Sustained-release injectable composition containing dutasteride

Abstract

The present invention relates to a sustained-release injectable composition containing dutasteride. Compared with the conventional Avodart (registered trademark) taken once a day, even if the dosage of dutasteride is the same as or less than that of Avodart, it is possible to show a sustained release effect of dutasteride for 3 months or more, and a long-term drug-taking effect can be shown by a single injection. In addition, it can show a therapeutic effect on benign prostatic hyperplasia, prostate cancer, and hair loss continuously for 3 months or more. The microparticles contained in the sustained-release injectable composition have a constant average diameter, can regulate the release of the drug, and maintain a constant effective drug concentration, and can reduce the foreign body sensation and pain when administered to patients as an injection.

Description

Technical Field

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

Background Art

[0002] Dutasteride represented by the following Chemical Formula 1 (Compound: 17β-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-4-aza-5α-androst-1-en-3-one) is a dual 5-α reductase inhibitor that inhibits both type 1 and type 2 of 5-α reductase, and is known to be useful for the treatment of benign prostatic hyperplasia, prostate cancer, and male pattern hair loss by suppressing the conversion of testosterone to dihydrotestosterone (DHT).

[0003]

Chem.

[0004] Dutasteride is currently marketed under the trade name AVODART (registered trademark), and AVODART is a product in which 0.5 mg of dutasteride is dissolved in a mixture of 349.5 mg of caprylic / capric acid mono- and di-glyceride oil and butylated hydroxytoluene (BHT) and filled into soft capsules.

[0005] However, there is a disadvantage in that the amount of excipient constituting the product is relatively large compared to the active ingredient, and the volume of the soft capsule becomes large, which is inconvenient for taking.

[0006] Conventionally, in the case of an oral dosage form containing dutasteride, research has been conducted on measures to reduce the volume to improve the convenience of taking and to improve the dissolution stability.

[0007] That is, there has been an attempt to reduce the volume as in the prior art to improve the convenience of taking, but there is a problem in that the convenience of taking is low in that the dosing time has to be taken daily.

[0008] Therefore, there is an urgent need to develop therapeutic agents for benign prostatic hyperplasia, prostate cancer, and alopecia that can improve the problems of conventional dosage forms containing dutasteride, maintain the drug effect for more than three months with a single administration, and are convenient for storage and handling.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0010] An object of the present invention is to provide a sustained-release injection composition containing dutasteride.

[0011] Another object of the present invention is to be able to exhibit a sustained release effect of dutasteride for more than three months even when the administration dose of dutasteride is the same as or less than that of Avodart (registered trademark) taken once a day, and to provide a sustained-release injection composition containing dutasteride that can exhibit a long-term drug-taking effect by a single injection.

[0012] Another object of the present invention is to be able to exhibit a therapeutic effect on benign prostatic hyperplasia, prostate cancer, and alopecia continuously for more than three months. The microparticles contained in the sustained-release injection composition have a constant average diameter, can regulate the release of the drug, and maintain a constant effective drug concentration, and to provide an injection composition containing sustained-release particles that can reduce the foreign body sensation and pain during administration to patients as an injection.

Means for Solving the Problems

[0013] In order to achieve the above object, the present invention provides a sustained-release injection composition containing dutasteride, which contains 8 mg to 100 mg of dutasteride. The dutasteride is uniformly distributed within the microparticles. After in vivo injection, the microparticles can continuously release dutasteride for 3 to 6 months, and the average diameter of the microparticles is 30 μm to 90 μm.

[0014] After more than 1 week has elapsed after injecting the injection composition into beagle dogs, the maximum blood concentration (C max ) of dutasteride can be shown.

[0015] The maximum blood concentration (C max ) value of the dutasteride is 200 ng / mL to 1,100 ng / mL.

[0016] The microparticles can contain two or more biodegradable polymers selected from the group consisting of polylactic acid, polylactide, poly(lactide-co-glycolide) (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, and polyamino acid.

[0017] The biodegradable polymers can contain polylactic acid and poly(lactide-co-glycolide) (PLGA) in a weight ratio of 1:1 to 1:4.

[0018] The microparticles can contain dutasteride and biodegradable polymers in a weight ratio of 1:2 to 1:5.

[0019] As a result of conducting an accelerated release experiment under the following conditions, the microparticles can release less than 50% by weight of dutasteride after 24 hours: [Experimental conditions] The dissolution test solution used was water containing 1% sodium lauryl sulfate. Micro-particles were mixed into the dissolution test solution. A shaking water bath was used as the dissolution tester, and a glass test container with an internal volume of 120 ml was used as the dissolution experiment container. The mixture was shaken at 45°C and 120 rpm.

[0020] The micro-particles can additionally include a coating layer on the outside.

[0021] The standard deviation (SD) with respect to the diameter of the micro-particles is 2 to 7.

