Sustained-release injectable compositions comprising dutasteride

Abstract

The present invention relates to a sustained-release injectable composition containing dutasteride, which can produce a sustained dutasteride release effect for more than 3 months even when the dosage of dutasteride administered is the same or lower than that of conventional once-daily Avodart®, thereby enabling a sustained drug administration effect for a long period of time with a single injection. In addition, it can continuously provide therapeutic effects for benign prostatic hyperplasia, prostate cancer, and hair loss for more than 3 months, and the microparticles included in the sustained-release injectable composition have a constant average diameter, so the release of the drug can be controlled to maintain a constant effective drug concentration, and the foreign body sensation and pain when administered to a patient as an injection can be reduced.

Description

Technology Field

[0001] The present invention relates to a sustained-release injectable composition comprising dutasteride. Background Technology

[0002] Dutasteride (compound: 17β-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-4-aza-5α-androst-1-en-3-one), represented by the chemical formula 1 below, is a dual 5-alpha reductase inhibitor that inhibits both type 1 and type 2 5-alpha reductases and is known to be useful in the treatment of benign prostatic hyperplasia, prostate cancer, and androgenetic alopecia by inhibiting the conversion of testosterone to dihydrotestosterone (DHT):

[0003] [Chemical Formula 1]

[0004]

[0005] Dutasteride is currently marketed under the brand name Avodart®, which is a product containing 0.5 mg of dutasteride dissolved in a mixture of 349.5 mg of mono- and di-glyceride oils of capryl / capric acid and butylated hydroxytoluene (BHT) and filled into a soft capsule.

[0006] However, there is a disadvantage in that the amount of excipients constituting the product is relatively large compared to the active ingredient, which increases the volume of the soft capsule and makes it inconvenient to take.

[0007] Conventionally, for oral formulations containing dutasteride, research has been conducted on methods to reduce volume to improve ease of administration and enhance dissolution stability.

[0008] In other words, as in the past, there have been attempts to improve ease of administration by reducing the volume, but there is a problem of low convenience due to the fact that it must be taken every day.

[0009] Accordingly, there is an urgent need to develop a treatment for benign prostatic hyperplasia, prostate cancer, and alopecia that improves upon the problems of conventional formulations containing dutasteride, maintains efficacy for more than 3 months with a single administration, and is easy to store and handle. Prior art literature

[0010] (Patent Document 0001) KR 10-1833280 B1 The problem to be solved

[0011] The object of the present invention is to provide a sustained-release injectable composition comprising dutasteride.

[0012] Another objective of the present invention is to provide a sustained-release injectable composition containing dutasteride that can produce a sustained dutasteride release effect for more than 3 months even when the dosage of dutasteride administered is the same or lower than that of conventional once-daily Avodart®, thereby producing a sustained drug administration effect for a long period of time with a single injection.

[0013] Another objective of the present invention is to provide an injectable composition containing sustained-release particles that can continuously exhibit therapeutic effects for benign prostatic hyperplasia, prostate cancer, and hair loss for more than 3 months, and the microparticles included in the sustained-release injectable composition have a constant average diameter, thereby controlling the release of the drug to maintain a constant effective drug concentration and reducing foreign body sensation and pain when administered to a patient as an injection. means of solving the problem

[0014] To achieve the above objective, the present invention is a sustained-release injectable composition comprising dutasteride, comprising 8 mg to 100 mg of dutasteride, wherein the dutasteride is evenly distributed within microparticles, and the microparticles continuously release dutasteride for 3 to 6 months after injection into the body, and the average diameter of the microparticles is 30 μm to 90 μm.

[0015] The above injectable composition, after at least one week has elapsed since injection into a Beagle dog, shows the maximum blood concentration of dutasteride (C max It can represent ).

[0016] The maximum blood concentration value of the above dutasteride (C max ) is 200 ng / mL to 1,100 ng / mL.

[0017] The above microparticles may include two or more biodegradable polymers selected from the group consisting of polylactic acid, polylactide, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalrate, polyhydroxybutyrate, and polyamino acid.

[0018] The above biodegradable polymer may contain polylactic acid and polylactide-co-glycolide (PLGA) in a weight ratio of 1:1 to 1:4.

[0019] The above microparticles may contain dutasteride and a biodegradable polymer in a weight ratio of 1:2 to 1:5.

[0020] As a result of conducting an accelerated emission experiment under the following conditions, the above microparticles can release less than 50 weight% of dutasteride after 24 hours:

[0021] [Experimental Conditions]

[0022] Water containing 1% sodium lauryl sulfate was used as the elution test solution, microparticles were mixed into the elution test solution, a shaking water bath was used as the elution test device, a glass test container with a capacity of 120 ml was used as the elution test container, and it was shaken at 45°C at a speed of 120 rpm.

[0023] The above microparticles may additionally include a coating layer on the outside.

[0024] The standard deviation (SD) for the diameter of the above microparticles is 2 to 7.

[0025] The width of the phase peak in the PSA analysis of the above microparticles is 5 to 15. Effects of the invention

[0026] The present invention can produce a continuous dutasteride release effect for more than 3 months even when the dosage of dutasteride administered is the same or lower than that of conventional once-daily Avodart®, thereby enabling a continuous drug administration effect for a long period of time with a single injection.

