Microparticles containing moxidectin and sustained-release injectable composition containing the same

Abstract

The present invention relates to microparticles containing moxidectin and a method for producing the same, which, unlike conventional heartworm preventive drugs that have a short half-life and must be administered daily or monthly, when microparticles containing moxidectin are administered, moxidectin is continuously released for more than three months, thereby maintaining the preventive effect against heartworms. In addition, by producing microparticles with a constant average particle diameter and a narrow diameter distribution, it is possible to prevent initial excessive release of moxidectin even when the microparticles are administered, and to control the release of the drug to maintain a constant concentration of effective moxidectin for more than three months, thereby reducing foreign body sensation and pain when the injection is administered.

Description

[Technical Field]

[0001] The present invention relates to microparticles containing moxidectin and sustained-release injectable compositions containing the same. [Background technology]

[0002] Heartworm disease (HWD) is caused by a parasite called Dirofilaria immitis, transmitted by mosquitoes, and infects dogs, cats, and weasels. As the name suggests, heartworm parasites infect the hearts of mammals.

[0003] Adult heartworms can grow up to 30 cm in length and primarily parasitize the pulmonary artery and right ventricle. Mature male and female heartworms produce very small larvae called microfilariae (L1). These larvae parasitize the blood of infected animals and are transmitted to other animals by mosquitoes. After two weeks in a mosquito's body, L1 larvae become infectious, and these infectious larvae can then be transmitted to other animals by mosquitoes. The larvae that infect other animals go through several stages of development and migrate to the pulmonary artery after 3-4 months. Thus, mature adult heartworms can survive for an average of 5-7 years, and both male and female heartworms produce a large number of larvae through reproduction.

[0004] Infected animals can have as few as one to as many as 200 heartworms in their hearts and pulmonary arteries. The infection causes the pulmonary arteries to thicken and become inflamed, forcing the heart to work harder to pump blood to the lungs while avoiding the heartworms. Inflammation also occurs in the lungs. When the number of heartworms is small, there may be no particular symptoms, but generally, infected animals may show initial symptoms such as avoidance of exercise, coughing, and weight loss. In severe cases, symptoms such as severe coughing, difficulty breathing, and heart failure may appear. When infected animals exhibit these symptoms, they may die from heart failure.

[0005] If a diagnosis confirms infection with heartworm, treatment can be carried out using arsenic drugs (caparsolates) to kill the adult heartworms or melarsomine. However, both of these treatments cause severe irritation at the injection site and can lead to some degree of liver and kidney damage as side effects.

[0006] Therefore, preventing heartworm infection before it occurs is economical and safe. Prevention should be given between 6 and 8 weeks of age. Heartworm preventives include diethylcarbamazine (DEC), which is given daily, or ivermectin, milbemycin, moxidectin, and selamectin, which are given monthly. While all preventives are highly effective when administered correctly, the fact that they must be given daily or monthly means that even a few missed doses expose the dog to the risk of infection.

[0007] Therefore, there is an urgent need to develop a canine heartworm preventative drug that uses moxidectin, which can prevent heartworm infestation, and maintains its efficacy for more than three months with a single dose, thereby improving the convenience of administration. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Korean Published Patent No. 10-2006-0005472 [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] The object of the present invention is to provide microparticles containing moxidectin and sustained-release injectable compositions containing the same.

[0010] Another object of the present invention is to provide microparticles containing moxidectin that, unlike conventional heartworm preventatives which have a short half-life and must be administered regularly every month, allow for the sustained release of moxidectin for more than three months when administered, thereby maintaining a preventative effect against heartworm in dogs.

[0011] Another object of the present invention is to provide a sustained-release injectable composition containing moxidectin that prevents initial excessive release of moxidectin even when the microparticles are administered, controls drug release to maintain a constant concentration of moxidectin that is effective for more than three months, and reduces foreign body sensation and pain when the injectable preparation is applied. [Means for solving the problem]

[0012] To achieve the above objective, the microparticles containing moxidectin according to the present invention are microparticles containing moxidectin and a biodegradable polymer, wherein the intrinsic viscosity of the biodegradable polymer is 0.1 dl / g to 1 dl / g, and the average diameter of the microparticles may be 60 to 110 μm.