[0022] Based on the PSA analysis results of the micro-particles, the width of the peak is 5 to 15.

Advantages of the Invention

[0023] In addition, the sustained-release injection of the present invention can show a therapeutic effect on benign prostatic hyperplasia, prostate cancer, and hair loss continuously for 3 months or more. The micro-particles contained in the sustained-release injection composition have a constant average diameter, can regulate the release of the drug to maintain a constant effective drug concentration, and can reduce the foreign body sensation and pain when administered to patients as an injection.

Brief Description of the Drawings

[0024]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Mode for Carrying Out the Invention

[0025] The present invention relates to a sustained-release injection composition containing 8 mg to 100 mg of dutasteride, wherein the dutasteride is uniformly distributed within micro-particles, and after in vivo injection, the micro-particles continuously release dutasteride for 3 to 6 months, and the average diameter of the micro-particles is 30 μm to 90 μm.

Examples

[0026] Hereinafter, the embodiments of the present invention will be described in detail so that those having ordinary knowledge in the technical field to which the present invention pertains can easily implement them. However, the present invention can be realized in various different forms and is not limited to the embodiments described herein.

[0027] The present invention relates to a sustained-release injection composition containing dutasteride, and is characterized in that it can exhibit a drug release effect lasting for 3 months or more by a single injection.

[0028] By showing a drug release effect lasting for 3 months or more by a single injection as described above, it is possible to show a therapeutic effect for benign prostatic hyperplasia, prostate cancer, and hair loss, and it can replace conventional products that were taken once a day, greatly improving the convenience of taking.

[0029] In order to achieve the above characteristics, specifically, the sustained-release injection composition containing dutasteride of the present invention contains 8 mg to 100 mg of dutasteride, the dutasteride is uniformly distributed within micro-particles, and after in vivo injection, the micro-particles continuously release dutasteride for 3 to 6 months, and the average diameter of the micro-particles may be 30 to 90 μm.

[0030] The sustained-release injection composition of the present invention contains dutasteride, and is characterized in that the dutasteride contained within a single administration dose is 8 mg to 100 mg.

[0031] In the case of Avodart (AVODART (registered trademark)), which was taken once a day, the dosage form administered once contains 0.5 mg of dutasteride. Judging based on the 84-day administration period (3 months), a total of 42 mg is administered.

[0032] In the present invention, compared with the above-mentioned Avodart (AVODART (registered trademark)), it is characterized in that even if it contains dutasteride at an equivalent level or at a lower dose, the drug can be released continuously for a long time.

[0033] Therefore, the sustained-release injection composition of the present invention is characterized in that after being injected into the body, it continuously releases dutasteride for 3 to 6 months. For example, in the case of a 3-month dosage form, the total sustained-release injection composition can contain 8 mg to 42 mg of dutasteride, can contain 15 mg to 42 mg, and can contain 25 mg to 42 mg. Even when containing dutasteride within the said range, the release effect of dutasteride can be shown continuously for 3 months.

[0034] Also, in the case of a 6-month dosage form, it can contain 16 mg to 84 mg, can contain 30 mg to 84 mg, and can contain 50 mg to 84 mg. Even when containing dutasteride within the said range, the release effect of dutasteride can be shown continuously for 3 months.

[0035] The sustained-release injection composition contains microparticles containing dutasteride, and the microparticles are uniform circular particles with dutasteride uniformly contained therein.

[0036] As described below, the microparticles of the present invention are circular particles having a uniform diameter, and the particles are contained in a plurality of sustained-release injection compositions. By containing particles having a uniform diameter as described above, after being injected into the body, a sustained release effect of dutasteride can be exhibited, and the release time of dutasteride can be adjusted.

[0037] That is, when the particle sizes are not uniform, differences may occur in the rate at which the particles are decomposed in the body, which may cause a problem that the release rate of dutasteride contained in the particles cannot be controlled. Therefore, in the present invention, the release rate of dutasteride can be adjusted by including only particles having a uniform diameter, and the release effect of dutasteride can be continuously exhibited for 3 to 6 months.

[0038] The average diameter of the microparticles is 30 μm to 90 μm, may be 35 μm to 85 μm, or may be 40 μm to 80 μm. By including uniform particles within the above range, excessive release of initial dutasteride injected into the body can be prevented, and after a certain period of time, the release of dutasteride can exhibit the maximum blood concentration and show a sustained release effect of dutasteride for 3 to 6 months.

[0039] Specifically, after more than 1 week has passed after the injection composition is injected into beagle dogs, the maximum blood concentration (C max ) of dutasteride is exhibited. Specifically, the maximum blood concentration (C max ) can be exhibited within 2 to 5 weeks.

[0040] As described above, after the sustained-release injection composition of the present invention is injected into beagle dogs, dutasteride is continuously released. After more than 1 week has passed, the maximum blood concentration (C max ) value of dutasteride is exhibited, and thereafter, the blood concentration of dutasteride decreases steadily and is released for a desired period.

