Microparticles comprising finasteride and method for preparing same

Abstract

The present invention relates to finasteride-containing microparticles, the finasteride-containing microparticles comprising finasteride and a biodegradable polymer, the finasteride-containing microparticles being in a form in which a finasteride drug is uniformly distributed in spherical biodegradable polymer microparticles, the average particle diameter of the finasteride-containing microparticles being 20 to 70 [mu] m. The present invention relates to sustained-release microparticles and a method for preparing the same, which can continuously maintain an effect of treating alopecia for one to three months in accordance with administration of microparticles containing finastlail. Furthermore, the present invention, by administering fine particles containing finasteride to a patient by injection, does not need to be stored and handled by the patient instead of an oral dosage form, and thus is easy to store and handled, enables a long-term administration effect of 1-3 months to be maintained, and, by preparing the average particle size to a certain micron size, makes it possible to improve the bioavailability of the finasteride composition. The present invention reduces foreign body sensation and pain when administered to a patient in the form of an injection, and thus makes it easy to administrate in the form of an injection.

Description

Technical Field

[0001] The present invention relates to microparticles containing finasteride and a preparation method thereof, and more particularly to microparticles containing finasteride as a physiologically active substance for hair growth and nourishment and a biodegradable polymer and a preparation method thereof. Background Art

[0002] Among the male hair loss treatment drugs currently used in Korea, finasteride and dutasteride are oral preparations. Figure 1 The mechanism of action shown is to block the 5-α-reductase inhibitor that converts testosterone into dihydrotestosterone (DHT), which can inhibit the production of the potent male hormone DHT, thereby inhibiting the hair root shrinkage caused by DHT in the scalp to treat androgenic alopecia.

[0003] 5-α-reductase inhibitors are divided into Type 1 and Type 2. Type 1 is distributed in the scalp and sebaceous glands, while Type 2 is distributed in the scalp and prostate. Finasteride only blocks Type 2 5-α-reductase inhibitors, but dutasteride blocks both Type 1 and Type 2. Through this mechanism, dutasteride is known to have a stronger DHT inhibitory effect than finasteride. However, based on the initial one-year use, dutasteride has a higher rate of side effects. Finasteride is currently widely used as a hair loss treatment and is the only FDA-approved product, with superior safety compared to dutasteride.

[0004] For example, according to Korean Patent Publication No. 10-2016-0002411, existing oral hair loss treatments only show therapeutic effects after daily use for at least three months. Furthermore, if discontinued, the efficacy decreases, making it difficult to restore the original level. Consequently, the problem is that continuous daily use at a prescribed time is required to maintain the efficacy and effectiveness of the treatment.

[0005] Hair loss treatments such as dutasteride and finasteride are contraindicated for use by women of childbearing age or pregnant women due to their association with male hormones. Exposure of these treatments to women of childbearing age or pregnant women can cause external genitalia in male fetuses, leading to the risk of birth defects. Therefore, care must be taken with the storage and handling of these treatments during use. Furthermore, these treatments can be absorbed through the skin and affect the fetus, so they must be avoided. This is especially important for those living with women of childbearing age or pregnant women.

[0006] Therefore, it is necessary to develop a hair loss treatment agent that can maintain its efficacy for more than one month after a single administration and is easy to store and handle, using finasteride, which has been recognized for its stability as a hair loss treatment agent. Summary of the Invention

[0007] Problems to be solved by the invention

[0008] The present invention relates to microparticles containing finasteride and a method for preparing the same.

[0009] The present invention aims to provide a sustained-release microparticle and a method for preparing the same. Unlike existing oral dosage forms that have a short half-life and require daily administration, the microparticles containing finasteride can maintain a sustained hair loss treatment effect for one to three months.

[0010] Another object of the present invention is to administer finasteride-containing microparticles to patients by injection, which, unlike oral dosage forms, does not require patients to store and handle the microparticles themselves, thereby facilitating storage and handling.

