Sustained release injection composition containing dutasteride

Abstract

The present invention relates to a composition for sustained release injection comprising dutasteride, which can exhibit a dutasteride release effect lasting for 3 months or more even if dutasteride is administered at the same dosage or less as # imgabs0 # (AVODART) which is administered once a day in comparison to conventional # imgabs0 # (AVODART), and thus can exhibit a long-term sustained medication effect by one injection. Furthermore, the composition for sustained-release injection can continuously exhibit a therapeutic effect on prostatic hyperplasia, prostatic cancer, and alopecia for 3 months or more, and the microparticles contained in the composition for sustained-release injection have a certain average diameter, can constantly maintain an effective drug concentration by adjusting drug release, and when administered to a patient as an injection, the composition for sustained-release injection has a good therapeutic effect on prostatic hyperplasia, prostatic cancer, and alopecia. And foreign body sensation and pain can be reduced.

Description

Technical Field

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

[0002] It is well known that dutasteride (compound: 17β-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-4-aza-5α-androst-1-en-3-one) represented by the following chemical formula 1 is a dual 5-α reductase inhibitor that inhibits both type 1 and type 2 of 5-α reductase, and is effective in treating benign prostatic hyperplasia, prostate cancer and male pattern baldness by inhibiting the conversion of testosterone into dihydrotestosterone (DHT).

[0003] [Chemical formula 1]

[0004]

[0005] Dutasteride is currently sold under the trade name (AVODART) is commercially available, and The product is a product prepared by dissolving 0.5 mg of dutasteride in a mixture of 349.5 mg of caprylic / capric monoglyceride and diglyceride oil and butylated hydroxytoluene (BHT) and filling the mixture into a soft capsule.

[0006] However, the amount of excipients constituting the product is large relative to the active ingredient, which leads to an increase in the volume of the soft capsule, thus causing the disadvantage of being inconvenient to take.

[0007] Conventionally, studies have been conducted on oral dosage forms containing dutasteride to improve the convenience of administration and dissolution stability by reducing the volume.

[0008] That is, similarly to the past, attempts have been made to improve the ease of taking the medicine by reducing its volume, but since it needs to be taken every day, there is a problem in that the ease of taking the medicine is low.

[0009] Therefore, there is an urgent need to develop a therapeutic agent for treating prostate hyperplasia, prostate cancer and hair loss, which improves the problems of existing dosage forms containing dutasteride, and the efficacy can be maintained for more than 3 months with only one administration and is easy to store and handle.

[0010] Prior art literature

[0011] Patent Literature

[0012] Patent Document 1KR10-1833280B1 Summary of the invention

[0013] Problem that the invention aims to solve

[0014] The object of the present invention is to provide a sustained-release injection composition comprising dutasteride.

[0015] Another object of the present invention is to provide a sustained-release injection composition comprising dutasteride, which is different from the existing once-daily injection. Compared with AVODART, even if the dosage of dutasteride is the same or less, the dutasteride release effect can be shown to be sustained for more than 3 months, so a long-term sustained medication effect can be shown with a single injection.

[0016] Another object of the present invention is to provide an injectable composition containing sustained-release particles, which can continuously show the therapeutic effect of prostate hyperplasia, prostate cancer and hair loss for more than 3 months, and the particles contained in the sustained-release injectable composition have a certain average diameter, and can constantly maintain an effective drug concentration by adjusting the drug release. When used as an injection and administered to patients, it can reduce foreign body sensation and pain.

[0017] Means used to solve problems

[0018] In order to achieve the above object, the present invention is a sustained-release injection composition comprising dutasteride, wherein the sustained-release injection composition comprises 8 mg to 100 mg of dutasteride, wherein the dutasteride is uniformly distributed in microparticles, and after being injected into the body, the microparticles continuously release dutasteride for 3 to 6 months, and the average diameter of the microparticles is 30 μm to 90 μm.

[0019] The composition for injection can show a maximum blood concentration of dutasteride (C max ).

[0020] The maximum blood concentration value of dutasteride (C max ) is 200ng / mL to 1100ng / mL.

[0021] The microparticles may include two or more biodegradable polymers selected from the group consisting of polylactic acid, polylactide, polylactide-co-glycolide (PLGA), polyphosphazene, polyimidocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate and polyamino acid.

[0022] The biodegradable polymer may include polylactic acid and poly(lactide-co-glycolide) (PLGA) in a weight ratio of 1:1 to 1:4.

[0023] The microparticles may include dutasteride and the biodegradable polymer in a weight ratio of 1:2 to 1:5.

[0024] The results of the accelerated release test under the following conditions showed that the microparticles could release less than 50% by weight of dutasteride in 24 hours:

[0025] [Experimental conditions]

[0026] The dissolution test solution used was water containing 1% sodium lauryl sulfate, and the microparticles were mixed in the dissolution test solution. The dissolution tester used a shaking waterbath. The dissolution test container used a glass test container with a net capacity of 120 ml, and was shaken at a speed of 120 rpm at a temperature of 45°C.

