Microsphere 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] Contraceptives 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] Contraceptives use components of estrogen and / or progesterone to artificially regulate hormone concentrations and suppress ovulation. Contraceptives 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 contraceptives are high-content estrogen single agents, and side effects such as the risk of thrombosis and irregular bleeding are serious, and they have been withdrawn from the market. The second-generation contraceptives have levonorgestrel as the main component of progesterone, and side effects such as acne and hirsutism have been reported. Third-generation contraceptives with progesterone as the main component, such as gestoden, desogestrel, and norgestimate, improve the hirsutism and acne-inducing effects, which are side effects of the second-generation contraceptives, and there are commercial products such as Melian, Myvlar, and Mercilon.

[0004] When these contraceptives are used as oral contraceptives for contraceptive purposes, it is absolutely necessary to pay attention to taking them in a way that one tablet is taken 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 plannedly (Korean Patent Publication No. 10-2007-0087141).

[0005] As an alternative to oral contraceptives that require such inconvenient administration methods, transdermal contraceptives have emerged. Absorption of drugs through the skin, i.e., transdermal drug delivery, can avoid many undesirable side effects. In particular, it enables the use of pharmacologically active agents with a short biological half-life, reduces degradation in the digestive system, so that the effectiveness obtained with a lower total daily dose of the drug, fewer opportunities for over- or under-dosing, provides a simplified dosing method, and offers the advantage that drug injection can be quickly terminated by removing the drug delivery system from the skin surface.

[0006] As an example of a transdermal delivery contraceptive, a transdermal contraceptive delivery system in the form of a polymer patch containing an adhesive polymer matrix has been disclosed (Korean Registered Patent No. 10-0758757). However, the polymer patch has an inherent problem that the skin permeability of the drug, which is the active ingredient, is low due to the skin barrier, and the drug delivery efficiency is not sufficient. In addition, in order to optimize the efficacy of the contraceptive, the hormone, which is the active ingredient, must be capable of sustained release. In the case of a polymer patch, however, for sustained release, it must be applied for a long time every day, which may cause the skin to sag and is uncomfortable when taking a shower in summer, etc., and there are many problems.

[0007] Therefore, there is a need to develop a transdermal contraceptive delivery system that is convenient for dosing, has excellent skin drug permeability, and enables sustained release of the active ingredient. Summary of the Invention Problems to be Solved by the Invention

[0008] Therefore, as a result of continuous research to meet the requirements in the prior art, the inventors have developed sustained-release estrogen microspheres and sustained-release progesterone microspheres suitable for manufacturing contraceptive microneedles, contain these microspheres as active ingredients, and manufactured contraceptive microneedles that are convenient for dosing, have excellent skin drug permeability, and enable sustained release of the drug, thus completing the present invention.

[0009] Therefore, an object of the present invention is to provide a microsphere composition for contraceptive microneedles that has convenient dosing, excellent skin drug permeability, and enables sustained release of the drug.

[0010] Another object of the present invention is to provide a contraceptive microneedle that has convenient dosing including the microsphere composition, excellent skin drug permeability, and enables sustained release of the drug.

[0011] Another object of the present invention is to provide a contraceptive microneedle patch including the microneedle.

Means for Solving the Problems

[0012] In order to achieve the object of the present invention, there is provided a microsphere composition for contraceptive microneedles that has convenient dosing, excellent skin drug permeability, and enables sustained release of the drug.

[0013] In the present invention, the drug means estrogen and progesterone.

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

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

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

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

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

[0019] In the present invention, the sustained-release estrogen microspheres can comprise 400-600 parts by weight of a biodegradable polymer with respect to 100 parts by weight of estrogen. Most preferably, the sustained-release estrogen microspheres comprise 100 parts by weight of estrogen and 400 parts by weight of a biodegradable polymer. If the content of estrogen contained in the microspheres is within the above range, sustained-release for more than one week is possible.

[0020] The above-mentioned biodegradable polymer means a polymer that does not cause high cytotoxicity, inflammatory reactions, etc. when administered in vivo and is decomposed in vivo.