[0011] Another object of the present invention is to provide sustained-release particles containing finasteride that can maintain a long-term drug administration effect of one to three months. At the same time, by preparing the average particle size to a certain micron size, the release of the drug from the particles is controlled, and a certain effective drug concentration can be maintained. When applied to an injection composed of particles of uniform size, the foreign body sensation and pain when the injection is administered to the patient are reduced.

[0012] Means used to solve problems

[0013] In order to achieve the above-mentioned purpose, as a specific example of the present invention, the present invention relates to a microparticle containing finasteride, which contains finasteride and a biodegradable polymer. The microparticle is in a shape in which the finasteride drug is uniformly distributed in spherical biodegradable polymer particles, and the average particle size of the microparticle is 20 to 70 μm.

[0014] As a specific example of the present invention, the microparticles of the present invention may contain the biodegradable polymer and finasteride at a weight ratio of 4:1 to 15:1.

[0015] As a specific example of the present invention, the microparticles of the present invention can continuously release finasteride for 1 to 3 months.

[0016] As a specific example of the present invention, the biodegradable polymer of the present invention can be selected from the group consisting of polylactic acid, polylactide, polylactic acid-glycolic acid copolymer, polylactide-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid and combinations thereof, preferably polylactide-glycolide (PLGA), but not limited to the above examples.

[0017] As a specific example of the present invention, the microparticles of the present invention are prepared using a microchannel, and the width (w) of the channel cross section relative to the average diameter (d') of the microparticles is in a ratio range of 0.7 to 1.3.

[0018] As a specific example of the present invention, the microparticles of the present invention are prepared using microchannels, and the ratio of the height (d) of the channel cross section to the average diameter (d') of the microparticles is in the range of 0.7 to 1.3.

[0019] As a specific example of the present invention, the composition for treating, preventing hair loss and promoting hair growth of the present invention comprises the above-mentioned fine particles.

[0020] As a specific example of the present invention, the present invention relates to a method for preparing microparticles containing finasteride, comprising: 1) dissolving a biodegradable polymer and finasteride in an organic solvent to prepare a first mixture, 2) dissolving a surfactant in water to prepare a second mixture, 3) injecting the first mixture of step 1) into a linear microchannel and causing it to flow, 4) injecting the second mixture of step 2) into a microchannel formed on both sides or one side and causing it to flow so as to form an intersection with the microchannel in step 3) in which the first mixture flows linearly, the linear flow of the first mixture and the second mixture flow intersecting to prepare microparticles in which finasteride is uniformly distributed in spherical biodegradable polymer particles, 5) collecting microparticles generated at the intersection of step 4), 6) stirring the microparticles collected in step 5) to evaporate and remove the organic solvent present in the microparticles, and 7) washing and drying the microparticles of step 6), wherein the average particle size of the microparticles is 20 to 70 μm.

[0021] As a specific example of the present invention, the first mixture in step 1) of the present invention may contain 10 to 20 weight % of a biodegradable polymer.

[0022] As a specific example of the present invention, the first mixture in step 1) of the present invention may include the biodegradable polymer and finasteride in a weight ratio of 4:1 to 15:1.

[0023] As a specific example of the present invention, the biodegradable polymer of the present invention can be selected from the group consisting of polylactic acid, polylactide, polylactic acid-glycolic acid copolymer, polylactide-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid and combinations thereof, preferably polylactide-glycolide (PLGA), but not limited to the above examples.

[0024] As a specific example of the present invention, the organic solvent in step 1) of the present invention can be any one or more selected from the group consisting of dichloromethane, chloroform, ethyl chloride, dichloroethane, trichloroethane and mixtures thereof.

[0025] As a specific example of the present invention, the second mixture in step 2) of the present invention may contain a surfactant in an amount of 0.2 wt % to 0.3 wt %.

[0026] As a specific example of the present invention, the surfactant in step 2) of the present invention can be any one or more selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants and mixtures thereof.

[0027] As a specific example of the present invention, in the step 3) of the present invention, the first mixture can be injected into the linear microchannel at a pressure of 600 to 1000 mbar.

[0028] As a specific example of the present invention, the step 4) of the present invention injects the second mixture into the microchannel formed on both sides or one side to form an intersection with the microchannel in the straight direction of the first mixture flowing, and the second mixture can be injected at a pressure of 1200 to 1600 mbar.