[0027] The exterior of the microparticles may also include a coating.

[0028] The standard deviation (SD) of the microparticle diameters was 2 to 7.

[0029] The PSA analysis result of the microparticles showed a peak width of 5 to 15.

[0030] Effects of the Invention

[0031] In addition, the sustained-release injection of the present invention can show a therapeutic effect on prostate hyperplasia, prostate cancer and hair loss that lasts for more than 3 months, and the microparticles contained in the sustained-release injection composition have a certain average diameter, and the effective drug concentration can be constantly maintained by adjusting the drug release. When used as an injection and administered to patients, the foreign body sensation and pain can be reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the experimental result of accelerated release of microparticles according to one embodiment of the present invention.

[0033] Figure 2 It is the PK analysis result of the sustained-release injection composition according to one embodiment of the present invention.

[0034] Figure 3 It is the PK analysis result of the sustained-release injection composition according to one embodiment of the present invention.

[0035] Figure 4 It is the PK analysis result of the sustained-release injection composition according to one embodiment of the present invention.

[0036] Figure 5 is a SEM image of microparticles according to an embodiment of the present invention.

[0037] Figure 6 is a SEM image of microparticles according to an embodiment of the present invention.

[0038] Figure 7FIG. 4 is a SEM image of particles that have aggregated according to an embodiment of the present invention. DETAILED DESCRIPTION

[0039] The present invention relates to a sustained-release injection composition containing dutasteride, wherein the sustained-release injection composition contains 8 mg to 100 mg of dutasteride, wherein the dutasteride is uniformly distributed in microparticles, and after being injected into the body, the microparticles continuously release dutasteride for 3 to 6 months, and the average diameter of the microparticles is 30 μm to 90 μm. Specific embodiments

[0041] Hereinafter, the embodiments of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein.

[0042] The present invention relates to a sustained-release injection composition containing dutasteride, which is characterized in that a sustained drug release effect of more than 3 months can be exhibited through a single injection.

[0043] As described above, since a single injection can produce a sustained drug release effect for more than three months, it can show therapeutic effects on prostate hyperplasia, prostate cancer and hair loss. Therefore, it can replace existing products that are taken once a day, thereby significantly improving the convenience of taking.

[0044] In order to achieve the above-mentioned features, specifically, the sustained-release injection composition containing dutasteride of the present invention may contain 8 mg to 100 mg of dutasteride, and the dutasteride may be evenly distributed in the microparticles, and after being injected into the body, the microparticles may continuously release dutasteride for 3 to 6 months, and the average diameter of the microparticles may be 30 μm to 90 μm.

[0045] The sustained-release injection composition of the present invention is characterized in that it contains dutasteride, and the dutasteride contained in one administration dose is 8 mg to 100 mg.

[0046] Take once a day For AVODART, a single dose contains 0.5 mg of dutasteride. If 84 days (3 months) of use are taken as the standard, a total of 42 mg is administered.

[0047] In the present invention, it is characterized in that Compared with AVODART, even if dutasteride is contained at the same level or at a lower dose, the drug can be released continuously for a long time.

[0048] Thus, the sustained-release injection composition of the present invention is characterized in that, after being injected into the body, dutasteride is continuously released for 3 to 6 months. For example, in the case of a 3-month dosage form, 8 to 42 mg, 15 to 42 mg, or 25 to 42 mg of dutasteride may be included in the entire sustained-release injection composition. Even when dutasteride is included within the above range, the release effect of dutasteride can be shown to last for 3 months.

[0049] In addition, in the case of a 6-month dosage form, it may contain 16 mg to 84 mg, 30 mg to 84 mg, or 50 mg to 84 mg. Even when dutasteride is contained within the above range, the release effect of dutasteride can be exhibited for 3 months.

[0050] The sustained-release injection composition comprises microparticles, the microparticles contain dutasteride, the microparticles are uniform round particles, and the dutasteride is uniformly distributed.

[0051] As described later, the microparticles of the present invention are round particles having a uniform diameter, and a plurality of the particles are contained in the sustained-release injection composition. When the particles having a uniform diameter as described above are contained, after injection into the body, a sustained release effect of dutasteride can be exhibited, and the release time point of dutasteride can be adjusted.

[0052] That is, when the particle size is not uniform, the speed of particle decomposition in the body may vary, and thus the release rate of dutasteride contained in the particles may not be controlled. Therefore, in the present invention, it is characterized in that the release rate of dutasteride can be adjusted by including only particles having a uniform diameter, so that the release effect of dutasteride can be exhibited for 3 to 6 months.

[0053] The average diameter of the microparticles may be 30 μm to 90 μm, 35 μm to 85 μm, or 40 μm to 80 μm. With uniform particles within the above range, the initial burst release of dutasteride injected into the body can be prevented, and after a certain period of time, the maximum blood concentration is exhibited with the release of dutasteride, thereby exhibiting a continuous release effect of dutasteride for 3 to 6 months.

