of dichloromethane (DCM) and dissolved by mixing and sonication for 30 minutes to prepare the oil phase. The aqueous and oil phases were mixed and homogenized at 12,000 rpm for 10 seconds to prepare the mixture. 100 ml of polyvinyl alcohol solution (5% PVA in DW) was stirred at 1600 rpm while the mixture was dropped into the polyvinyl alcohol solution at a rate of 2 ml / min using a syringe pump, while stirring was continued for 12 hours to allow the DCM to volatilize and produce microspheres. Subsequently, the produced microspheres were precipitated using a centrifuge (2000 rpm, 10 min). After filtering the precipitated microspheres (using a 0.2 μm PVDF membrane filter), the washing process using DW was repeated twice, and then the microspheres were dried at room temperature for 12 hours to complete the production of microspheres.

[0101] [Table 13]

[0102] The manufactured microspheres were subjected to stability analysis (quantitative analysis of DSG using HPLC) using the same method as described above, both immediately after manufacturing and while stored for 8 weeks in a constant temperature and humidity stability chamber under accelerated conditions of 40°C and 75% humidity. The results are shown in Table 14 and Figure 6.

[0103] [Table 14]

[0104] As shown in Table 14 and Figure 6, microspheres produced by adding the stabilizer hydroxypropyl-β-cyclodextrin (HPβCD) to DSG in a molar ratio of 1:2 to 1:3 were confirmed to be stable, with DSG denaturation prevented even after 8 weeks of storage under accelerated conditions.

[0105] Manufacturing Example 4: Sustained-release desogestrel microspheres <Production of microspheres> 705 mg of HPβCD was added to 2 ml of DW, and the aqueous phase was prepared by mixing and sonication for 30 minutes. As shown in Table 15, PLGA 503H (50:50), 753H (75:25), 203H (100:0), and 503 (50:50) (Evonik Ltd., Germany), each with different ratios of desogestrel (DSG), lactic, and glycol, were added to 10 ml of dichloromethane (DCM), and the oil phase was prepared by mixing and sonication for 30 minutes. The aqueous phase and the oil phase were mixed and homogenized at 12,000 rpm for 10 seconds to prepare the mixture. 100 ml of polyvinyl alcohol solution (5% PVA in DW) was stirred at 1600 rpm, and the mixture was injected into the polyvinyl alcohol solution at a rate of 2 ml / min using a syringe pump while stirring was continued for 12 hours to allow the DCM to volatilize and produce microspheres. Subsequently, the produced microspheres were precipitated using a centrifuge (2000 rpm, 10 min). After filtering the precipitated microspheres (0.2 μm PVDF membrane filter), the washing process using DW was repeated twice, and then the microspheres were dried at room temperature for 12 hours to complete the production of microspheres.

[0106] [Table 15]

[0107] <Yield, inclusion rate, and inclusion efficiency of microglobules> Drugs encapsulated in microspheres produced using an HLPC (Agilent 1200 HPLC system) were analyzed, and the yield, encapsulation rate, and encapsulation efficiency of the microspheres were calculated using the aforementioned formulas and are shown in Table 16.

[0108] [Table 16]

[0109] The yields were similar to those for PLGA grade, and it was confirmed that PLGA formulations with a higher lactic / glycol ratio (MD-18 or MD-19) showed a 1-1.5% increase in encapsulation rate (loading).

[0110] <Particle morphology and particle size of microspheres> The morphology of the microspheres was observed using a SEM (Ultra Plus, Carl Zeiss), and the resulting photographs are shown in Figure 7. Pores were observed on the surface of the microspheres MD-18 and MD-19. This is thought to be due to an increase in the hydrophobicity of the outer phase and the faster diffusion out of the hydrophilic solvent in the inner phase.

[0111] Furthermore, the particle sizes of the microspheres, namely Dv 10, Dv 50, and Dv 90, were measured (wet measurement) using the Mastersizer 3000E equipment and are shown in Table 17.