[0029] As a specific example of the present invention, in step 5) of the present invention, the microparticles can be collected in a water tank filled with a mixed solution containing 0.2 wt % to 0.3 wt % of a surfactant.

[0030] As a specific example of the present invention, the step 6) of the present invention may include: 6-1) a step of stirring for the first time at a speed of 800 to 1200 rpm at 14 to 16°C for 1 to 2 hours; 6-2) after the first stirring step, a step of stirring for the second time at a speed of 800 to 1200 rpm at 19 to 21°C for 0.5 to 1.5 hours; and 6-3) after the second stirring step, a step of stirring for the third time at a speed of 800 to 1200 rpm at 24 to 26°C for 0.5 to 1.5 hours.

[0031] As a specific example of the present invention, the microchannels of steps 3) and 4) of the present invention are formed on the surface of the chip, and the average diameter of the microchannels is 40 to 100 μm, preferably 40 to 60 μm, and more preferably 50 μm, but is not limited to the examples.

[0032] Effects of the Invention

[0033] The present invention relates to sustained-release microparticles and a preparation method thereof, microparticles containing finasteride and a preparation method thereof. With administration of the microparticles containing finasteride, a sustained hair loss treatment effect can be maintained for one to three months.

[0034] In addition, the present invention utilizes a method of administering finasteride-containing microparticles to patients by injection. Unlike oral dosage forms, this method does not require the patient to personally store and handle the microparticles, making it easy to store and handle, and can maintain a long-term administration effect of 1 to 3 months. At the same time, by preparing the average particle size to a certain micron size, the foreign body sensation and pain when administering the microparticles to patients in the form of an injection are reduced, making it easy to administer the microparticles by injection. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the mechanism of action of hair loss treatment agents.

[0036] Figure 2 This is a flowchart of the method for preparing finasteride-containing microparticles of the present invention.

[0037] Figure 3 This is a graph showing the results of drug release period according to the weight ratio of the biodegradable polymer and finasteride according to the present invention.

[0038] Figure 4 is a SEM photograph of microparticles prepared by a method according to one embodiment of the present invention.

[0039] Figure 5 is a SEM photograph of microparticles prepared by a method according to one embodiment of the present invention.

[0040] Figure 6 is a SEM photograph of microparticles prepared by a method according to one embodiment of the present invention.

[0041] Figure 7 is a SEM photograph of microparticles prepared by a method according to one embodiment of the present invention.

[0042] Figure 8 This graph shows the relationship between the average diameter of microparticles and the cross-section of microchannels. DETAILED DESCRIPTION

[0043] According to one embodiment of the present invention, the present invention relates to a microparticle containing finasteride, which contains finasteride and a biodegradable polymer. The microparticle is in the shape of finasteride drug uniformly distributed in spherical biodegradable polymer particles, and the average particle size of the microparticle is 20 to 70 μm.

[0044] According to another embodiment of the present invention, the present invention relates to a method for preparing microparticles containing finasteride, comprising: 1) dissolving a biodegradable polymer and finasteride in an organic solvent to prepare a first mixture, 2) dissolving a surfactant in water to prepare a second mixture, 3) injecting the first mixture of step 1) into a microchannel in a linear direction and causing it to flow, 4) injecting the second mixture of step 2) into a microchannel formed on both sides or one side and causing it to flow so as to form an intersection with the microchannel in step 3) in which the first mixture flows in a linear direction, the linear flow of the first mixture and the second mixture flow intersecting to prepare microparticles in which finasteride is uniformly distributed in spherical biodegradable polymer particles, 5) collecting the microparticles generated at the intersection of step 4), 6) stirring the microparticles collected in step 5) to evaporate and remove the organic solvent present in the microparticles, and 7) washing and drying the microparticles of step 6), wherein the average particle size of the microparticles is 20 to 70 μm.

[0045] Hereinafter, the embodiments of the present invention will be described in detail to facilitate implementation by those skilled in the art. However, the present invention can be implemented in various forms and is not limited to the embodiments described herein.