[0027] In addition, the sustained-release injectable of the present invention can continuously provide therapeutic effects for benign prostatic hyperplasia, prostate cancer, and hair loss for more than 3 months, and the microparticles included in the sustained-release injectable composition have a constant average diameter, so the release of the drug can be controlled to maintain a constant effective drug concentration, and the foreign body sensation and pain when administered to a patient as an injection can be reduced. Brief explanation of the drawing

[0028] Figure 1 is the result of an accelerated emission experiment of microparticles according to one embodiment of the present invention. Figure 2 is the result of PK analysis for a sustained-release injectable composition according to one embodiment of the present invention. Figure 3 is the result of PK analysis for a sustained-release injectable composition according to one embodiment of the present invention. Figure 4 is the result of PK analysis for a sustained-release injectable composition according to one embodiment of the present invention. Figure 5 is an SEM image of a microparticle according to one embodiment of the present invention. Figure 6 is an SEM image of a microparticle according to one embodiment of the present invention. FIG. 7 is an SEM image of microparticles that have exhibited clumping according to one embodiment of the present invention. Specific details for implementing the invention

[0029] Hereinafter, embodiments of the present invention are described in detail so that those skilled in the art can easily implement the invention. However, the present invention may be embodied in various different forms and is not limited to the embodiments described herein.

[0030] The present invention relates to a sustained-release injectable composition comprising dutasteride, characterized by being able to produce a sustained drug release effect for more than 3 months with a single injection.

[0031] As described above, since a single injection provides a continuous drug release effect for more than 3 months, it can provide therapeutic effects for benign prostatic hyperplasia, prostate cancer, and hair loss, thereby replacing conventional products that are taken once a day and significantly improving convenience of administration.

[0032] To achieve the above characteristics, specifically, the sustained-release injectable composition containing dutasteride according to the present invention comprises 8 mg to 100 mg of dutasteride, wherein the dutasteride is evenly distributed within microparticles, and the microparticles continuously release dutasteride for 3 to 6 months after injection into the body, and the average diameter of the microparticles may be 30 to 90 μm.

[0033] The sustained-release injectable composition of the present invention comprises dutasteride, characterized in that the dutasteride contained in a single dose is 8 mg to 100 mg.

[0034] In the case of Avodart®, which is taken once a day, a single-dose formulation contains 0.5 mg of dutasteride. Based on 84 days of use (3 months), a total of 42 mg is administered.

[0035] The present invention is characterized by enabling the drug to be released continuously over a long period, even when containing dutasteride at an equivalent level to or at a lower dose than that of the above-mentioned Avodart®.

[0036] Accordingly, the sustained-release injectable composition of the present invention is characterized by continuously releasing dutasteride for 3 to 6 months after being injected into the body. For example, in the case of a 3-month formulation, the total sustained-release injectable composition may contain 8 mg to 42 mg of dutasteride, 15 mg to 42 mg, or 25 mg to 42 mg. Even when dutasteride is included within the above ranges, the effect of continuously releasing dutasteride for 3 months can be exhibited.

[0037] In addition, for a 6-month formulation, it may be included in an amount of 16 mg to 84 mg, 30 mg to 84 mg, or 50 mg to 84 mg. Even when dutasteride is included within the above ranges, the release effect of dutasteride can be continuously exhibited for 3 months.

[0038] The above sustained-release injectable composition comprises microparticles containing dutasteride, wherein the microparticles are uniformly spherical particles and contain dutasteride uniformly.

[0039] As described below, the microparticles of the present invention are spherical particles having a uniform diameter, and a plurality of such particles are included in a sustained-release injectable composition. By including particles having a uniform diameter as described above, a sustained release effect of dutasteride can be exhibited after injection into the body, and the timing of the release of dutasteride can be controlled.

[0040] In other words, if the particle size is not uniform, there may be differences in the rate at which the particles decompose in the body, and this may result in a problem where the release rate of dutasteride contained in the particles cannot be controlled. Accordingly, the present invention is characterized by including only particles having a uniform diameter, thereby allowing the release rate of dutasteride to be controlled and enabling the continuous release effect of dutasteride to be exhibited for 3 to 6 months.

[0041] The average diameter of the microparticles may be 30㎛ to 90㎛, 35㎛ to 85㎛, or 40㎛ to 80㎛. By including uniform particles within the above range, it is possible to prevent the over-release of initial dutasteride injected into the body, and after a certain period of time, the release of dutasteride may result in a maximum blood concentration, thereby providing a continuous dutasteride release effect for 3 to 6 months.

[0042] Specifically, the above-mentioned injectable composition, after at least one week has elapsed since injection into a Beagle dog, the maximum blood concentration of dutasteride (C max It represents ), specifically the maximum blood concentration (C) within 2 to 5 weeks. max It can represent ).

[0043] As described above, the sustained-release injectable composition of the present invention is characterized by the fact that, after being injected into a beagle dog, dutasteride is continuously released, exhibits a maximum blood concentration (Cmax) of dutasteride after one week or more has elapsed, and subsequently, the blood concentration of dutasteride decreases steadily and is released for a desired period.

[0044] That is, in order to provide a sustained-release injectable composition as in the present invention and to produce a continuous release effect of dutasteride for 3 to 6 months, after injecting the injectable composition into a Beagle dog, the blood concentration of dutasteride reaches a maximum blood concentration (C) within 2 to 5 weeks after 1 week. max It can be characterized by representing the value.