[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. When the particle size (Dv 90) of the microspheres exceeds the above range, the particle size becomes large and it is not suitable for encapsulation in microneedles for use.

[0022] In the present invention, biodegradable polymers that can be used in the sustained-release estrogen microspheres can be selected from the group consisting of poly(lactide-co-glycolide) (PLGA; poly(lactide-co-glycolide)), polylactide (PLA; polylactide), polyglycolide (PGA; polyglycolide), poly(lactide-co-glycolide) glucose, and mixtures thereof, and most preferably poly(lactide-co-glycolide) (PLGA).

[0023] In the present invention, the sustained-release estrogen microspheres can be produced by the O / W (oil-in-water) type single solvent evaporation method in which an O / W (oil-in-water) type emulsion containing a biodegradable polymer, estrogen, and a solvent is produced and aggregated into microspheres. Specifically, after producing an oil phase containing estrogen and a solvent, it is dispersed in an aqueous phase in which a surfactant is dissolved to produce O / W type microspheres.

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

[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 carried out at a speed of 1600 rpm or more for 12 hours or more. When the stirring is carried out 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 microneedles 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 encapsulation in microneedles (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 (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 to 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, it is possible to achieve a sustained release of progesterone for one week or more.

[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. When the particle size of the microspheres exceeds the above range, the particle size becomes large, and they are not suitable for encapsulation in microneedles for use.

[0032] As the biodegradable polymer that can be used in the sustained-release progesterone microspheres in the present invention, it can be selected from the group consisting of poly(lactide-co-glycolide) (PLGA) with a glycolic:lactic ratio of 1:2 to 4, poly(lactide-co-glycolide) glucose, and mixtures thereof. Most preferably, it is poly(lactide-co-glycolide) (PLGA) with a glycolic:lactic ratio of 1:3.

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

[0034] The solvent can be selected from the group consisting of dichloromethane (DCM), chloroform, acetonitrile, dimethyl sulfoxide, dimethylformamide, ethyl acetate, and mixtures thereof. Most preferably, it is dichloromethane (DCM).

[0035] It is preferable that stirring is performed at a speed of 1600 rpm or more for 12 hours or more during the dispersion. When the stirring proceeds at a speed of less than 1600 rpm, the average particle size of the microspheres becomes large and they cannot be used after being encapsulated in the microneedles.

[0036] The surfactant can be selected from the group consisting of polyvinyl alcohol (PVA), polysorbate 20, polysorbate 60, polysorbate 80, or mixtures thereof. 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 being encapsulated in microneedles and pores are formed on the surface of the microspheres, and a sustained-release property of progesterone for more than one week appears (Figs. 7 and 8).

[0038] According to another object of the present invention, a contraceptive microneedle containing the microsphere composition is provided.

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

[0040] The soluble material in the present invention is one that can be excreted outside the body by being naturally biodegradable in the body and constitutes the form of the microneedle. Therefore, the microneedle of the present invention is water-soluble and dissolves in body fluids in the skin. The soluble material can be at least one selected from the group consisting of hyaluronic acid (HA) or its salt, alginic acid (AA) or its salt, 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, and most preferably hyaluronic acid or its salt is used.

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

[0042] The above stabilizer plays a role in contributing to the stability during the production of micro-needles, and at least one or more selected from the group consisting of xylitol, trehalose, lactose, sucrose, polyhydric alcohol, cyclodextrin, dextrin, starch, glucose, maltose, lactulose, turanose, melibiose, sorbitol, and mannitol can be used.

[0043] The stabilizer during the production of the micro-needles of the present invention can be contained in an amount of 3% to 10% by weight based on the entire solution.

[0044] During the production of the micro-needles of the present invention, the microsphere composition can be contained in an amount of 1% to 10% by weight based on the entire solution.

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

[0046] The composition of the present invention can further contain a pH adjuster as needed. As the pH adjuster, any of those commonly used during the production of micro-needles such as NaOH can be used.

[0047] In addition, the composition of the present invention can further contain a plasticizer, a surfactant, a preservative, etc. that are commonly used in the production of micro-needles as needed.