[0046] Figure 2 This is a flowchart of the method for preparing finasteride-containing microparticles of the present invention.

[0047] According to the sequence diagram, the preparation of the microparticles containing finasteride of the present invention is carried out in the following order: 1) a step of preparing a first mixture (S100); 2) a step of preparing a second mixture (S200); 3) a step of injecting the first mixture into a microchannel in a straight direction (S300); 4) a step of injecting the second mixture into a microchannel on both sides or one side (S400); 5) a step of collecting the microparticles (S500); 6) a step of stirring the collected microparticles (S600); and 7) a step of washing and drying the microparticles (S700).

[0048] The preparation method of finasteride-containing microparticles according to one embodiment of the present invention is described in more detail as follows.

[0049] 1) Step S100 is a step of preparing a first mixture, in which a biodegradable polymer and finasteride are dissolved in an organic solvent to prepare the first mixture. The biodegradable polymer can be selected from the group consisting of polylactic acid, polylactide, polylactic acid-glycolic acid copolymer, polylactide-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof, preferably polylactide-glycolide (PLGA), but not limited to the examples described above.

[0050] In addition, the organic solvent is not miscible with water, and for example, is one or more selected from the group consisting of chloroform, ethyl chloride, dichloroethane, trichloroethane, and mixtures thereof, preferably dichloromethane, but not limited to the examples. As long as it is an organic solvent that can dissolve the biodegradable polymer and finasteride, it is not limited to the examples above, and any organic solvent that can be easily selected by those skilled in the art can be used.

[0051] Step 1) S100 is a step for preparing a first mixture of the biodegradable polymer and finasteride, using the aforementioned organic solvent as the solvent. This utilizes the solubility characteristics of finasteride and the biodegradable polymer to completely dissolve them in the organic solvent. After complete dissolution, the first mixture contains the biodegradable polymer and finasteride in a weight ratio of 4:1 to 15:1.

[0052] When the weight ratio of the biodegradable polymer to finasteride is lower than 4:1, that is, when the biodegradable polymer is contained at a weight ratio lower than the above ratio, the weight ratio of the biodegradable polymer is low compared to the weight of finasteride, and it becomes difficult to prepare microparticles in which finasteride is uniformly contained in spherical biodegradable polymer particles. When the weight ratio of the biodegradable polymer to finasteride exceeds 15:1, that is, when the biodegradable polymer is contained at a weight ratio higher than the above ratio, due to the small amount of finasteride in the microparticles, a large number of microparticles must be administered to administer the drug at the required concentration.

[0053] More specifically, the biodegradable polymer in the first mixture comprises 10 to 20% by weight, preferably 15% by weight, but not limited to this example.

[0054] Said 2) step S200 is a step of preparing a second mixture, wherein a surfactant is dissolved in water to prepare a second mixture. The surfactant is not limited as long as it can help the biodegradable polymer solution form a stable emulsion. Specifically, it is any one or more selected from the group consisting of nonionic surfactants, negative ionic surfactants, positive ionic surfactants and mixtures thereof, more specifically, it is any one or more selected from the group consisting of methylcellulose, polyvinyl pyrrolidone, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, sodium lauryl sulfate, sodium stearate, esteramines, linear diamines, cyclic amines and mixtures thereof, preferably polyvinyl alcohol, but not limited to the examples.

[0055] The above-mentioned step 3) S300 and step 4) S400 are steps of injecting the first mixture and the second mixture into the microchannel formed on the wafer and causing them to flow.

[0056] More specifically, aluminum is deposited on a silicon wafer using an electron beam evaporator, and then patterned with photoresist using photolithography. The aluminum is then etched using the photoresist as a mask. After removing the photoresist, the silicon is etched using deep reactive ion etching (DRIE) using the aluminum as a mask. After removing the aluminum, the wafer is positively bonded to glass and sealed to create the microchannel.