[0045] According to the results of the release of dutasteride as described above, after injecting the injectable composition of the present invention into a beagle dog, the degree of release of dutasteride is low within 1 day, that is, within 24 hours, but thereafter the amount of release of dutasteride continuously increases, reaches a maximum value after 1 week, within 2 to 5 weeks, and thereafter the amount of release continuously decreases, and the release of dutasteride is completed at about 3 months, 4 months, 5 months, or 6 months.

[0046] More specifically, after injecting the sustained-release injectable composition of the present invention into a Beagle dog, the blood concentration of dutasteride was measured, and as a result, at the time 24 hours elapsed, the maximum blood concentration of dutasteride (C 24h ) may be 4 ng / mL to 40 ng / mL, 5 ng / mL to 38 ng / mL, 6 ng / mL to 35 ng / mL, and 8 ng / mL to 32 ng / mL.

[0047] In addition, after more than one week has elapsed, the maximum blood concentration of dutasteride (C max) is 200 ng / mL to 2,500 ng / mL, 400 ng / mL to 2,500 ng / mL, and may be 500 ng / mL to 2,500 ng / mL. The maximum blood concentration of the above dutasteride (C max ) may vary depending on whether the sustained-release injectable composition of the present invention is a 3-month, 4-month, 5-month, or 6-month formulation, and specifically, in the case of the 3-month formulation, the maximum blood concentration of dutasteride (C max ) may be 500 ng / mL to 1,100 ng / mL. That is, in order to provide a formulation that continuously releases dutasteride for a longer period of time, the content of dutasteride included in the injectable composition is increased, and as a result, when the injectable composition is administered to a Beagle dog, the maximum blood concentration of dutasteride (C max ) can also change.

[0048] According to the results of analyzing the blood concentration of dutasteride after injecting the sustained-release injectable composition of the present invention into the Beagle dog, the release amount of dutasteride is low within 24 hours, and the maximum blood concentration (C) is observed after more than one week has elapsed. max It can be clearly confirmed that it indicates ). When the blood dutasteride concentration value as described above is shown, a continuous release effect of dutasteride can be shown for 3 months or more, or for 3 to 6 months.

[0049] The above microparticles comprise two or more biodegradable polymers selected from the group consisting of polylactic acid, polylactide, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalrate, polyhydroxybutyrate, and polyamino acid, and specifically may include polylactic acid and polylactide-co-glycolide as biodegradable polymers.

[0050] When microparticles are manufactured by including two or more types of biodegradable polymers as described above, by using biodegradable polymers with different biodegradation periods, it is possible to achieve the effect of degrading over a desired period and releasing dutasteride.

[0051] In other words, when using only one type of biodegradable polymer, or when using only a biodegradable polymer with a short biodegradation period, the dutasteride release effect can be exhibited only for a short period.

[0052] In addition, while using biodegradable polymers with a long biodegradation period allows for a longer release of dutasteride, there is a problem in that the initial release of dutasteride after administration as an injection is too insignificant, making it difficult for the pharmacological effect of dutasteride to take effect. In other words, in order to produce the pharmacological effect of dutasteride in the body, the blood concentration of dutasteride must be above a certain level, but when using biodegradable polymers with a long biodegradation period, there is a problem in that the degree of degradation is insignificant in the initial period after being introduced into the body as an injection, making it difficult for the pharmacological effect of dutasteride to take effect.

[0053] The above-mentioned biodegradable polymer contains polylactic acid and polylactide-co-glycolide (PLGA) in a weight ratio of 1:1 to 1:4, and may contain them in a weight ratio of 1:2 to 1:3. When mixed and used in such weight ratios, the release effect of dutasteride can be exhibited for a desired period as described above.

[0054] The above microparticles may contain dutasteride and a biodegradable polymer in a weight ratio of 1:2 to 1:5, in a weight ratio of 1:2 to 1:4, or in a weight ratio of 1:2 to 1:3. When mixed and used within the above ranges, dutasteride may be continuously released for a long time due to the degradation of the biodegradable polymer.

[0055] As a result of conducting an accelerated emission experiment under the following conditions, the above microparticles can release less than 50 weight% of dutasteride after 20 hours:

[0056] [Experimental Conditions]

[0057] Water containing 1% sodium lauryl sulfate was used as the elution test solution, microparticles were mixed into the elution test solution, a shaking water bath was used as the elution test device, a glass test container with a capacity of 120 ml was used as the elution test container, and it was shaken at 45°C at a speed of 120 rpm.

[0058] The aforementioned accelerated release experiment is designed to verify the sustained release of a drug after manufacturing drug-containing particles using a biodegradable polymer. In other words, it is an experiment to indirectly confirm whether the drug can be continuously released over an extended period.

[0059] The present invention is characterized by releasing less than 50% by weight of dutasteride at the time when 20 hours have elapsed, as a result of conducting an accelerated release experiment under the above conditions.

[0060] As described above, the microparticles of the present invention maintain the degree of dutasteride release at less than 50 weight% at the point where 20 hours have elapsed as a result of the accelerated release experiment, and can continuously exhibit the effect of releasing dutasteride for 3 to 6 months.

[0061] The ability to control the release level of dutasteride as described above may be due to the inclusion of two or more types of biodegradable polymers to manufacture microparticles. As described below, when only one type of biodegradable polymer is used, it can be confirmed that a dutasteride release effect of 70 weight% or more is exhibited after 20 hours. That is, when microparticles containing dutasteride are manufactured using only one type of biodegradable polymer, a problem may arise in that a continuous dutasteride release effect for 3 to 6 months cannot be exhibited as in the present invention.