[0054] Specifically, the composition for injection can show a maximum blood concentration (C max ), specifically, the maximum blood drug concentration (C max ).

[0055] As described above, the sustained-release injection composition of the present invention is characterized in that, after being injected into beagle dogs, dutasteride is continuously released, and after more than one week, a maximum blood concentration (C max ) value, after which the blood concentration of dutasteride decreases steadily and is released over the desired time period.

[0056] That is, as shown in the present invention, it is characterized in that in order to show the effect of sustained release of dutasteride for 3 to 6 months, a sustained-release injection composition is provided, and after the injection composition is injected into beagle dogs, the blood concentration of dutasteride shows a maximum blood concentration (C max )value.

[0057] According to the release results of dutasteride as described above, it is characterized in that after the composition for injection of the present invention is injected into beagle dogs, the release degree of dutasteride is small within 1 day, that is, within 24 hours, but thereafter, the release amount of dutasteride continues to increase, and after 1 week, it shows a maximum value within 2 weeks to 5 weeks, and then the release amount continues to decrease, and the release of dutasteride is completed in about 3 months, 4 months, 5 months or 6 months.

[0058] More specifically, after the sustained-release injection composition of the present invention was injected into beagle dogs, the concentration of dutasteride in the blood was measured. After 24 hours, the maximum blood concentration of dutasteride (C 24h ) can be from 4ng / mL to 40ng / mL, can be from 5ng / mL to 38ng / mL, can be from 6ng / mL to 35ng / mL, can be from 8ng / mL to 32ng / mL.

[0059] In addition, after more than 1 week, the maximum plasma concentration of dutasteride (C max ) may be 200 ng / mL to 2500 ng / mL, may be 400 ng / mL to 2500 ng / mL, may be 500 ng / mL to 2500 ng / mL. The maximum blood concentration (C max ) may differ depending on whether the sustained-release injection composition of the present invention is a 3-month dosage form, a 4-month dosage form, a 5-month dosage form or a 6-month dosage form. Specifically, for the 3-month dosage form, the maximum blood concentration of dutasteride (C max ) may be 500 ng / mL to 1100 ng / mL. That is, in order to provide a dosage form of sustained release of dutasteride for a longer period of time, the content of dutasteride contained in the composition for injection is increased, and thus, when the composition for injection is administered to beagle dogs, the maximum blood concentration of dutasteride (C max ) can also be changed.

[0060] After the sustained-release injection composition of the present invention was injected into the beagle dog, the concentration of dutasteride in the blood was analyzed, and it was clearly confirmed that the release amount of dutasteride was small within 24 hours, and the maximum blood concentration (C max ). When the concentration value of dutasteride in the blood is shown as above, the release effect of dutasteride can be shown to last for more than 3 months, and for 3 to 6 months.

[0061] The microparticles may include two or more biodegradable polymers selected from the group consisting of polylactic acid, polylactide, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate and polyamino acid. Specifically, the biodegradable polymers may include polylactic acid and polylactide-co-glycolide.

[0062] As described above, when microparticles are prepared by including two or more biodegradable polymers, as biodegradable polymers having biodegradation periods different from each other are used, the effect of releasing dutasteride can be exhibited by decomposition within a desired period.

[0063] That is, when one biodegradable polymer is used, if only a biodegradable polymer with a short biodegradation period is used, the release effect of dutasteride can be exhibited only for a short period of time.

[0064] In addition, when a biodegradable polymer with a long biodegradation period is used, although the release effect of dutasteride can be shown for a longer period of time, the initial release degree of dutasteride administered as an injection is too weak, so there is a problem that the drug effect based on dutasteride is difficult to exert. That is, in order to show the drug effect based on dutasteride in the body, the concentration value of dutasteride in the blood should be above a certain level, and when a biodegradable polymer with a long biodegradation period is used, the initial decomposition degree of dutasteride administered as an injection in the body is weak, and there is a problem that the drug effect based on dutasteride is difficult to exert.

[0065] The biodegradable polymer may include polylactic acid and poly(lactide-co-glycolide) (PLGA) in a weight ratio of 1:1 to 1:4, and may include in a weight ratio of 1:2 to 1:3. When mixed and used in the weight ratio as described above, as described above, the release effect of dutasteride may be exhibited over a desired period of time.

[0066] The microparticles may contain dutasteride and the biodegradable polymer in a weight ratio of 1:2 to 1:5, and may contain dutasteride in a weight ratio of 1:2 to 1:4, and may contain dutasteride in a weight ratio of 1:2 to 1:3. When mixed and used within the above range, dutasteride can be released continuously for a long time by decomposition of the biodegradable polymer.