[0041] That is, as in the present invention, in order for dutasteride to be provided as a sustained-release injection composition and exhibit a sustained release effect for 3 to 6 months, after injecting the injection composition into beagle dogs, the blood concentration of dutasteride reaches its maximum blood concentration (C max ) value after 1 week and within 2 to 5 weeks.

[0042] According to the release results of dutasteride as described above, after injecting the injection composition of the present invention into beagle dogs, the degree of dutasteride release decreases within 1 day, that is, within 24 hours. Thereafter, the amount of dutasteride released continuously increases, reaches its maximum value after 1 week and within 2 to 5 weeks, and thereafter, the release amount continuously decreases, and the release of dutasteride is completed in about 3 months, 4 months, 5 months or 6 months.

[0043] More specifically, after injecting the sustained-release injection composition of the present invention into beagle dogs and measuring the blood concentration of dutasteride, as a result, at the time point when 24 hours have elapsed, the maximum blood concentration (C 24h ) of dutasteride may be 4 ng / mL to 40 ng / mL, 5 ng / mL to 38 ng / mL, 6 ng / mL to 35 ng / mL, or 8 ng / mL to 32 ng / mL.

[0044] Also, after 1 week or more has elapsed, the maximum blood concentration (C max ) of dutasteride may be 200 ng / mL to 2,500 ng / mL, 400 ng / mL to 2,500 ng / mL, or 500 ng / mL to 2,500 ng / mL. The maximum blood concentration (C max ) of the dutasteride may vary depending on whether the sustained-release injection composition of the present invention is a 3-month formulation, 4-month formulation, 5-month formulation or 6-month formulation. Specifically, in the case of the 3-month formulation, the maximum blood concentration (C max) may be 500 ng / mL to 1,100 ng / mL. That is, in order to provide a dosage form that releases dutasteride more continuously for a longer period of time, the content of dutasteride contained in the injectable composition increases. As a result, when the injectable composition is administered to beagle dogs, the maximum blood concentration (C max ) can also change.

[0045] According to the results of analyzing the concentration of dutasteride in the blood after injecting the sustained-release injectable composition of the present invention into the beagle dogs, the amount of dutasteride released within 24 hours decreases, and it is clearly confirmed that the maximum blood concentration (C max ) is shown when more than 1 week has passed. When showing the concentration value of dutasteride in the blood as described above, it is possible to show a continuous dutasteride release effect for 3 months or more, and for 3 to 6 months.

[0046] The microparticles contain two or more biodegradable polymers selected from the group consisting of polylactic acid, polylactide, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, and polyamino acid. Specifically, polylactic acid and polylactide-co-glycolide can be included as biodegradable polymers.

[0047] When producing microparticles containing two or more biodegradable polymers as described above, by using biodegradable polymers with different biodegradation periods, it is possible to show the effect of releasing dutasteride by decomposing over a desired period.

[0048] That is, when using one type of biodegradable polymer, if only a biodegradable polymer with a short biodegradation period is used, the dutasteride release effect can only be shown for a short period.

[0049] In addition, when using a biodegradable polymer with a long biodegradation period, although it can exhibit a longer release effect of dutasteride, there is a problem that the initial release degree of dutasteride administered as an injection is too small and it is difficult to exert the medicinal effect of dutasteride. That is, in order to exhibit the medicinal effect of dutasteride in the body, the concentration value of dutasteride in the blood must be above a certain level. However, when using a biodegradable polymer with a long biodegradation period, there is a problem that the degree of degradation is small in the initial stage when it is introduced into the body as an injection, and it is difficult to exert the medicinal effect of dutasteride.

[0050] The biodegradable polymer contains polylactic acid and polylactide-co-glycolide (PLGA) in a weight ratio of 1:1 to 1:4, and can contain them in a weight ratio of 1:2 to 1:3. When mixed and used in the above weight ratio, it can exhibit the release effect of dutasteride for a desired period as described above.

[0051] The micro-particles can contain dutasteride and the biodegradable polymer in a weight ratio of 1:2 to 1:5, in a weight ratio of 1:2 to 1:4, and in a weight ratio of 1:2 to 1:3. When mixed and used within the above range, dutasteride can be continuously released for a long time due to the degradation of the biodegradable polymer.

[0052] As a result of conducting an accelerated release experiment on the micro-particles under the following conditions, it is possible to release less than 50% by weight of dutasteride after 20 hours: [Experimental conditions] The elution test solution uses water containing 1% sodium lauryl sulfate. The micro-particles are mixed into the elution test solution. A shaking water bath is used as the elution tester. A glass test container with an internal volume of 120 ml is used as the elution experiment container, and it is shaken at a speed of 120 rpm at 45°C.