[0062] In contrast, the microparticles of the present invention can exhibit a continuous dutasteride release effect for a long time, in that the point at which 80 weight percent of dutasteride is released is after 50 hours or 70 hours or more have elapsed.

[0063] The above microparticles may additionally include a coating layer on the outside. The coating layer may be formed using mannitol. When a coating layer is formed on the surface of the microparticles using mannitol as described above, flowability is improved during filling for use as an injectable, allowing only the desired amount of microparticles to be efficiently filled. Furthermore, microparticles with a coating layer formed using mannitol as described above do not exhibit clumping between particles during freeze-drying.

[0064] In contrast, microparticles that do not form a coating layer may clump together as shown in Fig. 7 when freeze-dried. Additionally, flowability is poor during filling, and differences in the inclusion of microparticles may occur.

[0065] As previously described, the microparticles of the present invention may have an average diameter of 30 µm to 90 µm, 35 µm to 85 µm, or 40 µm to 80 µm. Additionally, the standard deviation (SD) of the average diameter of the microparticles may be 2 to 7. The standard deviation (SD) refers to the degree of distribution of the average diameter, and a very small standard deviation (SD) implies that the particles have a uniform size.

[0066] In addition, the width of the peaks in the PSA analysis results may be 5 to 15. The above peak width refers to the width of each peak (width from 16 to 84%), and as described below, the microparticles produced by the manufacturing method of the present invention do not show multiple peaks in the PSA analysis. This implies that the produced microparticles themselves are very uniform.

[0067] By including uniform particles within the above range, it is possible to prevent the initial over-release of dutasteride injected into the body, and by releasing dutasteride after a certain period of time, it can exhibit a maximum blood concentration and a continuous dutasteride release effect for 3 to 6 months.

[0068] A method for preparing a sustained-release injectable composition containing dutasteride according to another embodiment of the present invention may comprise: 1) a step of preparing an oil phase solution by mixing dutasteride and a biodegradable polymer; 2) a step of preparing an aqueous solution by dissolving a surfactant in a solvent; 3) a step of injecting the oil phase solution and the aqueous solution into a first microchannel and a second microchannel, respectively, formed at an intersection point to allow them to flow and generate microparticles at the intersection point; 4) a step of collecting the microparticles in a tank containing the aqueous solution; 5) a step of removing an organic solvent present in the collected microparticles; 6) a step of washing and drying the microparticles from which the organic solvent has been removed with purified water; and 7) a step of mixing the dried microparticles with a suspension solution.

[0069] Step 1) above is a step of preparing an oil phase solution, wherein the oil phase solution is prepared by dissolving dutasteride and a biodegradable polymer in an organic solvent, and the biodegradable polymer may be two or more selected from the group consisting of polylactic acid, polylactide, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalrate, polyhydroxybutyrate, and polyamino acid, and preferably polylactide-co-glycolide (PLGA) and polylactide (PLA), but is not limited to the above examples.

[0070] In addition, the above organic solvent is immiscible with water and is, for example, one or more selected from the group consisting of chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof, preferably dichloromethane, but is not limited to such examples. Any organic solvent capable of dissolving the biodegradable polymer and dutasteride, and not limited to such examples, that is readily selectable by a person skilled in the art, may be used.

[0071] Step 1) above involves preparing an oil phase solution in which dutasteride and a biodegradable polymer are dissolved, and as described above, an organic solvent is used as the solvent. This utilizes the dissolution properties of dutasteride and the biodegradable polymer to completely dissolve them using an organic solvent.

[0072] The above oil phase solution may have a weight ratio of dutasteride to a biodegradable polymer of 1:2 to 1:5, 1:2 to 1:4, or 1:2 to 1:3. When mixed and used within the above ranges, dutasteride may be continuously released for a long time due to the degradation of the biodegradable polymer.

[0073] When the weight ratio of the above-mentioned dutasteride and biodegradable polymer is less than 1:1, that is, when the biodegradable polymer is included in an amount less than the above-mentioned weight ratio, the weight ratio of the biodegradable polymer is low compared to the weight of dutasteride, so a problem arises in that it is difficult to manufacture sustained-release particles in which dutasteride is evenly distributed and included in spherical biodegradable polymer particles. When the weight ratio of the biodegradable polymer and dutasteride exceeds 1:5, that is, when the biodegradable polymer is included in an amount greater than the above-mentioned weight ratio, the dutasteride content in the sustained-release particles is low, so a problem may arise in that a large amount of sustained-release particles must be administered to administer the drug at the desired concentration.

[0074] More specifically, the biodegradable polymer in the above oil solution comprises 15 to 25 weight%, preferably 20 weight%, but is not limited to the above examples.

[0075] Step 2) above is a step of preparing an aqueous solution, wherein a surfactant is dissolved in water to prepare the aqueous solution. The surfactant may be used without limitation as long as it helps to form a stable emulsion in an oil phase solution in which the biodegradable polymer and dutasteride are dissolved. Specifically, it is one or more selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof, and more specifically, it is one or more selected from the group consisting of methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sodium lauryl sulfate, sodium stearate, esteramine, linear diamine, patiamine, and mixtures thereof, preferably polyvinyl alcohol, but is not limited to examples.