[0057] In addition, the average diameter of the microchannel is 40 to 100 μm, preferably 40 to 60 μm, and more preferably 50 μm, but is not limited to this example. When the average diameter of the microchannel is less than 40 μm, there is a possibility that the prepared microparticles will be prepared into small particles with a diameter of less than 20 μm. After injection into the human body, the possibility of being phagocytosed by macrophages increases, thereby affecting effective drug release and biological absorption. In addition, when the average diameter of the channel is greater than 100 μm, there is a possibility that the prepared microparticles will be prepared into particles with a size of 70 μm or greater. When administered as an injection, the foreign body sensation and pain increase, the particle size distribution of the prepared particles increases, and it is difficult to prepare microparticles with uniform particle size.

[0058] In addition, the cross-sectional width (w) and cross-sectional height (d) of the microchannel are closely related to the average diameter (d') of the prepared microparticles. Figure 8As shown, the width (w) of the microchannel section is in the ratio range of 0.7 to 1.3 relative to the average diameter (d') of the microparticles, and the height (d) of the microchannel section is in the ratio range of 0.7 to 1.3 relative to the average diameter (d') of the microparticles.

[0059] That is, once the average diameter (d') of the microparticles to be produced is determined, microparticles of the desired size can be produced only by setting the ratio of the width (w) and height (d) of the microchannel cross section to d' within a range of 0.7 to 1.3.

[0060] The 3) step S300 is a step of injecting the first mixture into the linear microchannel and causing it to flow, and the 4) step S400 is a step of injecting the second mixture into the microchannels formed on both sides or one side of the intersection with the linear microchannel and causing it to flow.

[0061] That is, the first mixture flows along the linear microchannel, and the second mixture flows along the microchannel that forms an intersection with the linear microchannel on both sides or one side based on the linear microchannel, and intersects with the first mixture flow.

[0062] When the first mixture is injected into the linear microchannel, it is injected at a predetermined pressure and flow rate. The pressure is, however, not limited to 600 to 1000 mbar, preferably 800 mbar. Furthermore, when the second mixture is injected into the microchannels on either or one side, it is injected at a predetermined pressure and flow rate. The pressure is, however, not limited to 1200 to 1600 mbar, preferably 1400 mbar.

[0063] That is, in order to make the second mixed flow forming an intersection with the first mixed flow flow at a faster flow rate than the first mixed flow injected into the microchannel in a linear direction, the second mixed flow is made to flow under a higher pressure condition.

[0064] As described above, the flow rates of the first mixture and the second mixture are made different, and the flow rate of the second mixture is made faster than the flow rate of the first mixture. At the point where the first mixture flow and the second mixture flow intersect, the second mixture with a relatively faster flow rate will compress the first mixture. At this time, due to the repulsive force between the first mixture and the second mixture, the biodegradable polymer and finasteride in the first mixture generate spherical particles. More specifically, particles in the form of finasteride uniformly distributed in the spherical biodegradable polymer are formed.

[0065] The step 5) S500 is a step of collecting particles, in which the particles are collected in a water tank filled with the second mixture to prevent aggregation of particles generated in the early stage.

[0066] The step 5) S500 utilizes the second mixture prepared in the step 2) S200, i.e., a mixed solution of a surfactant and water. After the second mixture is prepared in the step 2) S200, a portion is injected into the microchannel, and the other portion is moved to the water tank of the step 5) S500 to prevent aggregation between the collected particles.

[0067] Step 6) S600 is the step of stirring the collected particles in a water tank. The particles are stirred at a predetermined temperature and stirring speed to evaporate and remove the organic solvent present on the particle surface. The stirring conditions are as follows: a first stirring step at 800 to 1200 rpm for 1 to 2 hours at 14 to 16°C; a second stirring step at 800 to 1200 rpm for 0.5 to 1.5 hours at 19 to 21°C; and a third stirring step at 800 to 1200 rpm for 0.5 to 1.5 hours at 24 to 26°C. The stirring speed is 800 to 1200 rpm, preferably 1000 rpm, but is not limited to this example. The stirring speed for the particles remains the same during the first, second, and third stirring steps, but the stirring is performed gradually while the temperature is increased. This stepwise temperature increase regulates the evaporation rate of the organic solvent present on the particle surface. That is, the organic solvent present on the surface of the fine particles is gradually evaporated, thereby making it possible to prepare fine particles having a smooth surface.