[0013] The microparticles are spherical and can uniformly contain moxidectin.

[0014] The coefficient of variation (CV) of the microparticles may be between 5% and 20%.

[0015] The microparticles may contain a biodegradable polymer and moxidectin in a weight ratio of 2:1 to 12:1.

[0016] The aforementioned microparticles can continuously release moxidectin for more than three months.

[0017] The biodegradable polymer may be selected from the group consisting of polylactide (PLA), polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and mixtures thereof.

[0018] The micro-particles may be 0.3 to 3 according to the following formula 1. [Formula 1] C max-peak n / C max―peak n+1

[0019] Here, Micro-particles containing moxidectin were mixed into a suspension solution to produce an injection, and the injection was administered to beagle dogs, and the blood concentration of moxidectin was measured. C max-peak n is the injection input and is the n-th Cmax value, C max-peak n+1 is the (n + 1)-th Cmax value due to the blood concentration of moxidectin increasing again after the n-th Cmax value.

[0020] The sustained-release injection composition containing moxidectin according to another embodiment of the present invention may include the micro-particles containing moxidectin and a suspension solution.

Advantages of the Invention

[0021] Different from the conventional canine filarial worm preventive drug with a short half-life that had to be administered regularly every month, when micro-particles containing moxidectin are administered, moxidectin is released continuously for more than 3 months, and the preventive effect against canine filarial worms can be maintained.

[0022] Furthermore, by manufacturing microparticles with a smooth particle texture, a uniform average particle diameter, and a narrow diameter distribution, it is possible to prevent initial excessive release of moxidectin when these microparticles are administered, control drug release, maintain a constant concentration of moxidectin that is effective for more than three months, and reduce foreign body sensation and pain when the injectable preparation is administered. [Brief explanation of the drawing]

[0023] [Figure 1] These are experimental results regarding the moxidectin release pattern of microparticles according to one embodiment of the present invention. [Figure 2] These are experimental results regarding the moxidectin release pattern of microparticles according to one embodiment of the present invention. [Figure 3] These are experimental results regarding the moxidectin release pattern of microparticles according to one embodiment of the present invention. [Figure 4] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 5] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 6] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 7] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 8] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 9] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 10] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 11] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 12] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 13] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 14]This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 15] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 16] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 17] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 18] This is a SEM image of microparticles according to one embodiment of the present invention. [Figure 19] This shows the results regarding the blood moxidectin concentration measured after administering an injectable formulation containing microparticles according to one embodiment of the present invention to beagle dogs. [Modes for carrying out the invention]

[0024] The present invention relates to microparticles containing moxidectin and a biodegradable polymer, wherein the intrinsic viscosity of the biodegradable polymer is 0.1 dl / g to 1 dl / g, and the average diameter of the microparticles is 60 to 110 μm. [Examples]

[0025] Hereinafter, embodiments of the present invention will be described in detail so that they can be easily implemented by a person with ordinary skill in the art to which the present invention pertains. However, the present invention can be realized in various different forms and is not limited to the embodiments described herein.

[0026] Microparticles containing moxidectin according to one embodiment of the present invention are microparticles containing moxidectin and a biodegradable polymer, the intrinsic viscosity of the biodegradable polymer is 0.1 dl / g to 1 dl / g, and the average diameter of the microparticles may be 60 to 110 μm.

[0027] The moxidectin of this invention refers to a compound represented by the following chemical formula 1, and means a substance used as a preventative measure against heartworm in animals.

[0028] [ka]

[0029] The microparticles are characterized by being spherical and having a smooth surface.

[0030] Furthermore, the microparticles contain a biodegradable polymer and moxidectin, and are characterized by a uniform mixture of the biodegradable polymer and moxidectin, with moxidectin uniformly distributed within the microparticles.

[0031] The microparticles are used in the form of an injectable agent and can be injected into an animal's body. Once injected into the animal's body, the microparticles release moxidectin gradually as the biodegradable polymer is broken down.