[0076] The surfactant included in the above aqueous solution may be included in an amount of 0.1 to 1.0 weight%, 0.1 to 0.5 weight%, or 0.25 weight%. The remainder is all water.

[0077] Step 3) above is a step of injecting an oil phase solution and an aqueous phase solution into a microchannel formed on a wafer and allowing them to flow.

[0078] More specifically, microchannels may be formed in a material selected from the group consisting of silicon wafers or polymer films, but the examples of said materials are not limited to those examples, and any material capable of forming microchannels may be used.

[0079] The polymer film may be selected from the group consisting of polyimide, polyethylene, fluorinated ethylene propylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polysulfone, and mixtures thereof, but is not limited to the above examples.

[0080] As an example, aluminum is deposited on a silicon wafer using an e-beam evaporator, and a photoresist is patterned on the aluminum using a photolithography technique. Subsequently, the aluminum is etched using the photoresist as a mask, and after removing the photoresist, the silicon is etched using DRIE (deep ion reactive etching) with the aluminum as a mask, and after removing the aluminum, glass is anode-bonded onto the wafer to seal it, thereby manufacturing the above-mentioned microchannel.

[0081] The average diameter of the above microchannel varies depending on whether it is a 7-channel chip or a 140-channel chip. A 140-channel chip was used for the microchannels to manufacture the microparticles of the present invention. In the case of the 140-channel chip, the average diameter of the channels when the oil phase solution and the aqueous solution are injected into the microchannels is 300 μm to 500 μm, and the oil phase solution and the aqueous solution pass through the resistance channel after moving through each channel. The average diameter of the resistance channel is 10 μm to 50 μm. After passing through the resistance channel, the oil phase solution and the aqueous solution pass through a junction channel where they intersect, and the diameter of the junction channel may be 50 μm to 150 μm. After the oil phase solution and the aqueous solution intersect within the junction channel to form an emulsion, they immediately pass through a microchannel with a diameter of 70 μm to 90 μm, and then pass through a microchannel with a diameter of 200 μm to 300 μm. If the average diameter of the aforementioned conjugation channel is 50㎛ or less, there is a possibility that small sustained-release particles with a diameter of less than 30㎛ may be produced, which may affect the release and in vivo absorption of the effective drug. Additionally, if the average size of the produced sustained-release particles exceeds 100㎛, foreign body sensation and pain may increase when administered as an injection, and it is difficult to produce sustained-release particles with uniform particle size distribution due to the large particle size distribution.

[0082] However, the average diameter of the microchannel may change depending on the range of injection pressure. In addition, the average diameter of the microchannel is closely related to the average diameter of the particles, but is also closely related to the injection pressure of the oil phase solution and the aqueous solution.

[0083] Step 3) above involves allowing the oil phase solution and the aqueous phase solution to flow into the first microchannel and the second microchannel formed at the intersection under the injection pressure conditions.

[0084] That is, the oil phase solution flows along the first microchannel, and the aqueous solution flows along the second microchannel, which is shaped to form an intersection with the first microchannel, and meets the flow of the oil phase solution.

[0085] More specifically, when the above-mentioned oil solution is injected into the first microchannel, the pressure can be increased to a first condition of 1 to 5 mbar / min after injection at a pressure condition of 200 to 800 mbar, and when the injection pressure condition reaches 500 to 1,000 mbar, the pressure can be increased to a second condition of 1 to 5 mbar / min.

[0086] In addition, the aqueous solution can be injected into the second microchannel at a pressure condition 4 to 12 times that of the pressure condition when the oil solution is injected into the first microchannel.

[0087] Specifically, in the manufacturing method using the microchannel described above, when the flow rate of the oil phase solution and the aqueous solution flowing inside the microchannel is set to a constant value using a flow meter and the pressure is measured through feedback control, it was confirmed that the pressure required to make the oil phase solution flow through the microchannel at a constant flow rate gradually increases over time.

[0088] Therefore, by using a method of steadily increasing the pressure applied to the above oil phase solution, the variability of the flow rate is minimized, and as the above oil phase solution gradually hardens inside the microchannel, problems such as non-uniformity of microparticle distribution or channel blockage are prevented, and the manufacturing yield of the target microparticles can be increased.

[0089] In addition, the pressure conditions when injecting the above oil phase solution and water phase solution into the microchannel are intended to control the average diameter of the manufactured microparticles. If the above range is not specifically satisfied, problems may arise such as the size of the manufactured particles being non-uniform, failing to satisfy the average diameter range of the microparticles of the present invention, or failing to satisfy the value of Equation 1.

[0090] That is, in order to make the flow of the aqueous solution that forms an intersection with the flow of the oil phase solution flow at a faster rate than the flow of the oil phase solution injected into the microchannel, the aqueous solution is flowed under higher pressure conditions.

[0091] As described above, by making the flow rates of the oil phase solution and the aqueous solution different and making the flow rate of the aqueous solution faster than that of the oil phase solution, the aqueous solution having a relatively faster flow rate compresses the oil phase solution at the point where the flow of the oil phase solution and the flow of the aqueous solution meet. At this time, due to the repulsive force between the oil phase solution and the aqueous solution, the biodegradable polymer and dutasteride in the oil phase solution form spherical microparticles, and more specifically, microparticles in which dutasteride is evenly distributed on the spherical biodegradable polymer are formed.

[0092] The above step 4) is a step for collecting microparticles, in which microparticles are collected in a tank containing an aqueous solution to prevent aggregation among the initially generated microparticles.