[0068] More specifically, in step S600 6), the mixture is stirred at 14 to 16° C. for 1 to 2 hours, preferably at 15° C. for 1.5 hours. The mixture is then stirred at 19 to 21° C. for 0.5 to 1.5 hours, preferably at 20° C. for 1 hour. The mixture is then stirred at 24 to 26° C. for 0.5 to 1.5 hours, preferably at 25° C. for 1 hour.

[0069] The temperature of the first and second mixtures while passing through the microchannels is similarly 14 to 16°C, preferably 15°C. Specifically, after the microchannels flow and form intersections to generate microparticles, the temperature is maintained at a constant low temperature of 14 to 16°C until the collected microparticles are first stirred. Maintaining a low temperature during the microparticle production process allows for the production and maintenance of spherical particles. In other words, if the conditions are not kept low enough, it becomes difficult to produce particles with a consistently spherical shape.

[0070] Finally, step 7) S700 is a step of washing and drying the particles. The particles are washed multiple times with sterile filtered pure water by stirring to completely remove the organic solvent on the surface of the particles, thereby removing the surfactant remaining in the particles, and then freeze-dried.

[0071] The resulting microparticles consist of finasteride uniformly distributed within spherical biodegradable polymer particles. The average particle size of the microparticles ranges from 20 to 70 μm, and the biodegradable polymer and finasteride are contained in a weight ratio of 3:1 to 9:1. When the average particle diameter is less than 20 μm, the microparticles are more likely to be phagocytosed by macrophages after injection into the human body, thereby affecting drug release and in vivo absorption. When the average particle diameter exceeds 70 μm, patients receiving the drug contained in the injection must use a wide-caliber syringe needle, which can increase pain during administration.

[0072] The weight ratio of the biodegradable polymer and finasteride contained in the microparticles is the same as the weight ratio in the first mixture. As the microparticles are prepared and the organic solvent is completely evaporated and removed, microparticles containing the biodegradable polymer and finasteride can be prepared at the same weight ratio as in the first mixture.

[0073] Example 1

[0074] Preparation of microparticles containing finasteride

[0075] Poly(lactide-glycolide) (PLGA) and finasteride were dissolved in dichloromethane to prepare a first mixture. The first mixture contained 15% by weight of PLGA, and the weight ratio of PLGA to finasteride was 4:1.

[0076] Polyvinyl alcohol as a surfactant was mixed into water to prepare a second mixture containing 0.25 wt% of polyvinyl alcohol.

[0077] The first and second mixtures were injected into microchannels formed on a silicon wafer and allowed to flow. To maintain a constant flow rate, the first mixture was flowed at a pressure of 800 mbar, while the second mixture was flowed at a pressure of 1400 mbar. The temperature was maintained at 15°C.

[0078] Particles generated at the intersection of the first and second mixed streams were collected in a water tank containing the second mixed stream. The collected particles were stirred at 15°C at 1000 rpm for 1.5 hours. The temperature was then raised to 20°C and stirred at 1000 rpm for 1 hour. The temperature was then raised to 25°C and stirred at 1000 rpm for a third time for 1 hour.

[0079] The stirred microparticles were washed several times with sterile-filtered purified water and freeze-dried to prepare microparticles.

[0080] Example 2

[0081] The same method as in Example 1 was used to prepare the product except that the weight ratio of polylactide-glycolide to finasteride was 9:1.

[0082] Example 3

[0083] The same method as in Example 1 was used to prepare the product except that the weight ratio of polylactide-glycolide to finasteride was 2:1.

[0084] Example 4

[0085] The same method as in Example 1 was used to prepare the product except that the weight ratio of polylactide-glycolide to finasteride was 12:1.

[0086] Example 5

[0087] The same method as in Example 1 was used to prepare the product except that the weight ratio of polylactide-glycolide to finasteride was 15:1.