[0067] The results of the accelerated release test under the following conditions showed that the microparticles could release less than 50% by weight of dutasteride after 20 hours:

[0068] [Experimental conditions]

[0069] The dissolution test solution used was water containing 1% sodium lauryl sulfate, and the microparticles were mixed in the dissolution test solution. The dissolution tester used a shaking waterbath. The dissolution test container used a glass test container with a net capacity of 120 ml, and was shaken at a speed of 120 rpm at a temperature of 45°C.

[0070] The accelerated release test is a test for confirming the sustained release of the drug by preparing drug-containing particles using a biodegradable polymer. In other words, it is a test for indirectly confirming whether the drug is continuously released for a long time.

[0071] The present invention is characterized in that, as a result of the accelerated release test under the conditions, less than 50% by weight of dutasteride is released at the time point of 20 hours.

[0072] As described above, according to the results of the accelerated release experiment, the release degree of dutasteride of the microparticles of the present invention remains less than 50% by weight at the 20-hour time point, and thus the release effect of dutasteride can be continuously exhibited within 3 to 6 months.

[0073] In order to prepare microparticles, as two or more biodegradable polymers are included, the release degree of dutasteride as described above can be adjusted. As described later, when only one biodegradable polymer is used, it can be confirmed that 70% by weight or more of dutasteride release effect is exhibited at a time point of 20 hours. That is, when only one biodegradable polymer is used to prepare microparticles containing dutasteride, as shown in the present invention, a problem may arise that a sustained dutasteride release effect cannot be exhibited within 3 to 6 months.

[0074] In contrast, the microparticles of the present invention can show a long-term sustained dutasteride release effect at a time point after 50 hours or 70 hours or more have passed from the time point when 80% by weight of dutasteride is released.

[0075] The microparticles may also include a coating on the outside. The coating may be applied using mannitol. As described above, when mannitol is used to form a coating on the surface of the microparticles, in order to be used as an injection, only the microparticles at a desired level can be effectively filled by improving the fluidity during filling. In addition, as described above, during freeze drying, the microparticles coated with mannitol do not produce aggregation between particles.

[0076] In contrast, during freeze drying, Figure 7 As shown, the particles without coating may aggregate. In addition, even during the filling process, the inclusion degree of the particles varies due to poor fluidity.

[0077] As described above, the average diameter of the microparticles of the present invention may be 30 μm to 90 μm, 35 μm to 85 μm, or 40 μm to 80 μm. In addition, 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 this means that the standard deviation (SD) is very small and has a uniform particle size.

[0078] In addition, the peak width (Width) of the PSA analysis result can be 5 to 15. The peak width refers to the width of each peak (= 16 to 84% of the width). As described later, the microparticles prepared by the preparation method of the present invention cannot confirm multiple peaks in the PSA analysis. This means that the produced microparticles themselves are very uniform.

[0079] By including uniform particles within the above range, the initial burst release of dutasteride injected into the body can be prevented, and after a certain time point, the maximum blood concentration is exhibited as dutasteride is released, and a sustained release effect of dutasteride can be exhibited within 3 to 6 months.

[0080] Another embodiment of the present invention provides a method for preparing a sustained-release injection composition containing dutasteride, which may include: step 1), mixing dutasteride and a biodegradable polymer to prepare an oil phase solution; step 2), dissolving a surfactant in a solvent to prepare an aqueous phase solution; step 3), injecting the oil phase solution and the aqueous phase solution into a first microchannel and a second microchannel forming an intersection respectively and allowing them to flow, and generating microparticles at the intersection; step 4), collecting the microparticles in a water tank filled with the aqueous phase solution; step 5), removing the organic solvent present in the collected microparticles; step 6), washing the microparticles from which the organic solvent has been removed with pure water and drying them; and step 7), mixing the dried microparticles with a suspension.

[0081] The step 1) is a step of preparing an oil phase solution, wherein dutasteride and a biodegradable polymer are dissolved in an organic solvent to prepare an oil phase solution, wherein the biodegradable polymer may be selected from two or more of the group consisting of polylactic acid, polylactide, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate and polyamino acid, preferably polylactide-co-glycolide (PLGA) and polylactide (PLA), but is not limited to the examples.

[0082] In addition, the organic solvent is a solvent that is not miscible with water, for example, 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, and the organic solvent that can dissolve the biodegradable polymer and dutasteride is not limited to the examples, as long as it is an organic solvent that can be easily selected by those skilled in the art, it can be used.

[0083] In step 1), an oil phase solution for dissolving dutasteride and biodegradable polymer is prepared. As mentioned above, an organic solvent is used as the solvent. This is to utilize the solubility characteristics of dutasteride and biodegradable polymer and use an organic solvent to completely dissolve them.

[0084] In the oil phase solution, the weight ratio of dutasteride to the biodegradable polymer can be 1:2 to 1:5, 1:2 to 1:4, 1:2 to 1:3. When mixed and used within the above range, dutasteride can be released continuously for a long time through the decomposition of the biodegradable polymer.