[0048] The microneedle of the present invention can include a needle portion protruding in one direction and a matrix layer supporting the needle portion. The needle portion has a shape that easily penetrates the skin. The shape of the needle portion of the microneedle according to the present invention is a conical shape, a pyramid shape, a lanceolate shape, a brachycephalic shape, a wedge shape, a blade shape, etc., and these must all be shapes 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 so that it can be separated from the matrix layer when inserted into the skin, if necessary. The microneedle according to the present invention can, if necessary, also have the matrix layer made of other materials. Therefore, in the microneedle of the present invention, the microparticles of the present invention can be evenly distributed in the needle portion and the matrix layer, or can be distributed only in the needle portion.

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

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

[0052] The microneedle of the present invention has the convenience of dosing with one use per period of one week or more. Since the microneedle makes a small hole in the skin and enters, the skin drug permeability is also excellent, and there is an advantage that the sustained-release microparticles of the present invention can be used to achieve sustained-release of the drug for one week or more.

[0053] According to another object of the present invention, a contraceptive microneedle patch containing the microneedle is provided.

[0054] The contraceptive micro-needle patch of the present invention has an adhesive layer laminated on one surface of the matrix layer, and the micro-needle patch can be used by attaching it to the skin. The micro-needle patch can also include a protective film on the adhesive layer.

[0055] The contraceptive micro-needle patch of the present invention enables sustained release of a drug for more than one week even with a short application time within 3 hours, and is useful as a female contraceptive.

Effects of the Invention

[0056] The microsphere composition for contraceptive micro-needles according to the present invention has a drug stably encapsulated therein, exhibits sustained release of the drug for more than one week, and has a particle size (Dv 90) suitable for being encapsulated in the micro-needles.

[0057] The contraceptive micro-needles according to the present invention are convenient for dosing as they can be used once a week for more than one week, have excellent skin drug permeability, can be used with a short wearing time, and enable sustained release of the drug for more than one week.

[0058] The contraceptive micro-needle patch according to the present invention enables sustained release of a drug for more than one week even with a short application, and is useful for use as a female contraceptive.

Brief Description of the Drawings

[0059]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Mode for Carrying Out the Invention

[0060] Hereinafter, in order to assist in the understanding of the present invention, the configuration and effects of the present invention will be described in more detail through specific examples. However, the following examples are illustrative for a clearer understanding of the present invention, and the scope of the rights of the present invention is not limited by the following examples.

[0061] Production Example 1: Sustained-release ethinyl estradiol microspheres <Production of microspheres> Ethinyl estradiol (EE) and PLGA 503H (Evonik Ltd., Germany) were added to 10 ml of dichloromethane (DCM) in the capacity as shown in Table 1, and dissolved by mixing and sonication for 30 minutes to produce an oil phase. While stirring 100 ml of a polyvinyl alcohol solution (5% PVA in D.W) at the stirring speed (rpm) as shown in Table 1, the oil phase was injected into the polyvinyl alcohol solution at 2 ml / min using a syringe pump, and stirring was continued for 12 hours so that DCM would volatilize to produce microspheres. Thereafter, the microspheres produced were precipitated using a centrifuge (2000 rpm, 10 min). After filtering the precipitated microspheres through a 0.2 μm PVDF membrane filter, the process of washing with D.W was repeated twice, and then dried at room temperature for 12 hours to complete the production of microspheres.

[0062]

Table 1

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

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

[0065]

Table 2

[0066] In the case of the microspheres of Comparative Example 4, the encapsulation efficiency (about 10.13%) was low and it was unsuitable. It was confirmed that when the mixing amount of ethinyl estradiol (EE) was large, the encapsulation efficiency decreased.

[0067] <Particle morphology and particle size of microspheres> The particle morphology of the microspheres was observed using an SEM instrument (Ultra Plus, Carl Zeiss), and the resulting photograph is shown in Fig. 1. All the microspheres showed a spherical particle morphology.

[0068] Also, the particle size of the microspheres, namely Dv 10, Dv 50, and Dv 90, was measured (wet measurement) using a Mastersizer 3000E instrument and shown in Table 3.