[0088] Example 6

[0089] The same method as in Example 1 was used to prepare the product except that the weight ratio of polylactide-glycolide to finasteride was 20:1.

[0090] Example 7 to Example 11

[0091] Although the preparation was carried out in the same manner as in Example 1, after collecting the fine particles in the water tank containing the second mixture, the stirring process was carried out under the stirring conditions shown in Table 1 below.

[0092]

Table 1

[0093]

[0094] [Experimental Example 1: Drug Release Experiment of Finasteride-Containing Microparticles]

[0095] 1. In-vivo PK

[0096] Approximately 100 mg of the microparticles from Examples 1 to 6 were placed in a 120 mL glass test container, followed by 100 mL of the release test solution. As accelerated drug release testing conditions, the microparticles were placed in a 45°C water bath, shaken at an amplitude of 4 cm and a frequency of 120 repetitions per minute. For sampling, the bottle was shaken thoroughly and 1 mL of the solution was sampled. After centrifugation at 13,000 rpm for 3 minutes, the supernatant was collected and analyzed by high-performance liquid chromatography.

[0097] The results of drug release experiments are shown in Table 2 and Figure 3 .

[0098]

Table 2

[0099]

[0100]

[0101] (Unit: ng / ml) Figure 3 As shown in Table 2, in Example 3, the initial drug release was excessive, and release was essentially complete after 14 days, making it difficult to demonstrate a long-term drug release effect. Furthermore, in Example 6, the initial drug release was extremely low, resulting in a weak therapeutic effect of finasteride.

[0102] In contrast, in Example 1, sustained release of the finasteride drug was confirmed for 1 month, and in Examples 2, 4, and 5, sustained release of the finasteride drug was confirmed for up to 3 months.

[0103] [Experimental Example 2: Study on the Properties of Microparticles]

[0104] In order to investigate the properties of the fine particles depending on the stirring conditions, the properties of the fine particles prepared under the conditions of Example 1 and Examples 5 to 10 were investigated using SEM images.

[0105] The results are shown in Table 3 below.

[0106]

Table 3

[0107] Experiments based on stirring conditions Preparation results of microparticles Example 7 △ Example 8 △ Example 9 △ Example 10 ○ Example 11 ○ Example 1 ○

[0108] △ refers to, such as Figure 4 and Figure 5 As shown in the SEM photos, due to the influence of residual solvent, the particles aggregated and the properties of the particles were uneven. On the contrary, in Example 1, Example 10 and Example 11, as shown in Figure 6 and Figure 7 As shown in the SEM photograph, it was confirmed that the microparticles were uniform in shape and no aggregation occurred.

[0109] That is, it was confirmed that the properties of the fine particles and the occurrence of aggregation phenomena are affected by temperature conditions during stirring.

[0110] Industrial application possibilities

[0111] The present invention relates to microparticles containing finasteride and a method for preparing the same.

[0112] The present invention aims to provide sustained-release microparticles and a method for preparing the same. Unlike existing oral dosage forms that have a short half-life and require daily administration, sustained-release microparticles containing finasteride can maintain a hair loss treatment effect for one to three months.

[0113] Another object of the present invention is to administer finasteride-containing microparticles to patients by injection, which, unlike oral dosage forms, does not require the patient to store and handle the microparticles themselves, thereby facilitating storage and handling.

[0114] Another object of the present invention is to provide sustained-release particles containing finasteride that can maintain a long-term drug administration effect of one to three months. At the same time, by preparing the average particle size to a certain micron size, the release of the drug from the particles is controlled, and a certain effective drug concentration can be maintained. When applied to an injection composed of particles of uniform size, the foreign body sensation and pain when the injection is administered to the patient are reduced.

Claims

1. A microparticle comprising finasteride, wherein: Contains microparticles of finasteride and biodegradable polymers. The microparticles are in the shape of finasteride drugs uniformly distributed in spherical biodegradable polymer microparticles. The average particle size of the microparticles is 20 to 70 μm.

2. The finasteride-containing microparticles according to claim 1, wherein The microparticles contain a biodegradable polymer and finasteride in a weight ratio of 4:1 to 15:

1.