[0053] The accelerated release experiment is an experiment for confirming the duration of drug release after manufacturing particles containing a drug using a biodegradable polymer. That is, it is an experiment for indirectly confirming whether the drug can be continuously released for a long time.

[0054] In the present invention, as a result of conducting the accelerated release experiment under the above conditions, at the time point when 20 hours have elapsed, dutasteride is released at less than 50% by weight.

[0055] As described above, due to the results of the accelerated release experiment, the micro-particles of the present invention maintain the release degree of dutasteride at less than 50% by weight at the time point when 20 hours have elapsed, and can continuously exhibit the release effect of dutasteride for 3 to 6 months.

[0056] The reason why the release degree of dutasteride as described above can be adjusted is that two or more biodegradable polymers are included in manufacturing the micro-particles. As will be described later, when only one type of biodegradable polymer is used, it can be confirmed that the release effect of 70% by weight or more of dutasteride is exhibited at the time point when 20 hours have elapsed. That is, when manufacturing micro-particles containing dutasteride using only one type of biodegradable polymer, there may occur a problem that the continuous release effect of dutasteride for 3 to 6 months as in the present invention cannot be exhibited.

[0057] On the other hand, the micro-particles of the present invention can exhibit a long-term continuous release effect of dutasteride in that the time point when 80% by weight of dutasteride is released is after 50 hours or 70 hours or more have elapsed.

[0058] The micro-particles can additionally include a coating layer on the outside. The coating layer may be formed by coating with mannitol. When forming a coating layer on the surface of the micro-particles with mannitol as described above, during filling for use as an injection, the flowability can be improved, and only the micro-particles to the desired degree can be efficiently filled. Further, the micro-particles having a coating layer formed with mannitol as described above do not exhibit agglomeration phenomena between particles during lyophilization.

[0059] In contrast, micro-particles without a coating layer may exhibit agglomeration phenomena as shown in FIG. 7 during lyophilization. Also, the flowability is poor during filling, and differences may occur in the degree of inclusion of micro-particles.

[0060] As described above, the micro-particles 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. Also, the standard deviation (SD) with respect to the average diameter of the micro-particles may be 2 to 7. The standard deviation (SD) means the degree of distribution of the average diameter, and it can be said that a very small standard deviation (SD) means having a uniform particle size.

[0061] Also, based on the PSA analysis results, the width of the peak may be 5 to 15. The width of the peak means the width of each peak (= width up to 16% to 84%), and as described later, the micro-particles produced by the manufacturing method of the present invention do not show multiple peaks in the PSA analysis. It can be said that it means that the produced micro-particles themselves are very uniform.

[0062] By including uniform particles within the above range, excessive release of the initially injected dutasteride in the body can be prevented, and by the release of dutasteride after a certain time has passed, the maximum blood concentration can be shown, and a continuous dutasteride release effect for 3 to 6 months can be shown.

[0063] A method for manufacturing a sustained-release injection composition containing dutasteride according to another embodiment of the present invention includes: 1) mixing dutasteride and a biodegradable polymer to produce an oil-phase solution; 2) dissolving a surfactant in a solvent to produce an aqueous-phase solution; 3) injecting the oil-phase solution and the aqueous-phase solution into a first microchannel and a second microchannel where intersections are formed, respectively, and flowing them so that micro-particles are generated at the intersections; 4) collecting the micro-particles in a water tank containing the aqueous-phase solution; 5) removing the organic solvent present in the collected micro-particles; 6) washing and drying the micro-particles from which the organic solvent has been removed with purified water; and 7) mixing the dried micro-particles with a suspension solution.

[0064] The step 1) is a step of producing an oil-phase solution, in which dutasteride and a biodegradable polymer are dissolved in an organic solvent to produce an oil-phase solution. The biodegradable polymer may be two or more selected from the group consisting of polylactic acid, polylactide, poly(lactide-co-glycolide) (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, and polyamino acid, and preferably, poly(lactide-co-glycolide) (PLGA) and polylactide (PLA), but not limited to the above examples.

[0065] Also, the organic solvent is immiscible with water, and for example, any one or more selected from the group consisting of chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof, and preferably, dichloromethane, but not limited to this example. As an organic solvent capable of dissolving a biodegradable polymer and dutasteride, it can be said that not only the above examples but also any organic solvent that can be easily selected by those skilled in the art can be used.

[0066] The step 1) is to produce an oil-phase solution in which dutasteride and a biodegradable polymer are dissolved. As described above, an organic solvent is used as the solvent. This is to completely dissolve them using an organic solvent by taking advantage of the dissolution characteristics of dutasteride and the biodegradable polymer.

[0067] In the oil-phase solution, the weight ratio of dutasteride to the biodegradable polymer may be 1:2 to 1:5, 1:2 to 1:4, or 1:2 to 1:3. When mixed and used within the above range, dutasteride can be continuously released for a long time due to the degradation of the biodegradable polymer.