[0112] [Table 17]

[0113] In the case of the microspheres in Comparative Example 7, the particle size Dv 90 was large at approximately 23 μm, making them unsuitable for use in microneedles.

[0114] <Dissolution Test - Sustained-Release Test> The microspheres produced as described above were subjected to release tests using the same method as in Production Example 1, and their sustained release properties were analyzed. The results are shown in Figure 8 and Table 18.

[0115] [Table 18]

[0116] According to Table 18 and Figure 8, the microgranules of Example 3 showed approximately 75% drug release after 120 hours, and were judged to be suitable for sustained-release over one week.

[0117] Due to the influence of pores on the surface of the microparticles, the microparticles of Example 3 (MD-18) showed a fast elution profile after 4 hours, while the microparticles of Comparative Example 8 (MD-19), despite the presence of pores, showed an increased lactic / glycol ratio (increased hydrophobicity) and a delayed elution profile.

[0118] The analysis results indicate that the sustained-release progesterone granules of the present invention contain 700 to 900 parts by weight of biodegradable polymer per 100 parts by weight of progesterone, with hydroxypropyl-β-cyclodextrin included in a molar ratio of progesterone to hydroxypropyl-β-cyclodextrin of 1:2 to 1:3, and the biodegradable polymer has a glycol to lactic ratio of 1:2 to 4. It is also found that stirring at a speed of 1600 rpm or higher for 12 hours or more is suitable during manufacturing.

[0119] Manufacturing Example 5: Manufacturing of Contraceptive Microneedles <Manufacturing of solutions for microneedle production> Using the ethinylestradiol microspheres from Example 2 and the desogestrel microspheres from Example 3 (Figure 9), a solution for manufacturing microneedles was prepared with the composition shown in Table 19.

[0120] [Table 19]

[0121] Specifically, after adding microparticles (119.23 mg in Example 4, 32.40 mg in Example 5, and 121.13 mg of MD-18 and 34.17 mg of ME-6 in Example 6) to the reactor, 1500 mg of purified water was added, and vortexing was performed for 3 minutes and sonication for 2 minutes to ensure that no aggregated microparticles remained. 133.33 mg of xylitol was added to the reactor, and vortexing was performed for 3 minutes and sonication for 2 minutes until completely dissolved. 600 mg of hyaluronic acid (HA; sodium hyaluronate) was added to the reactor, and vortexing was performed for 5 minutes and sonication for 2 minutes until completely dissolved. After that, the pressure was reduced to remove air bubbles and produce a solution for microneedle manufacturing.

[0122] <Microneedle Manufacturing> 0.2 g of the solution prepared as described above was loaded into each PMDS intaglio mold, which had circular patch-shaped microneedles engraved on it. After loading, the molds were placed in a desiccator, and the solution was filled into the intaglio mold under reduced pressure. After removing air bubbles using compressed air, the molds were dried at room temperature for 16 hours, and the finished microneedles were separated from the molds to produce the microneedles. Photographs of the produced microneedles and the needle portion are shown in Figure 10.

[0123] If necessary, the recovered microneedles can be made into patches by attaching colloidal bands or similar materials to the back to improve their usability.

[0124] As shown in Figure 10, the microneedles with the compositions of Examples 4-6 are well formed, and it can be confirmed that microspheres are encapsulated in the needle portion.

[0125] Test Example 1: Analysis of Microneedle Strength and Drug Content <Microneedle strength> For each of the microneedles from Examples 4 to 6 manufactured in Manufacturing Example 5, the compressive strength was measured using a universal material testing machine (Instron 34sc-05) at a test speed of 0.1 mm / s and a test termination condition of 100 N. For data analysis, the force value corresponding to the compressive displacement at the point where the total length of the needle portion is 1 / 3 was taken for each manufactured microneedle, and the force value for one microneedle was calculated using the formula measured force value / number of needles. The results are shown in Table 20.