[0032] The release of moxidectin by the microparticles of the present invention occurs when the biodegradable polymer on the surface is broken down, and moxidectin is released. Subsequently, as multiple holes are formed inside the microparticles, the moxidectin contained inside the microparticles can be released into the animal's body.

[0033] As a result of the release of moxidectin as described above, the microparticles of the present invention can release moxidectin in the body of an animal for more than 3 months, and preferably can continuously release moxidectin for 6 months or 12 months.

[0034] The release of moxidectin may be at or above the concentration range required for the treatment or prevention of heartworm in dogs. That is, it does not simply mean a prolonged release of moxidectin, but rather a sustained release at or above a blood concentration that is substantially sufficient to exert the therapeutic effect of moxidectin.

[0035] As described above, the ability of the microparticles of the present invention to exhibit sustained moxidectin release and preventive effects against heartworm is due to the average diameter of the microparticles explained earlier, the coefficient of variation (CV) described later, and the intrinsic viscosity of the biodegradable polymer.

[0036] The microparticles of the present invention may have an average diameter of 60 to 110 μm, 60 to 100 μm, or 70 to 100 μm. When used within the above range, they can exhibit a moxidectin release effect for a desired period, can be administered by injection without causing a foreign body sensation, and can prevent absorption by macrophages in the body.

[0037] The aforementioned microparticles may have a coefficient of variation (CV) of 5% to 20%, 6% to 19%, 7% to 18.5%, or 8% to 18.5%. The coefficient of variation is a value that indicates the monodispersity of the particle size distribution diagram, and a smaller CV value means that the particle size is more uniform.

[0038] The coefficient of variation can be calculated using the following equation 2. [Formula 2] (Standard deviation of diameter / Mean diameter) * 100

[0039] By including microparticles having a coefficient of variation within the aforementioned range, the release pattern of moxidectin can be controlled. Furthermore, as described later, when manufactured by the method for producing microparticles of the present invention, it is possible to produce microparticles of uniform size, thereby enabling the production of microparticles containing different biodegradable polymers, which can then be mixed and used.

[0040] As explained earlier, microparticles containing drugs such as moxidectin can release the drug when the biodegradable polymer is broken down in the body. Therefore, the microparticles must be of a uniform size to continuously release the drug for the desired period.

[0041] Specifically, when microparticles are distributed across a variety of sizes, smaller microparticles may be rapidly broken down in the body or fail to release drugs due to macrophages. In other words, even if small microparticles release drugs, they only act initially in the body, making long-term drug release impossible.

[0042] Furthermore, if the microparticles are large, the initial drug release effect may be minimal, and the drug may be released for an excessively long period of time. The microparticles are intended to release the drug for a desired period of time, and if the drug is released for longer than the desired period, the drug release pattern cannot be adjusted, which can make repeated administration difficult.

[0043] As explained earlier, microparticles of various sizes include both small and large microparticles. This means that the size of the microparticles cannot be controlled, which in turn means that the drug release time cannot be controlled, potentially leading to difficulties in continuous use rather than single-dose applications.

[0044] The microparticles of the present invention are characterized by having an average particle diameter of 60 to 110 μm and a coefficient of variation of 5% to 20%. This means that the microparticles are distributed within the average diameter range and that the invention contains only microparticles with a uniform diameter.

[0045] As described above, by containing uniformly sized microparticles, the material can be injected into an animal's body to prevent initial excessive release of moxidectin and to exhibit a moxidectin-releasing effect for 3 months, 6 months, or 12 months.

[0046] The biodegradable polymer may be selected from the group consisting of polylactide (PLA), polylactide-coglycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxybarate, polyhydroxybutyrate, polyamino acid, and mixtures thereof.

[0047] The biodegradable polymer may preferably be selected from the group consisting of polylactide (PLA), polylactide-coglycolide (PLGA), and mixtures thereof.

[0048] Specifically, it may contain polylactide (PLA) or polylactide-coglycolide (PLGA), and may contain both polylactide (PLA) and polylactide-coglycolide (PLGA).

[0049] More specifically, the microparticles may contain PLA and moxidectin, or PLGA and moxidectin, or may contain PLA, PLGA and moxidectin. Containing all of PLA and PLGA means that when the biodegradable polymer and moxidectin are dissolved in an organic solvent, as described below, all of PLA and PLGA are contained, and the manufactured microparticles contain all of PLA and PLGA.