[0068] When the weight ratio of dutasteride to the biodegradable polymer is less than 1:1, that is, when the biodegradable polymer is contained in an amount less than the above weight ratio, the weight ratio of the biodegradable polymer is small compared to the weight of dutasteride, and it is difficult to produce sustained-release particles in which dutasteride is uniformly distributed and contained in spherical biodegradable polymer particles. When the weight ratio of the biodegradable polymer to dutasteride exceeds 1:5, that is, when the biodegradable polymer is contained in an amount exceeding the above weight ratio, the content of dutasteride in the sustained-release particles is small, and a problem may occur in that a large amount of sustained-release particles must be administered for drug administration at a desired concentration.

[0069] More specifically, the biodegradable polymer in the oil-phase solution contains 15 to 25% by weight, preferably 20% by weight, but is not limited to the above example.

[0070] The step (2) is to produce an aqueous solution by dissolving a surfactant in water. The surfactant can be used without limitation as long as it can assist in forming a stable emulsion of the oil phase solution in which the biodegradable polymer and dutasteride are dissolved. Specifically, it is any one or more selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof. More specifically, it is any 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, ester amine, linear diamine, patiamine, and mixtures thereof. Preferably, it is polyvinyl alcohol, but not limited to this example.

[0071] The surfactant contained in the aqueous 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 all water.

[0072] The step (3) is to inject and flow the oil phase solution and the aqueous solution into the microchannels formed on the wafer.

[0073] More specifically, the microchannels can be formed of a material selected from the group consisting of a silicon wafer or a polymer film. However, the examples of the material are not limited to the above examples, and any material capable of forming microchannels can be used.

[0074] The polymer film can be selected from the group consisting of, but not limited to the examples, polyimide, polyethylene, fluorinated ethylene propylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polysulfone, and mixtures thereof.

[0075] 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. Thereafter, aluminum etching is performed using the photoresist as a mask, and after removing the photoresist, silicon is etched by DRIE (deep ion reactive etching) using the aluminum as a mask. After removing the aluminum, glass is anodically bonded and sealed onto the wafer to manufacture the microchannel.

[0076] The average diameter of the microchannels varies depending on whether it is a 7-channel chip or a 140-channel chip. The microchannels for manufacturing the micro-particles of the present invention use a 140-channel chip. In the case of the 140-channel chip, the average diameter of the channels when the oil-phase solution and the water-phase solution are injected into the microchannels is 300 μm to 500 μm. After the oil-phase solution and the water-phase solution move through each channel, they pass through the resistance channels. The average diameter of the resistance channels is 10 μm to 50 μm. After passing through the resistance channels, they pass through the intersecting junction channels between the oil-phase solution and the water-phase solution. The diameter of the junction channels may be 50 μm to 150 μm. After the oil-phase solution and the water-phase solution intersect in the junction channels 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. When the average diameter of the junction channels is 50 μm or less, sustained-release particles with a diameter of less than 30 μm may be produced, which may affect the effective drug release and in-vivo absorption. Also, when the average size of the produced sustained-release particles exceeds 100 μm, the foreign body sensation and pain may increase during administration as an injection, and the particle size distribution of the produced particles becomes larger, making it difficult to produce sustained-release particles with a uniform particle size.

[0077] However, the average diameter of the microchannels can be changed according to the range of the injection pressure. Also, the average diameter of the microchannels is closely related to the average diameter of the particles, but is also closely related to the injection pressures of the oil-phase solution and the water-phase solution.

[0078] In the step (3), the oil-phase solution and the water-phase solution are flowed under the injection pressure conditions into the first microchannel and the second microchannel where intersections are formed.

[0079] That is, the oil-phase solution flows along the first microchannel, and the water-phase solution flows along the second microchannel formed to intersect with the first microchannel so as to meet the flow of the oil-phase solution.

[0080] More specifically, when injecting the oil-phase solution into the first microchannel, after injection under a pressure condition of 200 to 800 mbar, the pressure is increased under the first condition of 1 to 5 mbar / min. When the injection pressure condition reaches 500 to 1,000 mbar, the pressure can be increased under the second condition of 1 to 5 mbar / min.

[0081] Also, when injecting the oil-phase solution into the first microchannel, the water-phase solution can be injected into the second microchannel under a pressure condition 4 to 12 times that of the pressure condition comparison.

[0082] Specifically, in the manufacturing method using the microchannel, when the flow rates of the oil-phase solution and the water-phase solution flowing inside the microchannel are set to constant values using a flow meter and the pressure is measured by feedback control, it was confirmed that the pressure required for the oil-phase solution to flow through the microchannel at a constant flow rate gradually increases with time.