[0085] When the weight ratio of dutasteride to the biodegradable polymer is less than 1:1, that is, when the content of the biodegradable polymer is lower than the weight ratio, the weight ratio of the biodegradable polymer is small compared to the weight of dutasteride, so it may be difficult to prepare sustained-release particles in which dutasteride is uniformly distributed in spherical biodegradable polymer particles. When the weight ratio of the biodegradable polymer to dutasteride exceeds 1:5, that is, when the content of the biodegradable polymer exceeds the weight ratio, due to the small content of dutasteride in the sustained-release particles, in order to make the drug concentration reach the desired concentration, a large amount of sustained-release particles may need to be administered.

[0086] More specifically, the oil phase solution contains 15 wt % to 25 wt % of the biodegradable polymer, preferably 20 wt %, but not limited to the example.

[0087] The step 2) is a step of preparing an aqueous phase solution, wherein a surfactant is dissolved in water to prepare an aqueous phase solution. The surfactant can be used without restriction as long as it helps the oil phase solution in which the biodegradable polymer and dutasteride are dissolved to form a stable emulsion. Specifically, the surfactant is selected from one or more of the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants and mixtures thereof, more specifically, selected from one or more of 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, esteramine, linear diamine, fatty amine and mixtures thereof, preferably polyvinyl alcohol, but not limited to the examples.

[0088] The surfactant contained in the aqueous phase solution may be contained in an amount of 0.1 to 1.0 wt %, 0.1 to 0.5 wt %, or 0.25 wt %. The rest is water.

[0089] The step 3) is a step of injecting the oil phase solution and the water phase solution into the microchannel formed on the wafer and allowing them to flow.

[0090] More specifically, the microchannel may be formed in a material selected from the group consisting of a silicon wafer or a polymer film, but examples of the material are not limited to the examples, and any material capable of forming a microchannel may be used.

[0091] The polymer film may be selected from the group consisting of polyimide, polyethylene, fluorinated ethylene propylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polysulfone and a mixture thereof, but is not limited to the examples.

[0092] As an example, aluminum is deposited on a silicon wafer using an e-beam evaporator, and a photoresist is patterned on the aluminum using photolithography. The photoresist is then used as a mask to etch the aluminum, and after removing the photoresist, the aluminum is used as a mask to etch the silicon using deep ion reactive etching (DRIE), and after removing the aluminum, glass is anodically bonded to the wafer and sealed to prepare the microchannels described above.

[0093] The average diameter of the above-mentioned microchannels is different depending on the case of a 7-channel chip and a 140-channel chip. A 140-channel chip is used for the microchannel used to prepare the microparticles of the present invention. As for the 140-channel chip, when the oil phase solution and the aqueous phase solution are injected into the microchannel, the average diameter of the channel is 300 μm to 500 μm, and the oil phase solution and the aqueous phase solution will 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 phase solution can pass through the intersecting junction channel, and the diameter of the junction channel can be 50 μm to 150 μm. In the junction channel, after the oil phase solution and the aqueous phase solution intersect and 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. When the average diameter of the joint channel is 50 μm or less, there is a possibility that the diameter of the prepared sustained-release particles is less than 30 μm and small sustained-release particles are prepared, thereby affecting effective drug release and in vivo absorption. In addition, when the average size of the prepared sustained-release particles exceeds 100 μm, when used as an injection, foreign body sensation and pain may increase, and as the particle size distribution of the prepared particles increases, it is difficult to prepare sustained-release particles with uniform particle size.

[0094] However, the average diameter of the microchannels can be changed according to the range of injection pressure. In addition, the average diameter of the microchannels is closely related to the average diameter of the particles and is also closely related to the injection pressure of the oil phase solution and the water phase solution.

[0095] In the step 3), the oil phase solution and the water phase solution are made to flow in the first microchannel and the second microchannel forming the intersection under the injection pressure condition.

[0096] That is, the oil phase solution flows along the first microchannel, and the water phase solution flows along the second microchannel formed in such a manner as to form an intersection with the first microchannel, and intersects with the flow of the oil phase solution.

[0097] More specifically, when the oil phase solution is injected into the first microchannel, after injection at a pressure condition of 200 mbar to 800 mbar, the pressure can be increased at a first condition of 1 mbar / minute to 5 mbar / minute, and when the injection pressure condition reaches 500 mbar to 1000 mbar, the pressure can be increased at a second condition of 1 mbar / minute to 5 mbar / min.

[0098] In addition, when the oil phase solution is injected into the first microchannel, the water phase solution may be injected into the second microchannel under a pressure condition 4 to 12 times higher than the pressure condition.

[0099] Specifically, in the preparation method using the microchannel, a flow meter is used to set the flow rate of the oil phase solution and the water phase solution flowing through the inside of the microchannel to a certain value. When the pressure is measured by feedback control, it is confirmed that the oil phase solution flows through the microchannel at a certain flow rate and the required pressure gradually increases over time.