[0093] Step 4) above uses the aqueous solution prepared in Step 2), that is, a mixed solution of surfactant and water. After preparing the aqueous solution in Step 2), some of it is injected into the microchannel, and other parts are transferred to the water bath in Step 4) to prevent clumping among the collected microparticles.

[0094] Step 5) above is a step for removing organic solvent present on microparticles collected in a water bath, by stirring at a constant temperature condition and stirring speed to evaporate and remove organic solvent present on the surface of sustained-release particles. At this time, the stirring conditions are: 5-1) a first stirring step at a speed of 100 to 300 rpm for 20 to 40 minutes at 15 to 20°C; 5-2) a second stirring step at a speed of 100 to 300 rpm for 60 to 120 minutes at 30 to 40°C; and 5-3) a third stirring step at a speed of 100 to 300 rpm for 4 to 8 hours at 40 to 45°C.

[0095] The above stirring speed is carried out by performing the stirring process with different temperature conditions and stirring durations in the first and second stirring stages.

[0096] As described above, the method is characterized by increasing the temperature conditions in the second stirring process compared to the first stirring process and stirring, and by gradually increasing the temperature, the evaporation rate of the organic solvent present on the surface of the microparticles can be controlled. That is, the organic solvent present on the surface of the microparticles can be slowly evaporated to produce microparticles.

[0097] The temperature at which the oil and aqueous solutions flow through the microchannel is also 15 to 20°C, preferably 17°C. That is, after flowing through the microchannel and forming an intersection to generate microparticles, a constant low temperature of 15 to 20°C is maintained until the collected microparticles are stirred for the first time. Spherical particles can only be manufactured and maintained if a low temperature is maintained during the microparticle manufacturing process. In other words, if low temperature conditions are not met, a problem arises where it is difficult to manufacture particles with a consistent spherical shape.

[0098] Subsequently, the second and third stirring processes gradually increase the temperature and increase the stirring time to allow the organic solvent present on the surface of the microparticles to evaporate slowly, thereby minimizing the impact on the surface of the microparticles as the organic solvent evaporates from the surface. In other words, if the organic solvent evaporates rapidly, the surface of the microparticles may become rough and uneven due to the evaporation. To prevent this problem, the evaporation rate of the organic solvent can be controlled by gradually increasing the temperature conditions as described above and increasing the stirring time, and the surface roughness of the manufactured microparticles can be controlled through this control of the organic solvent evaporation rate.

[0099] Finally, the above step 6) is a step of washing and drying the microparticles, and the microparticles, from which all organic solvent on the surface has been removed by stirring, can be washed several times with sterilized filtered purified water to remove any surfactants remaining on the microparticles.

[0100] The microparticles from which the residual surfactant has been removed can form a coating layer using an aqueous mannitol solution. Specifically, an aqueous mannitol solution is added to the microparticles from which the surfactant has been removed to form a mannitol coating layer on the outside of the microparticles, and then freeze-dried.

[0101] The finally produced microparticles are in the form of spherical biodegradable polymer microparticles in which dutasteride is evenly distributed, and may contain dutasteride and biodegradable polymer in a weight ratio of 1:2 to 1:5.

[0102] The weight ratio of dutasteride and the biodegradable polymer contained in the above microparticles is the same as the weight ratio in the oil phase solution. This is because microparticles containing dutasteride and the biodegradable polymer can be produced in the same ratio as the weight ratio in the oil phase solution by manufacturing the microparticles and removing all of the organic solvent by evaporation.

[0103] The above-mentioned microparticles can be mixed with a suspension solvent to produce an injectable composition.

[0104] The above suspension solvent includes an isotonic agent, a suspending agent, and a solvent.

[0105] More specifically, the isotonic agent may be selected from the group consisting of D-Mannitol, Maltitol, Sorbitol, Lactitol, Xylitol, Sodium chloride, and mixtures thereof, preferably D-Mannitol, but is not limited to the above examples.

[0106] The above-mentioned suspending agent is from the group consisting of sodium carboxymethylcellulose, polysorbate 80, starch, starch derivatives, polyhydric alcohols, chitosan, chitosan derivatives, cellulose, cellulose derivatives, collagen, gelatin, hyaluronic acid (HA), alginic acid, algin, pectin, carrageenan, chondroitin, chondroitin sulfate, dextran, dextran sulfate, polylysine, titin, fibrin, agarose, fluran, xanthan gum, and mixtures thereof. Selected, preferably sodium carboxymethylcellulose and polysorbate 80, but not limited to the above examples.

[0107] The above solvent may be injection water, and any solvent usable as injection water may be used without restriction.

[0108] Preparation Example 1

[0109] Preparation of microparticles containing dutasteride

[0110] An oil phase solution was prepared by dissolving dutasteride, PLGA, and PLA in dichloromethane. The biodegradable polymer in the oil phase solution may contain PLGA and PLA in a weight ratio of 2:1, and dutasteride and the biodegradable polymer may be contained in a weight ratio of 1:3.

[0111] Polyvinyl alcohol, a surfactant, was mixed with water to prepare an aqueous solution containing 0.25% by weight of polyvinyl alcohol.

[0112] The above oil solution and aqueous solution were injected into microchannels formed on a silicon wafer and allowed to flow.