[0083] Therefore, by using a method of constantly increasing the pressure applied to the oil-phase solution, the variability of the flow rate is minimized. As the oil-phase solution gradually hardens inside the microchannel, problems such as non-uniform micro-particle distribution or channel blockage can be prevented, and the production yield of the target micro-particles can be increased.

[0084] Also, the pressure conditions when injecting the oil-phase solution and the water-phase solution into the microchannel are for adjusting the average diameter of the manufactured micro-particles. If the above range cannot be specifically satisfied, problems such as non-uniform size of the manufactured particles, failure to satisfy the average diameter range of the micro-particles of the present invention, or failure to satisfy the value of Formula 1 may occur.

[0085] 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 higher flow rate than the flow of the oil-phase solution injected into the microchannel, the aqueous solution is caused to flow under higher pressure conditions.

[0086] 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 at the point where the flow of the oil-phase solution and the flow of the aqueous solution meet compresses the oil-phase solution. At this time, the biodegradable polymer and dutasteride in the oil-phase solution generate spherical microparticles due to the repulsive forces of the oil-phase solution and the aqueous solution. More specifically, microparticles in a form in which dutasteride is uniformly distributed in the spherical biodegradable polymer are formed.

[0087] The step 4) is a step of collecting microparticles. The microparticles are collected in a water tank containing the aqueous solution to prevent the aggregation phenomenon between the initially generated microparticles.

[0088] The step 4) uses the aqueous solution produced in the step 2), that is, a mixed solution of a surfactant and water. After the aqueous solution is produced in the step 2), a part of it is injected into the microchannel, and the other part is moved to the water tank in the step 4) and used to prevent the aggregation phenomenon between the collected microparticles.

[0089] The step 5) is a step for removing the organic solvent present in the microparticles collected in the water tank. The mixture is stirred under certain temperature conditions and stirring speed to evaporate and remove the organic solvent present on the surface of the sustained-release particles. At this time, the stirring conditions include: 5-1) a step of primary stirring at 15 to 20 °C for 20 to 40 minutes at a speed of 100 to 300 rpm; 5-2) a step of secondary stirring at 30 to 40 °C for 60 to 120 minutes at a speed of 100 to 300 rpm; and 5-3) a step of tertiary stirring at 40 to 45 °C for 4 to 8 hours at a speed of 100 to 300 rpm.

[0090] The stirring speed is such that in the primary and secondary stirring stages, the stirring process is carried out while varying the temperature conditions and the stirring progress time.

[0091] As described above, it is characterized in that the temperature condition is raised in the secondary stirring process compared to the primary stirring process and stirring is carried out, and by raising the temperature stepwise, the evaporation rate of the organic solvent present on the surface of the microparticles can be adjusted. That is, the organic solvent present on the surface of the microparticles can be gradually evaporated to produce microparticles.

[0092] The temperature when the oil-phase solution and the water-phase solution flow through the microchannel is also 15 to 20 °C, preferably 17 °C. That is, after flowing through the microchannel, forming an intersection and generating microparticles, the temperature is kept low at 15 to 20 °C constantly until the collected microparticles are subjected to primary stirring. Only by maintaining a low temperature during the production process of the microparticles can spherical particles be produced and maintained. That is, when the temperature condition is not low, there will be a problem that it is difficult to produce certain spherical particles.

[0093] Thereafter, in the secondary stirring process and the tertiary stirring process, the temperature is gradually raised and the stirring time is extended so that the organic solvent present on the surface of the microparticles gradually evaporates. By evaporating the organic solvent on the surface, the influence on the surface of the microparticles can be minimized. That is, when the organic solvent evaporates rapidly, there may be a problem that the surface of the microparticles becomes rough instead of smooth due to the evaporation of the organic solvent. To prevent such a problem, as described above, the temperature condition is gradually raised and the time for carrying out the stirring process is also increased to adjust the evaporation rate of the organic solvent, and by adjusting the evaporation rate of such an organic solvent, the surface roughness of the produced microparticles can be controlled.

[0094] Finally, the step 6) is a step of washing and drying the microparticles. The microparticles obtained by stirring to remove all the organic solvent on the surface are washed several times with purified water subjected to sterile filtration to remove the surfactant remaining in the microparticles.

[0095] The remaining surfactant-removed microparticles can form a coating layer using a mannitol aqueous solution. Specifically, a mannitol aqueous solution can be added to the surfactant-removed microparticles to form a mannitol coating layer outside the microparticles, and then lyophilized.

[0096] The finally produced microparticles are in a form in which dutasteride is uniformly distributed in the spherical biodegradable polymer microparticles, and can contain dutasteride and the biodegradable polymer in a weight ratio of 1:2 to 1:5.

[0097] The weight ratio of dutasteride and the biodegradable polymer contained in the microparticles is the same as the weight ratio in the oil phase solution. This is because by manufacturing the microparticles and evaporating and removing all the organic solvents, microparticles containing dutasteride and the biodegradable polymer in the same ratio as the weight ratio in the oil phase solution can be produced.