3. The finasteride-containing microparticles according to claim 1, wherein The microparticles continuously release finasteride for 1 to 3 months.

4. The finasteride-containing microparticles according to claim 1, wherein The biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic acid-glycolic acid copolymer, polylactide-glycolide, polyphosphazene, polyiminocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid and combinations thereof.

5. The finasteride-containing microparticles according to claim 4, wherein The biodegradable polymer is polylactide-glycolide.

6. The finasteride-containing microparticles according to claim 1, wherein The microparticles are prepared using microchannels, The width of the channel cross section relative to the average diameter of the microparticles is in the ratio range of 0.7 to 1.

3.

7. The finasteride-containing microparticles according to claim 1, wherein The microparticles are prepared using microchannels, The height of the channel cross section relative to the average diameter of the microparticles is in the ratio range of 0.7 to 1.

3.

8. A composition for treating, preventing hair loss and promoting hair growth comprising the microparticles according to claim 1.

9. A method for preparing microparticles containing finasteride, wherein: include: 1) dissolving the biodegradable polymer and finasteride in an organic solvent to prepare a first mixture, 2) a step of dissolving a surfactant in water to prepare a second mixture, 3) injecting the first mixture of step 1) into a linear microchannel to allow it to flow, 4) injecting the second mixture of step 2) into the microchannels formed on both sides or one side and allowing it to flow so as to form an intersection with the microchannel of step 3) in which the first mixture flows in a straight line. The linear flow of the first mixture and the second mixture flow intersect to prepare microparticles in the form of finasteride uniformly distributed in spherical biodegradable polymer particles, 5) a step of collecting the microparticles generated at the intersection of step 4), 6) stirring the microparticles collected in step 5) to evaporate and remove the organic solvent present in the microparticles, and 7) washing and drying the microparticles obtained in step 6); The average particle size of the microparticles is 20 to 70 μm.

10. The method for preparing microparticles containing finasteride according to claim 9, wherein: The first mixture in step 1) comprises 10 to 20 weight % of the biodegradable polymer.

11. The method for preparing microparticles containing finasteride according to claim 9, wherein: The first mixture in step 1) comprises a biodegradable polymer and finasteride in a weight ratio of 4:1 to 15:

1.

12. The method for preparing microparticles containing finasteride according to claim 9, wherein: The biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic acid-glycolic acid copolymer, polylactide-glycolide, polyphosphazene, polyiminocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid and combinations thereof.

13. The method for preparing microparticles containing finasteride according to claim 9, wherein: The organic solvent in step 1) is dichloromethane.

14. The method for preparing microparticles containing finasteride according to claim 9, wherein: The second mixture in step 2) comprises a surfactant in an amount of 0.2 to 0.3 wt%.

15. The method for preparing microparticles containing finasteride according to claim 9, wherein: In the step 3), the first mixture is injected into the linear microchannel at a pressure of 600 to 1000 mbar.

16. The method for preparing microparticles containing finasteride according to claim 9, wherein: In the step 4), the second mixture is injected into the microchannels formed on both sides or one side to form an intersection with the microchannel in the linear direction where the first mixture flows. The second mixture is injected at a pressure of 1200 to 1600 mbar.

17. The method for preparing microparticles containing finasteride according to claim 9, wherein: In the step 5), the particles are collected in a water tank containing the second mixture.

18. The method for preparing microparticles containing finasteride according to claim 9, wherein: The step 6) comprises: 6-1) a step of first stirring at 800 to 1200 rpm for 1 to 2 hours at 14 to 16° C.; 6-2) After the first stirring step, stirring the mixture for a second time at 19 to 21° C. and 800 to 1200 rpm for 0.5 to 1.5 hours; and 6-3) After the second stirring step, stirring for a third time at 24 to 26° C. at a speed of 800 to 1200 rpm for 0.5 to 1.5 hours.

19. The method for preparing microparticles containing finasteride according to claim 9, wherein: The microchannels in steps 3) and 4) are formed on the surface of the wafer. The average diameter of the microchannels is 40 to 100 μm.

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