[0050] Furthermore, the microparticles of the present invention may be included in a sustained-release injectable composition, as described later, in which case the included microparticles may be selected from the group consisting of microparticles containing PLA and moxidectin, microparticles containing PLGA and moxidectin, microparticles containing PLA, PLGA and moxidectin, and mixtures thereof.

[0051] The microparticles contained in the injectable composition may contain only one type of biodegradable polymer, or may contain two or more different types of biodegradable polymers, or may contain two or more different types of microparticles containing one or more types of biodegradable polymers. The inclusion of such diverse types of microparticles is for the purpose of adjusting the release time of moxidectin.

[0052] The intrinsic viscosity of the biodegradable polymer may be 0.1 dl / g to 1 dl / g, 0.1 dl / g to 0.8 dl / g, 0.1 dl / g to 0.7 dl / g, or 0.1 dl / g to 0.6 dl / g. Furthermore, the molecular weight (MW) of the biodegradable polymer may be 10 kg / mol to 100 kg / mol, 11 kg / mol to 80 kg / mol, 12 kg / mol to 70 kg / mol, or 15 kg / mol to 65 kg / mol.

[0053] The microparticles of the present invention are intended to continuously release moxidectin for 3 months, 6 months, or 12 months, and preferably to continuously release moxidectin in the body of an animal for 6 months or 12 months.

[0054] As explained earlier, the release of moxidectin from the aforementioned microparticles is related to the average diameter of the particles, but is also greatly influenced by their intrinsic viscosity. Generally, the higher the viscosity of the biodegradable polymer, the more delayed the release of moxidectin may be. However, this characteristic is not always applicable, and the intrinsic viscosity of the biodegradable polymer and the viscosity of moxidectin mutually influence each other, affecting the degradation of the biodegradable polymer and the release of moxidectin.

[0055] The aforementioned biodegradable polymers are approved by the FDA and other authorities and can be used as injectable pharmaceuticals for human use. The decomposition period is specified depending on the type of biodegradable polymer. In other words, the biodegradation periods of specific polymers vary widely, such as 2-3 months, 6-9 months, and 10-14 months.

[0056] However, this refers to the biodegradation period for biodegradable polymers. When these polymers are mixed with moxidectin to produce microparticles, the biodegradation period of the biodegradable polymer may differ due to the influence of moxidectin.

[0057] Therefore, in order to sustainably release moxidectin in the body for a desired period of time, a combination of biodegradable polymers and moxidectin is important.

[0058] In other words, to release moxidectin for three months, it's not simply a matter of using a biodegradable polymer with a three-month biodegradation period; rather, it's necessary to investigate whether a combination of moxidectin and a biodegradable polymer can achieve three months of biodegradation.

[0059] Therefore, in the present invention, the intrinsic viscosity of the biodegradable polymer is limited to 0.1 dl / g to 1 dl / g, and when a biodegradable polymer having an intrinsic viscosity within the above range is used in combination with moxidectin, a sustained moxidectin release effect for a desired period can be achieved.

[0060] The microparticles may contain biodegradable polymers and moxidectin in a weight ratio of 2:1 to 12:1, 4:1 to 10:1, or 9:1. When the biodegradable polymers and moxidectin are contained within this range, initial excessive release can be prevented when injected into an animal's body, and a sustained release effect of moxidectin for a desired period can be achieved.

[0061] In the case of typical injectable formulations, side effects can occur due to excessive initial release of moxidectin. However, in the present invention, excessive initial release can be prevented even during injection, and the moxidectin release effect can be sustained for the desired period.

[0062] Furthermore, as explained earlier, the sustained release of moxidectin for 3, 6, or 12 months means that moxidectin is released at a level that can demonstrate a preventive or therapeutic effect against heartworm in dogs.