[0098] The produced microparticles can be mixed with a suspension solvent to produce an injectable composition.

[0099] The suspension solvent contains an isotonic agent, a suspending agent, and a solvent.

[0100] More specifically, the isotonic agent can be selected from the group consisting of D-mannitol, maltitol, sorbitol, lactitol, xylitol, sodium chloride, and mixtures thereof, and preferably D-mannitol, but is not limited to the above examples.

[0101] The suspending agent is selected 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, preferably sodium carboxymethylcellulose and polysorbate 80, but not limited to the above examples.

[0102] As the solvent, injection water can be used, and all solvents that can be used as injection water can be used without limitation.

[0103] Production Example 1 Production of Microspheres Containing Dutasteride Dutasteride, PLGA, and PLA were dissolved in dichloromethane to prepare an oil-phase solution. The biodegradable polymers in the oil-phase solution may contain PLGA and PLA in a weight ratio of 2:1, and dutasteride and the biodegradable polymers may be contained in a weight ratio of 1:3.

[0104] Polyvinyl alcohol, a surfactant, was mixed with water to prepare an aqueous solution containing 0.25% by weight of polyvinyl alcohol.

[0105] The oil-phase solution and the aqueous-phase solution were injected into and flowed through the microchannels formed on the silicon wafer.

[0106] At this time, in order to flow the oil-phase solution and the aqueous-phase solution at a constant flow rate, the oil-phase solution was flowed under the condition that the pressure was constantly increased at a rising rate of 2 mbar per minute starting from a pressure condition of 650 mbar, and the aqueous-phase solution was made to flow under a pressure condition of 2800 mbar. The temperature condition was 17 °C, and the stirring speed was maintained at 300 rpm.

[0107] The micro-particles generated at the intersection where the flow of the oil-phase solution and the flow of the aqueous-phase solution met were collected in a water tank containing the aqueous-phase solution. The micro-particles collected in the water tank were first stirred at 17 °C for 30 minutes at a speed of 300 rpm, the temperature was raised to 35 °C, and then secondarily stirred at a speed of 400 rpm for 1 hour. Thereafter, the temperature was raised to 43 °C, and then tertiarily stirred at a speed of 500 rpm for 5 hours.

[0108] The micro-particles after completion of stirring were washed several times with sterilized filtered purified water and freeze-dried to produce micro-particles with an average diameter (D 50 ) of 40 μm.

[0109] Production Example 2 Micro-particles were produced in the same manner as in Production 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 were contained in a weight ratio of 1:2.

[0110] Production Example 3 Micro-particles were produced in the same manner as in Production Example 1, except that only PLGA was used as the biodegradable polymer.

[0111] Production Example 4 Production was carried out in the same manner as in Production Example 3, except that the average diameter of the micro-particles was 80 μm.

[0112] Production Example 5 Production was carried out in the same manner as in Production Example 1, except that the average diameter of the micro-particles was 80 μm.

[0113] Production Example 6 It was produced in the same manner as in Production Example 2, except that the average diameter of the microparticles was 80 μm.

[0114] Experimental Example 1 Accelerated release experiment As the elution test solution, water containing 1% sodium lauryl sulfate was used. The microparticles were mixed into the elution test solution, and a shaking water bath was used as the elution tester. A glass test container with an internal volume of 120 ml was used as the elution experiment container, and it was shaken at 45°C at a speed of 120 rpm.

[0115] The results of conducting the accelerated release experiment on the microparticles of Production Examples 1 to 6 in Examples 1 to 6 are as shown in FIG. 1.

[0116] According to the above experiment, when only PLGA, a kind of biodegradable polymer, was used, it was confirmed that the release degree of dutasteride already exceeded 50% at the time point after 24 hours. In light of the above results, in the cases of Example 3 and Example 4, there is a problem that microparticles containing only PLGA are used, and when this is used, it is difficult to show a continuous release effect for 3 to 6 months.

[0117] On the other hand, in Example 1, Example 2, Example 5, and Example 6, it can be confirmed from the accelerated release experiment results that the time point when 90% or more is released starts after 72 hours or close to 100 hours.

[0118] Also, Example 1 and Example 5 and Example 2 and Example 6 only differ in the average diameter of the particles, and it can be confirmed that the larger the diameter of the particles, the more delayed the release rate of dutasteride.

[0119] Experimental Example 2 Pharmacokinetic property evaluation The microparticles of Production Example 1 were added to 1.5 ml of a suspension solvent per vial and then uniformly suspended to produce a composition for subcutaneous injection.

[0120] The suspension solvent was composed of the composition as shown in Table 1 below.

[0121]

Table 1

[0122] When producing a composition for subcutaneous injection using the microparticles of Production Example 1, the weight of dutasteride contained in the injection composition was produced to contain 8.4 mg (G2), 25.2 mg (G3), and 42 mg (G4).