[0069]

Table 3

[0070] In the case of the microspheres of Comparative Example 1, the particle size (Dv 90) was as large as 36.57 ± 2.62 μm and was not suitable for use in a micro needle. It was confirmed that by performing stirring during microsphere production at 1600 rpm or more, the particle size (Dv 90) was produced to be a desirable size of around 10 μm for mounting on a micro needle.

[0071] <Dissolution test - Sustained release test> For the microspheres produced above, the following dissolution test was performed to analyze the sustained release property.

[0072] 40 ml of a 0.5% Tween 80 (in PBS, pH 7.4, 1X) eluent was placed in a 50 ml conical tube in a shaking bath (37°C, 50 rpm). Then, the microspheres were weighed so that the amount of ethinyl estradiol (EE) would be 1000 μg, placed in the eluent, and the dissolution evaluation was carried out.

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

[0074] The values of the elution time and the elution rate results (up to an elution rate of less than 60%) were substituted into the following formula to calculate each kinetics:

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, the lower the PLGA ratio, the faster the elution rate. The microspheres of Example 1 and Example 2 showed a drug release of about 77.7% - 81% at 120 hours and were judged to be suitable for sustained release over one week.

[0079] According to Table 5, the elution pattern showed a sustained release pattern and conformed to Higuchi or Korsmeyer - peppas kinetics.

[0080] From the above analysis results, it can be seen that the sustained - release estrogen microspheres of the present invention are suitably mixed with 400 - 600 parts by weight of a biodegradable polymer with respect to 100 parts by weight of estrogen, and stirring during production is carried out at a speed of 1600 rpm or more for 12 hours or more.

[0081] Production Example 2: Derivation of Manufacturing Conditions for Desogestrel Microspheres <Manufacture 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 dissolved by mixing and sonication for 30 minutes to prepare an oil phase. While stirring a 100 ml polyvinyl alcohol solution (5% PVA in D.W) at the stirring speed (rpm) shown in Table 6, the oil phase was injected (dropped) into the polyvinyl alcohol solution at 2 ml / min using a syringe pump, and stirring was continued for 12 hours so that DCM would volatilize to produce microspheres. Thereafter, the microspheres produced were precipitated using a centrifuge (2000 rpm, 10 min). After filtering the precipitated microspheres through a 0.2 μm PVDF membrane filter, the process of washing with D.W was repeated twice, and then dried at room temperature for 12 hours to complete the production of microspheres.

[0082] [Table 6]

[0083] <Yield, Encapsulation Rate, and Encapsulation Efficiency of Microspheres> The drug encapsulated in the microspheres produced using an HLPC instrument (Agilent 1200 HPLC system) was analyzed, and the yield, encapsulation rate, and encapsulation efficiency of the microspheres were calculated using the above formulas and shown in Table 7.

[0084] [Table 7]

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

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

[0087]

Table 8

[0088] In the case of the microspheres of Comparative Example 4 and Comparative Example 5, the particle size Dv 90 was as large as about 55 μm, which was not suitable for use in the micro needle. It was confirmed that when the mixing amount of the biodegradable polymer was large, the size of the microspheres became too large. Also, it can be confirmed that by performing stirring during the production of the microspheres at 1600 rpm or more, the Dv 90 is produced to a size desirable for mounting on the micro needle at around 10 μm.

[0089] <Elution Test - Sustained Release Test> For the microspheres produced above, an elution test was conducted in the same manner as in Production Example 1 to analyze the sustained release property, and the test results are shown in FIG. 4 and Table 9.

[0090]

Table 9

[0091] According to Table 9 and FIG. 4, the microspheres of Comparative Examples 4 to 6 showed a drug release property of about 44% or less in 120 hours, were not suitable for one-week sustained release, and improvement in the stability of the drug (DSG) was required.

[0092] Production Example 3: Production of Desogestrel Microspheres with Different Stabilizers <Selection of Stabilizer> In order to select a stabilizer suitable for the production of desogestrel microspheres with enhanced stability, a composition for microspheres containing a stabilizer was produced with the composition as shown in Table 10, and the stability was tested by producing it in the form of a thin film.