[0113] At this time, in order to make the oil phase and water phase solutions flow at a constant flow rate, the oil phase solution was flowed under conditions where the pressure was increased at a constant rate of 2 mbar per minute starting from a pressure of 650 mbar, and the water phase solution was flowed under a pressure of 2800 mbar. The temperature was maintained at 17℃ and the stirring speed at 300 rpm.

[0114] Microparticles generated at the intersection where the flow of the oil phase solution and the flow of the aqueous phase solution meet were collected in a tank containing the aqueous phase solution. The microparticles collected in the tank were first stirred at a speed of 300 rpm for 30 minutes at 17°C, then the temperature was raised to 35°C and secondly stirred at a speed of 400 rpm for 1 hour, and then the temperature was raised to 43°C and thirdly stirred at a speed of 500 rpm for 5 hours.

[0115] The microparticles after stirring are washed several times with sterile filtered purified water and freeze-dried to obtain an average diameter (D 50 Microparticles with a size of 40㎛ were manufactured.

[0116] Preparation Example 2

[0117] Microparticles were prepared in the same manner as in Preparation Example 1, except that the biodegradable polymer in the oil phase solution contained PLGA and PLA in a weight ratio of 1:1, and dutasteride and the biodegradable polymer contained them in a weight ratio of 1:2.

[0118] Preparation Example 3

[0119] Microparticles were prepared using the same method as in Preparation Example 1, except that only PLGA was used as the biodegradable polymer.

[0120] Preparation Example 4

[0121] It was prepared in the same manner as Preparation Example 3, except that the average diameter of the microparticles was 80㎛.

[0122] Preparation Example 5

[0123] It was prepared in the same manner as Preparation Example 1, except that the average diameter of the microparticles was 80㎛.

[0124] Preparation Example 6

[0125] It was prepared in the same manner as Preparation Example 2, except that the average diameter of the microparticles was 80㎛.

[0127] Experimental Example 1

[0128] Accelerated emission experiment

[0129] Water containing 1% sodium lauryl sulfate was used as the elution test solution, microparticles were mixed into the elution test solution, a shaking water bath was used as the elution test device, a glass test container with a capacity of 120 ml was used as the elution test container, and it was shaken at 45°C at a speed of 120 rpm.

[0130] The results of conducting accelerated emission experiments on the microparticles of Manufacturing Examples 1 to 6 as Examples 1 to 6 are as shown in Fig. 1.

[0131] According to the above experiment, when only PLGA, a type of biodegradable polymer, was used, it was confirmed that the release of dutasteride already exceeded 50% after 24 hours. In light of the above results, in the case of Examples 3 and 4, microparticles containing only PLGA are used, and there is a problem in that it is difficult to continuously exhibit a release effect for 3 to 6 months.

[0132] On the other hand, in Examples 1, 2, 5, and 6, the accelerated emission test results showed that more than 90% of the emission occurred after 72 hours or close to 100 hours.

[0133] In addition, Examples 1 and 5 and Examples 2 and 6 differ only in the average diameter of the particles, and it can be confirmed that the release rate of dutasteride is delayed as the diameter of the particles increases.

[0134] Experimental Example 2

[0135] Evaluation of pharmacokinetic characteristics

[0136] The microparticles of Preparation Example 1 above were added to 1.5 ml of suspension solvent based on 1 vial, and then uniformly suspended to prepare a composition for subcutaneous injection.

[0137] The above suspension solvent was composed of the composition shown in Table 1 below.

[0138] Content Standards Purpose of formulation Ingredient name quantity unit 1.5 mL Topic D-Mannitol 75.0 mg Suspension agent Sodium Carboxymethylcellulose 3.75 mg Suspension agent Polysorbate 80 1.5 mg solvent Injection water remain

[0139] When preparing a subcutaneous injection composition using the microparticles of Preparation Example 1 above, the weight of dutasteride included in the injection composition was prepared to be 8.4 mg (G2), 25.2 mg (G3), and 42 mg (G4).

[0140] A subcutaneous injection composition (G5) was prepared by adding the microparticles of Preparation Example 2 above to a suspension solvent as described above.

[0141] As a comparative example (G1), 0.5 mg of Avodart (GSK) soft capsules were used.

[0143] The above G1 to G5 were administered to each beagle dog, and blood was collected to measure the blood concentration (PK) of dutasteride. For the experiment, the injectable compositions of G2 to G5 were administered to each of the five beagle dogs, and the administration route was subcutaneous injection. G1 was administered to the five beagle dogs once at the same time every day.

[0144] After blood collection, the average PK value for 5 Beagle dogs was calculated. The experimental results are shown in Figures 2 to 4.

[0145] Figure 2 shows the average PK measurement results for G1, and Figure 3 shows the average PK measurement results for G2 to G5. Figure 4 shows the log scale analysis results for G1 to G5.

[0146] In the case of G1, since it is taken daily, it can be confirmed that it consistently shows a constant PK value after 7 days.

[0147] In the case of G3 to G5, it can be observed that the blood concentration of dutasteride continuously increases, reaches a maximum blood concentration after one week, and then decreases. However, in the case of G2, it can be observed that the amount of dutasteride administered is too low, so the release effect of dutasteride does not appear for three months.