[0100] Therefore, the variability of the flow rate is minimized by using a method of constantly increasing the pressure applied to the oil phase solution, which slowly solidifies inside the microchannel, thereby preventing problems of uneven particle distribution or channel closure and increasing the production capacity of the target particles.

[0101] In addition, the pressure conditions when the oil phase solution and the aqueous phase solution are injected into the microchannel are used to adjust the average diameter of the prepared microparticles. When the above range is not met, the size of the prepared particles may be uneven, or the average diameter range of the microparticles of the present invention may not be met, or the value of Formula 1 may not be met.

[0102] That is, in order to make the flow of the aqueous solution forming an intersection with the flow of the oil phase solution faster than the oil phase solution injected into the microchannel, the aqueous solution is made to flow under a higher pressure condition.

[0103] As described above, by setting the flow rates of the oil phase solution and the aqueous phase solution differently and making the flow rate of the aqueous phase solution faster than the flow rate of the oil phase solution, the aqueous phase solution having a relatively faster flow rate at the location where the flow of the oil phase solution intersects the flow of the aqueous phase solution compresses the oil phase solution. At this time, due to the repulsive force between the oil phase solution and the aqueous phase solution, the biodegradable polymer and dutasteride in the oil phase solution generate spherical particles. More specifically, the particles can be formed in the form of dutasteride uniformly distributed in the spherical biodegradable polymer.

[0104] The step 4) is a step of collecting the microparticles, in which the microparticles are collected in a water tank filled with an aqueous solution to prevent aggregation of the microparticles generated in the early stage.

[0105] The step 4) utilizes the aqueous solution (i.e., a mixed solution of a surfactant and water) prepared in the step 2). After the aqueous solution is prepared in the step 2), a portion is injected into the microchannel, and the other portion is moved to the water tank of the step 4) and used to prevent aggregation between the collected particles.

[0106] The step 5) is a step for removing the organic solvent present in the microparticles collected in the water tank, and the stirring is carried out according to certain temperature conditions and stirring speeds to evaporate and remove the organic solvent present on the surface of the sustained-release particles. At this time, the stirring conditions are: step 5-1), at a temperature of 15°C to 20°C, the first stirring is carried out at a speed of 100rpm to 300rpm, and the stirring time is 20 minutes to 40 minutes; step 5-2), at a temperature of 30°C to 40°C, the second stirring is carried out at a speed of 100rpm to 300rpm, and the stirring time is 60 minutes to 120 minutes; and step 5-3), at a temperature of 40°C to 45°C, the third stirring is carried out at a speed of 100rpm to 300rpm, and the stirring time is 4 hours to 8 hours.

[0107] Regarding the stirring speed, the stirring process is performed by changing the temperature conditions and stirring time in the first and second stirring steps.

[0108] As described above, the present invention is characterized in that the stirring is performed by raising the temperature conditions in the second stirring step compared to the first stirring step, and the evaporation rate of the organic solvent present on the surface of the microparticles can be adjusted by stepwise temperature increase. That is, microparticles can be prepared by slowly evaporating the organic solvent present on the surface of the microparticles.

[0109] The temperature of the oil phase solution and the water phase solution when flowing through the microchannel is 15°C to 20°C, preferably 17°C. That is, after flowing through the microchannel and forming a cross point to generate microparticles, until the collected microparticles are stirred for the first time, the low temperature of 15°C to 20°C is constantly maintained. In the process of preparing microparticles, spherical particles can only be prepared and maintained by maintaining a low temperature. That is, in the case other than the low temperature condition, it is difficult to prepare certain spherical particles.

[0110] Next, the second stirring process and the third stirring process gradually increase the temperature and increase the stirring time, so that the organic solvent on the surface of the particles evaporates slowly, and as the organic solvent evaporates from the surface, the impact on the surface of the particles can be minimized. When the organic solvent evaporates quickly, the surface of the particles may become rough due to the evaporation of the organic solvent. In order to prevent this problem, as described above, the evaporation rate of the organic solvent can be adjusted by gradually increasing the temperature conditions and increasing the time for the stirring process. Due to the adjustment of the evaporation rate of the organic solvent, the surface roughness of the prepared particles can be controlled.

[0111] Finally, step 6) is a step of washing and drying the microparticles. The microparticles, from which all organic solvents on the surface are removed by stirring, are washed several times with sterile filtered pure water to remove the residual surfactant in the microparticles.

[0112] The residual surfactant-removed microparticles may be coated with a mannitol aqueous solution. Specifically, a mannitol aqueous solution may be added to the microparticles from which the surfactant has been removed, and a mannitol coating may be formed on the outside of the microparticles, followed by freeze drying.

[0113] The finally generated microparticles are in the shape of spherical biodegradable polymer microparticles on which dutasteride is uniformly distributed, and may contain dutasteride and the biodegradable polymer in a weight ratio of 1:2 to 1:5.