[0123] The microparticles of Production Example 2 were added to the suspension solvent as described above to produce a composition for subcutaneous injection (G5).

[0124] As a comparative example (G1), Avodart (registered trademark) (GSK) soft capsules 0.5 mg were used.

[0125] 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 injection compositions of G2 to G5 were administered to 5 beagle dogs each, and the administration route was the subcutaneous injection method. For G1, 5 beagle dogs were allowed to ingest it once at the same time every day.

[0126] After blood collection, the average value of PK for 5 beagle dogs was calculated. The experimental results are as shown in FIGS. 2 to 4.

[0127] FIG. 2 shows the average PK measurement results for G1, FIG. 3 shows the average PK measurement results for G2 to G5. FIG. 4 shows the analysis results on a log scale for G1 to G5.

[0128] In the case of G1, it can be confirmed that after 7 days, it continuously shows a constant PK value in terms of the daily administration method.

[0129] In the case of G3 - G5, it can be confirmed that the blood concentration of dutasteride continuously increases, shows the maximum blood concentration after 1 week, and then the concentration decreases. However, in the case of G2, it can be confirmed that the content of the administered dutasteride is excessively low and the release effect of dutasteride does not appear for 3 months.

[0130] The PK measurement results for the above - mentioned G2 - G5 are as shown in Table 2 below.

[0131]

Table 2

[0132] According to the above - mentioned measurement results, it can be confirmed that the maximum blood concentration of dutasteride is shown between 2 weeks and 5 weeks.

[0133] Experimental Example 3 Study on the properties of micro - particles In Production Examples 1 and 2, mannitol coating was carried out and the presence or absence of the formation of the mannitol coating layer was confirmed. Specifically, after removing the surfactant from the micro - particles of Production Examples 1 and 2, an aqueous mannitol solution was added to form a mannitol coating layer outside the micro - particles, and then freeze - dried. It can be confirmed that the micro - particles of Production Examples 1 and 2 have a mannitol coating layer as shown in Figures 5 and 6.

[0134] In contrast, for the micro - particles of Production Example 1 without mannitol coating, agglomeration phenomenon occurred as shown in Figure 7.

[0135] The PSA analysis results for the micro - particles produced in Production Examples 1 - 6 are as shown in Table 3 below.

[0136]

Table 3

[0137] As described above, the preferred embodiments of the present invention have been described in detail. However, the scope of the rights of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concept of the present invention defined in the following claims also belong to the scope of the rights of the present invention.

Industrial Applicability

[0138] The present invention relates to a sustained-release injection composition containing dutasteride.

Claims

1. Containing 8 mg to 100 mg of dutasteride, the dutasteride is uniformly distributed within the microparticles, and after the microparticles are injected into the body, the dutasteride is continuously released for 3 to 6 months, the average diameter of the microparticles is 30 μm to 90 μm, A sustained-release injection composition containing dutasteride.

2. After more than one week has passed after the injection composition is injected into beagle dogs, the maximum blood concentration (C ｍａｘ ) is shown, A sustained-release injection composition containing the dutasteride according to Claim 1.

3. The maximum plasma concentration (C ｍａｘ ) value of the dutasteride is from 200 ng / mL to 2,500 ng / mL, A sustained-release injection composition containing the dutasteride according to Claim 2.

4. The microparticles contain two or more biodegradable polymers selected from the group consisting of polylactic acid, polylactide, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, and polyamino acid, A sustained-release injection composition containing the dutasteride according to Claim 1.

5. The biodegradable polymer contains polylactic acid and polylactide-co-glycolide (PLGA) in a weight ratio of 1:1 to 1:4, A sustained-release injection composition containing the dutasteride according to Claim 4.

6. The microparticles contain dutasteride and a biodegradable polymer in a weight ratio of 1:2 to 1:5, A sustained-release injection composition containing the dutasteride according to Claim 1.

7. As a result of conducting an accelerated release experiment under the following conditions, less than 50% by weight of dutasteride is released after 24 hours, A sustained-release injection composition containing the dutasteride according to Claim 1: [Experimental conditions] The elution test solution uses water containing 1% sodium lauryl sulfate. The microparticles are mixed into the elution test solution. A shaking water bath is used as the elution tester. A glass test container with an internal volume of 120 ml is used as the elution experiment container, and it is shaken at a speed of 120 rpm at 45°C.

8. The microparticles additionally contain a coating layer on the outside, A sustained-release injection composition containing the dutasteride according to Claim 1.

9. The standard deviation (SD) with respect to the diameter of the microparticles is 2 to 7, A sustained-release injection composition containing the dutasteride according to Claim 1.

10. Based on the PSA analysis result of the microparticles, the width of the peak is 5 to 15, A sustained-release injection composition comprising the dutasteride according to claim 1.

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