[0063] The aforementioned microparticles may be 0.3 to 3 according to the following formula 1. [Formula 1] C max-peak n / C max―peak n+1

[0064] Here, Microparticles containing moxidectin were mixed with a suspension solution to prepare an injectable preparation, and the injectable preparation was administered to beagle dogs, and the blood concentration of moxidectin was measured. C max-peak n This is the nth-order Cmax value obtained by administering the injectable drug. C max-peak n+1 This is the (n+1)th Cmax value resulting from the increase in moxidectin blood concentration again after the nth Cmax value.

[0065] Formula 1 is obtained by administering the microparticles of the present invention as an injection to a beagle dog and measuring the blood concentration of moxidectin. The value obtained by Formula 1 may be 0.3 to 3, 0.5 to 3, or 0.5 to 2.5. When the ratio of the peak values ​​of the blood concentration of moxidectin falls within this range, it is possible to control the release of moxidectin for a desired long period of time.

[0066] The aforementioned Equation 1 represents the relationship resulting from the appearance of moxidectin blood concentration peaks due to the presence of different biodegradable polymers in the microparticles contained in the injectable drug.

[0067] Specifically, as explained above, the microparticles of the present invention can be manufactured from two or more different biodegradable polymers. Multiple microparticles may contain only one type of biodegradable polymer, but they can also contain different biodegradable polymers. That is, they can include microparticles containing PLGA and moxidectin, and microparticles containing PLA and moxidectin.

[0068] As described above, microparticles containing different biodegradable polymers can exhibit the nth-order maximum blood concentration of moxidectin (Cmax-peak n), and thereafter the n+1th-order maximum blood concentration of moxidectin (Cmax-peak n+1), as shown in Equation 1.

[0069] The nth-order maximum blood concentration of moxidectin is the maximum blood concentration of moxidectin after injection, representing the maximum value in the trend where the blood concentration of moxidectin gradually increases and then decreases again. The n+1th-order maximum blood concentration of moxidectin represents the maximum value in the trend where the blood concentration of moxidectin decreases again after the nth-order maximum blood concentration, and the injectable dosage form containing microparticles of the present invention can exhibit multiple maximum blood concentration values. The nth-order maximum blood concentration of moxidectin (Cmax-peak n) and the n+1th-order maximum blood concentration of moxidectin (Cmax-peak n+1) can be such that the nth-order maximum blood concentration of moxidectin is a larger value than the n+1th-order maximum blood concentration of moxidectin, and the n+1th-order maximum blood concentration of moxidectin is a larger value than the nth-order maximum blood concentration of moxidectin.

[0070] The aforementioned trend in blood concentration peaks changes because the release pattern of moxidectin differs depending on the type of biodegradable polymer. The microparticles of the present invention are manufactured by the manufacturing method described later, and the microparticles manufactured by the manufacturing method of the present invention are characterized by being precisely controllable to have a uniform particle size. For this reason, microparticles can be manufactured using different biodegradable polymers and then mixed and used.

[0071] As described above, microparticles produced using different biodegradable polymers can each exhibit a unique moxidectin release pattern, and these unique release patterns can result in the appearance of multiple blood concentration peaks.

[0072] As explained earlier, when the microparticles are manufactured using different biodegradable polymers, differences in the biodegradation rates of the biodegradable polymers occur. By utilizing this characteristic, when administering an injectable drug, it is possible to achieve a sustained moxidectin release effect over a long period by mixing microparticles that can exhibit an initial moxidectin release effect with microparticles that can exhibit a later moxidectin release effect.

[0073] In contrast, the microparticles of the present invention are characterized in that, after being administered into the body, the maximum blood concentration (Cmax) of moxidectin appears after a specific time point.

[0074] After administering the microparticles of the present invention, the maximum blood concentration (Cmax) of moxidectin in the body may be affected by the average diameter of the microparticles, the particle size distribution, the type of biodegradable polymer, and other factors.

[0075] For example, microparticles in a 3-6 month dosage form can reach a maximum blood concentration (Cmax) within 10-90 days after administration to the body. Specifically, the microparticles of the present invention suppress initial excessive release, and after infusion, the amount of moxidectin released gradually increases, reaching a maximum blood concentration within the range of 10-90 days. Thereafter, the amount of moxidectin released decreases, allowing for sustained release of moxidectin for 3 or 6 months. Unlike previously described, when only one type of biodegradable polymer is used, multiple maximum blood concentration peaks of moxidectin do not appear; only a single maximum blood concentration peak appears, and this maximum blood concentration can occur within the range of 10-90 days after injection.