[0114] The weight ratio of dutasteride to the biodegradable polymer contained in the microparticles is the same as the weight ratio in the oil phase solution. The microparticles are prepared, and as the organic solvent is completely evaporated and removed, microparticles containing dutasteride and the biodegradable polymer in the same weight ratio as in the oil phase solution can be prepared.

[0115] The prepared microparticles can be mixed with a suspending agent to prepare an injectable composition.

[0116] The suspension comprises an isotonic agent, a suspending agent and a solvent.

[0117] More specifically, the isotonic agent can be selected from the group consisting of D-mannitol, maltitol, sorbitol, lactitol, xylitol, sodium chloride and a mixture thereof, preferably D-mannitol, but not limited to the examples.

[0118] The suspending agent may be selected from the group consisting of sodium carboxymethylcellulose, polysorbate 80, starch, starch derivatives, polyols, 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 a mixture thereof, preferably sodium carboxymethylcellulose and polysorbate 80, but not limited to the examples.

[0119] As the solvent, water for injection can be used, and any solvent that can be used as water for injection can be used without limitation.

[0120] Preparation Example 1

[0121] Preparation of microparticles containing dutasteride

[0122] Dutasteride, PLGA and PLA are dissolved in dichloromethane to prepare an oil phase solution. The biodegradable polymer in the oil phase solution may include PLGA and PLA in a weight ratio of 2:1, and may include dutasteride and the biodegradable polymer in a weight ratio of 1:3.

[0123] Polyvinyl alcohol as a surfactant was mixed with water, and an aqueous phase solution containing 0.25 wt % of polyvinyl alcohol was prepared.

[0124] The oil phase solution and the water phase solution are injected into the microchannel formed on the silicon wafer and allowed to flow.

[0125] At this time, in order to make the oil phase solution and the water phase solution flow at a certain flow rate, the oil phase solution was started at a pressure condition of 650 mbar and the pressure was constantly increased at a rate of increase of 2 mbar / min, and the water phase solution was flowed at a pressure condition of 2800 mbar. The temperature condition was maintained at 17° C. and the stirring speed was maintained at 300 rpm.

[0126] The particles generated at the intersection of the flow of the oil phase solution and the flow of the water phase solution were collected in a water tank filled with an aqueous solution. The particles collected in the water tank were stirred at 300 rpm for 30 minutes at 17° C., heated to 35° C., stirred at 400 rpm for 1 hour, and then heated to 43° C. and stirred at 500 rpm for 5 hours.

[0127] The stirred microparticles were washed several times with sterile filtered pure water and freeze-dried to prepare the average diameter (D 50 ) are particles of 40 μm.

[0128] Preparation Example 2

[0129] 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 at a weight ratio of 1:1 and contained dutasteride and the biodegradable polymer at a weight ratio of 1:2.

[0130] Preparation Example 3

[0131] Microparticles were prepared in the same manner as in Preparation Example 1 except that only PLGA was used as the biodegradable polymer.

[0132] Preparation Example 4

[0133] Preparation was carried out in the same manner as in Preparation Example 3 except that the average diameter of the microparticles was 80 μm.

[0134] Preparation Example 5

[0135] Preparation was carried out in the same manner as in Preparation Example 1, except that the average diameter of the microparticles was 80 μm.

[0136] Preparation Example 6

[0137] Preparation was carried out in the same manner as in Preparation Example 2 except that the average diameter of the microparticles was 80 μm.

[0138] Experimental Example 1

[0139] Accelerated release experiment

[0140] The dissolution test solution used was water containing 1% sodium lauryl sulfate, and the microparticles were mixed in the dissolution test solution. The dissolution tester used a shaking water bath. The dissolution test container used a glass test container with a net capacity of 120 ml and was shaken at a speed of 120 rpm at a temperature of 45°C.

[0141] The results of the accelerated release experiments of the microparticles of Preparation Examples 1 to 6 were respectively carried out according to Examples 1 to 6. Figure 1 shown.

[0142] According to the experiment, when only one biodegradable polymer, namely PLGA, was used, it was confirmed that the release degree of dutasteride exceeded 50% at the time point of 24 hours. From the above results, Examples 3 and 4 are microparticles containing only PLGA. When the microparticles are used, there is a problem that it is difficult to continuously show the release effect within 3 to 6 months.

[0143] On the contrary, it can be confirmed that, according to the accelerated release test results of Examples 1, 2, 5 and 6, more than 90% of the release is achieved after 72 hours or nearly 100 hours.

[0144] In addition, Examples 1 and 5, and Examples 2 and 6 differ only in the average diameter of the particles, and it was confirmed that the larger the particle diameter, the slower the release rate of dutasteride.

[0145] Experimental Example 2

[0146] Evaluation of pharmacokinetic properties

[0147] Based on one vial, the microparticles of Preparation Example 1 were added to 1.5 ml of the suspending agent, which was then uniformly suspended to prepare a composition for subcutaneous injection.

[0148] The suspension concentrate is composed of the composition shown in Table 1 below.