[0126] [Table 20]

[0127] As shown in Table 20, the microneedles of Examples 4-6 had sufficient strength to penetrate the skin.

[0128] <Analysis of drug content in microneedles> The drug content of each microneedle from Examples 4-6, prepared in Manufacturing Example 5, was analyzed using HPLC (Agilent 1260 Infinity II Prime LC). Each microneedle was dissolved in 1 ml of 50% ACN aqueous solution as a sample. The analysis was performed as shown in Tables 21 (desogestrel) and 22 (ethinylestradiol), and the results are shown in Table 23.

[0129] [Table 21]

[0130] [Table 22]

[0131] [Table 23]

[0132] As shown in Table 23, it was confirmed that the microparticles were properly enclosed within the microneedles.

Claims

1. A microparticle composition for contraceptive microneedles, The composition contains sustained-release progesterone granules, The sustained-release progesterone microspheres are characterized by containing 700 to 900 parts by weight of a biodegradable polymer per 100 parts by weight of progesterone, and containing hydroxypropyl-β-cyclodextrin (HPβCD) in a molar ratio of progesterone:hydroxypropyl-β-cyclodextrin of 1:2 to 1:3, wherein the biodegradable polymer is one selected from the group consisting of poly(lactide-co-glycolide) (PLGA), poly(lactide-co-glycolide) glucose, and mixtures thereof, with a glycol:lactic ratio of 1:2 to 4, the particle size (Dv 90) of the microspheres being 20 μm or less, and 70 to 80% by weight of progesterone being sustainably released from the microspheres within 120 hours.

2. The composition for contraceptive microneedles according to Claim 1, further comprising sustained-release estrogen microparticles, wherein the sustained-release estrogen microparticles comprise 400 to 600 parts by weight of a biodegradable polymer per 100 parts by weight of estrogen, the biodegradable polymer contained in the sustained-release estrogen microparticles being one selected from the group consisting of poly(lactide-co-glycolide (PLGA), polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) glucose and mixtures thereof, the particle size (Dv 90) of the microparticles being 20 μm or less, and 70 to 80% by weight of estrogen being sustainably released from the microparticles within 120 hours.

3. The microparticle composition for contraceptive microneedles according to claim 2, characterized in that the sustained-release estrogen microparticles contain 400 parts by weight of a biodegradable polymer per 100 parts by weight of estrogen, and the biodegradable polymer contained in the sustained-release estrogen microparticles is poly(lactide-co-glycolide) (PLGA).

4. The microparticle composition for contraceptive microneedles according to claim 1, characterized in that the sustained-release progesterone microparticles contain 700 parts by weight of biodegradable polymer per 100 parts by weight of progesterone, and contain hydroxypropyl-β-cyclodextrin (HPβCD) in a molar ratio of progesterone:hydroxypropyl-β-cyclodextrin of 1:

2.

5. The microparticle composition for contraceptive microneedles according to claim 1, characterized in that the biodegradable polymer of the sustained-release progesterone microparticles is poly(lactide-co-glycolide) (PLGA) with a glycol:lactic ratio of 1:

3.

6. The microparticle composition for contraceptive microneedles according to claim 1, characterized in that the sustained-release progesterone microparticles have pores formed on their surface.

7. A contraceptive microneedle manufactured with the composition described in any one of claims 1 to 6, The microneedle is a contraceptive microneedle comprising a needle portion protruding in one direction and a matrix layer supporting the needle portion.

8. The contraceptive microneedle according to claim 7, characterized in that the needle portion is separable from the matrix layer when inserted into the skin.

9. The contraceptive microneedle according to claim 7, characterized in that the microneedle is manufactured using a mold.

10. A contraceptive microneedle patch comprising the microneedle described in claim 7.

11. The contraceptive microneedle patch according to claim 10, characterized in that the contraceptive microneedle patch is used once a week.

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