[0148] The PK measurement results for the above G2 to G5 are as shown in Table 2 below:

[0149] Time (w) Time (d) Time (h) G2 G3 G4 G5 0.0 0.0 0 No Peak No Peak No Peak No Peak 0.0 0.0 0.5 0.32325 0.3898 1.9858 0.36525 0.0 0.0 1 0.4186 0.9806 2.4434 0.5878 0.0 0.1 1.5 0.4966 0.685 2.6084 0.6906 0.0 0.1 2 0.588 0.8786 3.916 0.943 0.0 0.1 3 1.0458 1.875 5.2272 1.446 0.0 0.2 4 1.2242 2.1 6.1504 1.9622 0.0 0.3 6 2.1212 4.7562 9.9178 3.0732 0.0 0.3 8 2.0642 4.1252 11.5584 3.7702 0.1 0.4 10 2.0522 4.591 13.339 4.3352 0.1 0.5 12 2.1884 6.985 14.305 4.4168 0.1 0.8 18 2.9676 8.0476 21.5142 6.4272 0.1 1 24 4.0082 11.6678 30.1276 8.0218 0.3 2 48 6.7666 21.1678 53.6748 16.6622 0.4 3 72 9.8386 29.5632 64.0236 24.078 0.6 4 96 14.3968 40.6086 97.0532 27.0472 0.9 6 144 28.7132 64.3884 189.0906 64.633 1.1 8 192 64.3268 166.5396 333.4002 228.6784 1.6 11 264 85.1528 383.203 428.6358 438.0872 2 14 336 159.9186 637.5282 589.4112 700.6906 3 21 504 213.7886 770.474 836.1794 688.7982 4 28 672 209.102 617.7678 936.663 447.7378 5 35 840 202.3858 686.4664 1050.591 463.2668 6 42 1008 119.6382 446.0882 733.6584 542.6508 7 49 1176 64.9644 293.663 490.3916 541.1552 8 56 1344 31.7436 228.8524 414.9682 473.937 9 63 1512 23.5696 188.089 354.3624 351.9552 10 70 1680 10.7034 154.5424 259.0024 340.6144 11 77 1848 9.1374 134.1624 265.6142 303.364 12 84 2016 5.96525 95.9516 186.5662 246.6816 14 98 2352 0.199667 50.8484 127.0994 191.2418 16 112 2688 0.171 20.0644 63.4776 157.2748

[0150] According to the above measurement results, it can be confirmed that the maximum blood concentration of dutasteride is reached between 2 and 5 weeks.

[0151] Experimental Example 3

[0152] Review of the characteristics of microparticles

[0153] Preparation Examples 1 and 2 involved mannitol coating, and the formation of the mannitol coating layer was verified. Specifically, the microparticles of Preparation Examples 1 and 2 were prepared by removing the surfactant, adding an aqueous mannitol solution to form a mannitol coating layer on the outside of the microparticles, and then freeze-drying them. As shown in Figures 5 and 6, it can be confirmed that the microparticles of Preparation Examples 1 and 2 have a mannitol coating layer formed on them.

[0154] On the other hand, the microparticles of Preparation Example 1, which were not coated with mannitol, exhibited clumping as shown in Fig. 7.

[0155] The results of PSA analysis for the microparticles prepared in Preparation Examples 1 to 6 above are as shown in Table 3 below:

[0156] D50 SD Width Preparation Example 1 40.66 2.648 5.3 Preparation Example 2 40.91 2.714 5.43 Preparation Example 3 40.71 2.785 5.57 Preparation Example 4 81.06 5.29 10.57 Preparation Example 5 80.64 5.29 10.57 Preparation Example 6 82.77 6.58 13.16

[0157] Although preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concept of the present invention as defined in the following claims also fall within the scope of the present invention.

Claims

Claim 1 A sustained-release injectable composition comprising 25 mg to 84 mg of dutasteride, wherein the dutasteride is evenly distributed within microparticles, wherein the microparticles continuously release dutasteride for 3 to 6 months after injection into the body, wherein the average diameter of the microparticles is 30 µm to 90 µm, wherein the dutasteride and a biodegradable polymer are included in a weight ratio of 1:2 to 1:3, wherein the biodegradable polymer comprises polylactic acid and polylactide-co-glycolide (PLGA) in a weight ratio of 1:1 to 1:4, wherein the microparticles additionally include a mannitol coating layer on the outside, and wherein the dutasteride exhibits a maximum blood concentration (Cmax) of dutasteride after at least one week has elapsed since injection into a Beagle dog. Claim 2 delete Claim 3 In claim 1, the maximum blood concentration value of the dutasteride (C max A sustained-release injectable composition comprising 200 ng / mL to 2,500 ng / mL of indutasteride. Claim 4 delete Claim 5 delete Claim 6 delete Claim 7 In claim 1, the microparticles are a sustained-release injectable composition containing dutasteride that releases less than 50% by weight of dutasteride after 24 hours as a result of conducting an accelerated release experiment under the following conditions: [Experimental Conditions] Water containing 1% sodium lauryl sulfate was used as the dissolution test solution, microparticles were mixed into the dissolution test solution, a shaking water bath was used as the dissolution test device, a glass test container with a content of 120 ml was used as the dissolution test container, and it was shaken at a speed of 120 rpm at 45°C. Claim 8 delete Claim 9 A sustained-release injectable composition comprising dutasteride, wherein the standard deviation (SD) for the diameter of the microparticles in claim 1 is 2 to 7. Claim 10 A sustained-release injectable composition comprising dutasteride, wherein the width of the phase peak in the PSA analysis result of the microparticles is 5 to 15.

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