[0149] Table 1

[0150]

[0151]

[0152] When the microparticles of Preparation Example 1 were used to prepare a subcutaneous injection composition, the weight of dutasteride contained in the injection composition was prepared to contain 8.4 mg (G2), 25.2 mg (G3), and 42 mg (G4).

[0153] The microparticles of Preparation Example 2 were added to the suspension as described above to prepare a composition for subcutaneous injection (G5).

[0154] As a comparative example (G1), 0.5 mg of Avodart (GSK) soft capsules were used.

[0155] 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 injection composition of G2 to G5 was administered to each beagle dog (5 dogs), and the administration route was subcutaneous injection. G1 was taken once a day at the same time by 5 beagles.

[0156] After blood sampling, the average PK value of 5 beagle dogs was calculated. Figures 2 to 4 shown.

[0157] Figure 2 is the average PK assay result of G1, Figure 3 is the average PK assay result from G2 to G5. Figure 4 These are the logarithmic scale analysis results for G1 to G5.

[0158] As for G1, since it was taken every day, it was confirmed that a certain PK value continued to be exhibited after 7 days.

[0159] In G3 to G5, it was confirmed that the blood concentration of dutasteride continued to increase, and the maximum blood concentration was shown after 1 week, and then the concentration decreased. However, in G2, since the amount of dutasteride administered was too small, it was confirmed that the release effect of dutasteride was not shown within 3 months.

[0160] The PK test results of G2 to G5 are shown in Table 2 below.

[0161] Table 2

[0162]

[0163]

[0164] According to the measurement results, it was confirmed that the maximum blood concentration of dutasteride was achieved within 2 to 5 weeks.

[0165] Experimental Example 3

[0166] Confirmation of particle properties

[0167] Preparation Example 1 and Preparation Example 2 were coated with mannitol, and it was confirmed whether the mannitol coating was formed. Specifically, after removing the surfactant, the microparticles of Preparation Example 1 and Preparation Example 2 were added with a mannitol aqueous solution to form a mannitol coating on the outside of the microparticles, and then freeze-dried. Figure 5 and Figure 6 As shown, it can be confirmed that the microparticles of Preparation Example 1 and Preparation Example 2 are coated with mannitol.

[0168] On the contrary, Figure 7As shown, the microparticles of Preparation Example 1 which were not coated with mannitol showed aggregation.

[0169] The PSA analysis results of the microparticles prepared in Preparation Examples 1 to 6 are shown in Table 3 below.

[0170] Table 3

[0171]

[0172] Although the preferred embodiments of the present invention are described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concepts of the present invention defined in the claims also fall within the scope of the present invention.

[0173] Industrial Applicability

[0174] The present invention relates to a sustained-release injection composition comprising dutasteride.

Claims

1. A sustained-release injection composition comprising dutasteride, wherein: Contains 8mg to 100mg of dutasteride, The dutasteride is evenly distributed in the microparticles, and after being injected into the body, the microparticles continuously release dutasteride for 3 to 6 months. The average diameter of the microparticles is 30 μm to 90 μm.

2. The sustained-release injection composition comprising dutasteride according to claim 1, wherein: The composition for injection exhibits a maximum blood concentration of dutasteride after being injected into beagle dogs for more than one week.

3. The sustained-release injection composition comprising dutasteride according to claim 2, wherein: The maximum blood concentration value of dutasteride is 200 ng / mL to 2500 ng / mL.

4. The sustained-release injection composition comprising dutasteride according to claim 1, wherein: The microparticles include two or more biodegradable polymers selected from the group consisting of polylactic acid, polylactide, polylactide-co-glycolide, polyphosphazene, polyimidocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate and polyamino acid.

5. The sustained-release injection composition comprising dutasteride according to claim 4, wherein: The biodegradable polymer includes polylactic acid and poly(lactide-co-glycolide) in a weight ratio of 1:1 to 1:

4.

6. The sustained-release injection composition comprising dutasteride according to claim 1, wherein: The microparticles contain dutasteride and a biodegradable polymer in a weight ratio of 1:2 to 1:

5.

7. The sustained-release injection composition comprising dutasteride according to claim 1, wherein: As a result of an accelerated release test under the following conditions, the microparticles released less than 50% by weight of dutasteride after 24 hours. The experimental conditions are: The dissolution test solution used was water containing 1% sodium dodecyl sulfate, and the microparticles were mixed in the dissolution test solution. The dissolution tester used an oscillating water bath. The dissolution test container used a glass test container with a net capacity of 120 ml, and was oscillated at a speed of 120 rpm at a temperature of 45°C.

8. The sustained-release injection composition comprising dutasteride according to claim 1, wherein: The exterior of the microparticles also includes a coating.

9. The sustained-release injection composition comprising dutasteride according to claim 1, wherein: The standard deviation of the particle diameters was 2 to 7.

10. The sustained-release injection composition comprising dutasteride according to claim 1, wherein: The PSA analysis results of the microparticles showed a peak width of 5 to 15.

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