[0093]

Table 10

[0094] Specifically, after mixing an ethanol solution in which each stabilizer was added to and dissolved in the DSG drug and a DCM solution in which PLGA was dissolved, it was dried using a Nitrogen evaporator and then manufactured in the form of a film (thickness 50 - 100 μm).

[0095] For the manufactured films, stability analysis was performed immediately after production and while storing them in a constant temperature and humidity stability chamber at 30°C and 65% for 8 weeks under accelerated conditions.

[0096] Specifically for the stability analysis, after adding the total amount of each film sample to 5 ml of a dilution solvent (a 1:1 mixed solvent of Phosphate buffer solution pH 3.5 : 78% Acetonitrile) and shaking and mixing, quantitative analysis of DSG was performed using the HPLC method under the conditions shown in Table 11 below, and 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) among the stabilizers is used, it can be confirmed that DSG denaturation is prevented and stability is ensured after storing for 8 weeks under accelerated conditions.

[0100] <Manufacture and formulation ratio of stabilizer - incorporated microspheres> With a capacity as shown in Table 13, hydroxypropyl-β-cyclodextrin (HPβCD) was added to 2 ml of D.W, and dissolved by mixing and sonication for 30 minutes to produce an 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 produce an oil phase. The aqueous phase and the oil phase were mixed and homogenized with a homogenizer at 12,000 rpm for 10 seconds to produce a mixture. While stirring a 100 ml polyvinyl alcohol solution (5% PVA in D.W) at 1600 rpm, the mixture was injected into the polyvinyl alcohol solution at 2 ml / min using a syringe pump while continuously stirring for 12 hours to allow the DCM to volatilize so that microspheres were produced. Thereafter, the microspheres produced were precipitated using a centrifuge (2000 rpm, 10 min). After filtering the precipitated microspheres through a 0.2 μm PVDF membrane filter, the process of washing with D.W was repeated twice, and then dried at room temperature for 12 hours to complete the production of the microspheres.

[0101]

Table 13

[0102] For the produced microspheres, immediately after production and while storing in a thermo-hygrostat stability chamber at 40 °C and 75% under accelerated conditions for 8 weeks, stability analysis (quantitative analysis of DSG using the HPLC method) was performed in the same manner as described above, and the results are shown in Table 14 and Figure 6.

[0103]

Table 14

[0104] As shown in Table 14 and Figure 6, it can be confirmed that the microspheres produced by formulating the stabilizer hydroxypropyl-β-cyclodextrin (HPβCD) with DSG at a molar ratio of 1:2 to 1:3 prevent the denaturation of DSG and ensure stability even after storage under accelerated conditions for 8 weeks.

[0105] Production Example 4: Sustained Release Desogestrel Microspheres <Manufacture of Microspheres> 705 mg of HPβCD was added to 2 ml of D.W and dissolved by mixing and sonication for 30 minutes to prepare an aqueous phase. Poly(lactic-co-glycolic acid) 503H (50:50), 753H (75:25), 203H (100:0), 503 (50:50) (Evonik Ltd., Germany) with different ratios of desogestrel (DSG) to lactide and glycolide were added to 10 ml of dichloromethane (DCM) in the volumes shown in Table 15, respectively, and dissolved by mixing and sonication for 30 minutes to prepare an oil phase. The aqueous phase and the oil phase were mixed and homogenized with a homogenizer at 12,000 rpm for 10 seconds to prepare a mixture. While stirring 100 ml of a polyvinyl alcohol solution (5% PVA in D.W) at 1600 rpm, the mixture was injected into the polyvinyl alcohol solution at 2 ml / min using a syringe pump while continuously stirring for 12 hours so that DCM would volatilize to produce microspheres. Then, the microspheres produced were precipitated using a centrifuge (2000 rpm, 10 min). After filtering the precipitated microspheres through a 0.2 μm PVDF membrane filter, the process of washing with D.W was repeated twice, and then dried at room temperature for 12 hours to complete the production of microspheres.