[0076] Furthermore, in the case of the 12-month dosage form, the maximum blood concentration (Cmax) can be reached between 10 and 90 days, similar to the 3-month or 6-month dosage forms. However, as explained earlier, this can be affected by factors such as the average diameter of the microparticles, the particle size distribution, and the type of biodegradable polymer.

[0077] The range of dates for which the maximum blood concentration is observed may vary depending on the target population and dosage. However, as in the examples of the present invention, when the total amount of moxidectin administered to beagle dogs is 0.2 mg / kg to 1 mg / kg, the maximum blood concentration (Cmax) of moxidectin can be observed within 10 to 90 days. When the maximum blood concentration (Cmax) of moxidectin is observed within the above range, sustained release of moxidectin is possible for 3 months, 6 months, or 12 months, preferably for 6 months or 12 months.

[0078] Microparticles containing the aforementioned moxidectin were mixed with a suspension solution to prepare an injectable preparation, and the injectable preparation was administered to several beagle dogs. Using the same method as in Formula 1, 0.2 mg / kg of moxidectin was administered to 10 beagle dogs as the same injectable preparation. The blood moxidectin concentration in the beagle dogs was measured, and the standard deviation of the blood moxidectin concentration among the beagle dogs at the same time period was 0.01 to 10, 0.01 to 5, or 0.01 to 3.

[0079] The standard deviation of the blood moxidectin concentration as described above indicates excellent homogeneity of the manufactured microparticles, and the excellent reproducibility of in vivo experimental results suggests excellent efficacy and safety of moxidectin administration.

[0080] Even when the same injectable drug is administered to beagle dogs, differences in blood moxidectin concentrations can occur among them. This is due to differences in drug-metabolizing enzymes among the individuals being administered the drug, and differences can occur in the rate at which the drug is metabolized in the body, even when the same injectable drug is administered.

[0081] However, in order to provide it as a sustained-release dosage form, it is necessary to control the concentration of moxidectin in the blood after administration to prevent large differences, and this is a factor that can be affected by the quality of the moxidectin-containing particles produced.

[0082] The microparticles of the present invention are manufactured by the manufacturing method described later, and have a very uniform particle size, a smooth particle surface, and can be manufactured in a perfectly spherical shape.

[0083] In other words, by manufacturing microparticles with uniform size and properties as described above, even when administering them as an injectable agent to beagle dogs and other animals, some differences in blood moxidectin concentration may occur due to individual differences, but these differences are only slight.

[0084] In contrast to the present invention, in the case of microparticles that are not uniform in size or have an uneven texture, the size of the microparticles contained in the injectable drug varies, and when administered to beagle dogs or other animals, the difference in texture results in a large difference in blood moxidectin concentration not only between individuals but also between microparticles when measuring the concentration.

[0085] A sustained-release injectable composition containing moxidectin according to another embodiment of the present invention may include microparticles containing moxidectin and a suspension solution.

[0086] The aforementioned suspension solvent comprises an isotonic agent, a suspending agent, and a solvent.

[0087] More specifically, the isotonic agent may be selected from the group consisting of D-mannitol, maltitol, sorbitol, lactitol, xylitol, sodium chloride, and mixtures thereof, and is preferably D-mannitol, but is not limited to the above example.

[0088] The suspending agent is 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 A substance selected from the group consisting of gum, and mixtures thereof, preferably sodium carboxymethylcellulose and polysorbate 80, but not limited to the above example.

[0089] The aforementioned solvent can be water for injection, and any solvent that can be used as water for injection is permitted without restriction.