[0106]

Table 15

[0107] <Yield, Encapsulation Rate, Encapsulation Efficiency of Microspheres> The drug encapsulated in the microspheres produced using an HLPC instrument (Agilent 1200 HPLC system) was analyzed, and the yield, encapsulation rate, and encapsulation efficiency of the microspheres were calculated using the above formulas and shown in Table 16.

[0108]

Table 16

[0109] The yields for different PLGA grades are similar, and it was confirmed that for PLGA formulations (MD-18 or MD-19) with a high lactic / glycolic ratio, the loading increased by 1 - 1.5%.

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

[0111] Also, the particle size of the microspheres, namely Dv 10, Dv 50, and Dv 90, was measured (wet measurement) using a Mastersizer 3000E instrument and is shown in Table 17.

[0112]

Table 17

[0113] In the case of the microspheres of Comparative Example 7, the particle size Dv 90 was as large as approximately 23 μm, which was not suitable for use in micro needles.

[0114] <Elution test - Sustained release test> For the microspheres prepared above, a release test was conducted in the same manner as in Production Example 1 to analyze the sustained release, and the results are shown in Figure 8 and Table 18.

[0115]

Table 18

[0116] According to Table 18 and FIG. 8, the microspheres of Example 3 exhibited about 75% drug release in 120 hours and were judged to be suitable for one-week sustained release.

[0117] Due to the influence of pores on the surface of the microspheres, the microspheres (MD-18) of Example 3 showed a fast dissolution profile after 4 hours. In the case of the microspheres (MD-19) of Comparative Example 8, although there were pores, the lactide / glycolide ratio increased (hydrophobicity increased), showing a delayed dissolution profile.

[0118] As a result of the above analysis, it can be seen that the sustained-release progesterone microspheres of the present invention contain 700 to 900 parts by weight of a biodegradable polymer with respect to 100 parts by weight of progesterone, and hydroxypropyl-β-cyclodextrin is contained such that the molar ratio of progesterone:hydroxypropyl-β-cyclodextrin is 1:2 to 1:3. The biodegradable polymer has a glycolic:lactic ratio of 1:2 to 4, and it is suitable that stirring is carried out at a speed of 1600 rpm or more for 12 hours or more during production.

[0119] Production Example 5: Production of contraceptive micro needles <Production of solution for manufacturing micro needles> Using the ethinyl estradiol microspheres of Example 2 and the desogestrel microspheres of Example 3 (FIG. 9), a solution for manufacturing micro needles was produced with the composition shown in Table 19.

[0120]

Table 19

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

[0122] <Manufacture of Microneedles> 0.2 g of the solution prepared above was respectively loaded into a PMDS negative etching mold engraved with circular patch-shaped microneedles. The mold after loading was placed in a desiccator, the pressure was reduced to fill the solution into the negative etching mold, and after removing bubbles using compressed air, it was dried at room temperature for 16 hours, and then the completed microneedles were separated from the mold to manufacture microneedles. Photographs of the manufactured microneedles and the needle part are shown in Figure 10.

[0123] The recovered microneedles can be made more usable in the form of a patch by attaching a colloidal band or the like to the back as needed.

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

[0125] Test Example 1: Analysis of the Strength and Drug Content of Microneedles <Strength of Microneedles> For each of the micro-needles of Examples 4 to 6 manufactured in Production 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 test end condition: 100 N. For data analysis, for each manufactured micro-needle, the force value corresponding to the compressive displacement at a point that is 1 / 3 of the total length of the needle part was taken, and the force value of one micro-needle was calculated using the formula of the measured force value / number of needles. The results are shown in Table 20.

[0126]

Table 20

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

[0128] <Analysis of Micro-Needle Drug Content> For each of the micro-needles of Examples 4 to 6 manufactured in Production Example 5, the drug content was analyzed using HPLC (Agilent 1260 Infinity II Prime LC). As samples, each micro-needle was dissolved in 1 ml of 50% ACN aqueous solution and used. The analysis was performed as shown in Table 21 (Desogestrel) and Table 22 (Ethinyl Estradiol) below, 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 micro needles were appropriately encapsulated with the microspheres.

Claims

1. A microsphere composition for contraceptive micro needles, wherein the composition contains one selected from the group consisting of sustained-release estrogen microspheres, sustained-release progesterone microspheres, and mixtures thereof, the sustained-release estrogen microspheres contain 400 to 600 parts by weight of a biodegradable polymer with respect to 100 parts by weight of estrogen, and the biodegradable polymer is any one selected from the group consisting of poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) glucose, and mixtures thereof. Stirring is carried out at a speed of 1600 rpm or more for 12 hours or more during the production of the microspheres. The particle size (Dv 90) of the microspheres is 20 μm or less, and 70 to 80% by weight of estrogen is continuously released from the microspheres within 120 hours. The sustained-release progesterone microspheres contain 700 to 900 parts by weight of a biodegradable polymer with respect to 100 parts by weight of progesterone, and contain hydroxypropyl-β-cyclodextrin (HPβCD) at a molar ratio of progesterone:hydroxypropyl-β-cyclodextrin of 1:2 to 1:

3. As the biodegradable polymer, any one selected from the group consisting of poly(lactide-co-glycolide) (PLGA) with a glycolic:lactic ratio of 1:2 to 4, poly(lactide-co-glycolide) glucose, and mixtures thereof is used. The particle size (Dv 90) of the microspheres is 20 μm or less, and 70 to 80% by weight of progesterone is continuously released from the microspheres within 120 hours. A microsphere composition for contraceptive micro needles, characterized in that.

2. The estrogen is ethinylestradiol, and the progesterone is any one selected from the group consisting of desogestrel, gestodene, dienogest, levonorgestrel, norgestimate, norethisterone, drospirenone, trimegestone, and dydrogesterone. The microsphere composition for contraceptive micro needles according to claim 1 is characterized by this.

3. The sustained-release estrogen microspheres contain 400 parts by weight of a biodegradable polymer with respect to 100 parts by weight of estrogen, and the biodegradable polymer is poly(lactide-co-glycolide) (PLGA). The microsphere composition for contraceptive micro needles according to claim 1 is characterized by this.

4. The sustained-release progesterone microspheres contain 700 parts by weight of a biodegradable polymer with respect to 100 parts by weight of progesterone, and contain hydroxypropyl-β-cyclodextrin (HPβCD) with a molar ratio of progesterone:hydroxypropyl-β-cyclodextrin of 1:

2. The microsphere composition for contraceptive micro needles according to claim 1 is characterized by this.

5. The biodegradable polymer of the sustained-release progesterone microspheres is poly(lactide-co-glycolide) (PLGA) with a ratio of glycolic:lactic of 1:

3. The microsphere composition for contraceptive micro needles according to claim 1 is characterized by this.

6. The sustained-release progesterone microspheres are characterized in that pores are formed on the surface of the microspheres. The microsphere composition for contraceptive micro needles according to claim 1 is characterized by this.

7. The microsphere composition for contraceptive micro needles according to claim 1 is characterized in that the composition contains only the sustained-release estrogen microspheres.

8. The microsphere composition for contraceptive micro needles according to claim 1 is characterized in that the composition contains only the sustained-release progesterone microspheres.

9. The microsphere composition for contraceptive micro needles according to claim 1 is characterized in that the composition contains the sustained-release estrogen microspheres and the sustained-release progesterone microspheres.

10. A contraceptive micro-needle manufactured from the composition according to any one of Claims 1 to 9, wherein the micro-needle includes a needle portion protruding in one direction and a matrix layer supporting the needle portion, and is a contraceptive micro-needle.

11. The contraceptive micro-needle according to Claim 10, wherein the needle portion is separable from the matrix layer when inserted into the skin.

12. The contraceptive micro-needle according to Claim 10, wherein the micro-needle is manufactured using a mold.

13. A contraceptive micro-needle patch including the micro-needle according to Claim 10.

14. The contraceptive micro-needle patch according to Claim 13, wherein the contraceptive micro-needle patch is used once a week.

Images