[0090] A method for producing microparticles containing moxidectin according to another embodiment of the present invention is: 1) to produce an oil phase solution by dissolving a biodegradable polymer and moxidectin in an organic solvent; 2) to produce an aqueous phase solution by dissolving a surfactant in water; 3) to inject the oil phase solution from step 1) into a linear microchannel and let it flow; and 4) to inject the aqueous phase solution from step 2) into microchannels formed on both sides or one side so as to form an intersection with the microchannel through which the oil phase solution from step 3) flows linearly, and let it flow through the oil phase The method comprises the steps of: 5) creating microparticles uniformly containing moxidectin by crossing a flow of solution and a flow of aqueous solution; 6) collecting the microparticles generated at the intersection of step 4); 7) stirring the microparticles collected in step 5) to evaporate and remove any organic solvent present in the microparticles; and 8) washing and drying the microparticles from step 6). The intrinsic viscosity of the biodegradable polymer may be 0.1 dl / g to 1 dl / g, and the average particle diameter of the microparticles may be 60 to 110 μm.

[0091] Step 1) above is a step of producing an oil phase solution, which involves dissolving moxidectin and a biodegradable polymer in an organic solvent to produce an oil phase solution, wherein the biodegradable polymer is polylactide (PLA), preferably polylactide-co-glycolide (PLGA) or polylactide (PLA), but is not limited to the above example.

[0092] Furthermore, the organic solvent is immiscible with water and is one or more selected from the group consisting of, for example, chloroform, chloroethane, dichloroethane, dichloromethane, trichloroethane, and mixtures thereof. Preferably, it is dichloromethane, but it is not limited to examples, and any organic solvent that can dissolve biodegradable polymers and moxidectin and can be easily selected by a person skilled in the art can be used, not limited to the above examples.

[0093] Step 1) above is for producing an oil-phase solution in which moxidectin and biodegradable polymers are dissolved, and as mentioned above, an organic solvent is used as the solvent. This is done by utilizing the solubility properties of moxidectin and biodegradable polymers to completely dissolve them using an organic solvent. More specifically, moxidectin and biodegradable polymers were dissolved in an organic solvent to produce an oil-phase solution.

[0094] The oil phase solution may have a weight ratio of biodegradable polymer to moxidectin of 2:1 to 12:1, 4:1 to 10:1, or 9:1. When mixed and used within this range, moxidectin can be continuously released for a long period of time by the decomposition of the biodegradable polymer.

[0095] If the weight ratio of moxidectin to biodegradable polymer is less than 1:2, that is, if the biodegradable polymer is present in a weight ratio less than the aforementioned ratio, the weight ratio of the biodegradable polymer is small compared to the weight of moxidectin, making it difficult to manufacture microparticles in which moxidectin is uniformly distributed within spherical biodegradable polymer particles. If the weight ratio of biodegradable polymer to moxidectin is greater than 1:12, that is, if the biodegradable polymer is present in a weight ratio greater than the aforementioned ratio, the moxidectin content in the sustained-release particles is small, which may lead to the problem of having to administer a large amount of sustained-release particles to deliver the desired concentration of drug.

[0096] More specifically, the biodegradable polymer in the oil phase solution is present in an amount of 10 to 20% by weight, preferably 15% by weight, but is not limited to the above example.

[0097] Step 2) above is a step of producing an aqueous phase solution, in which a surfactant is dissolved in water to produce an aqueous phase solution. The surfactant can be used without limitation as long as the biodegradable polymer solution can help form a stable emulsion. Specifically, it is one or more selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof, and more specifically, it is one or more selected from the group consisting of methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, sodium lauryl sulfate, sodium stearate, esteramines, linear diamines, aliphatic amines, and mixtures thereof, and is preferably polyvinyl alcohol, but is not limited to examples.

[0098] The surfactant contained in the aqueous solution may be present in an amount of 0.1 to 1.0% by weight, 0.2 to 0.5% by weight, or 0.25% by weight. The remainder is all water.

[0099] Step 3) above is the step of injecting and flowing an oil phase solution and an aqueous phase solution into microchannels formed on a wafer or organic substrate.

[0100] Conventional microchannels used to manufacture the same microparticles as those of the present invention were manufactured by forming seven microchannels on a silicon wafer. The microchannels may include channels for flowing an aqueous solution, channels for flowing an oil-phase solution, and channels through which the generated emulsion moves after the aqueous and oil-phase solutions have intersected.

[0101] However, in the case of the conventional chip in which a total of seven channels are formed on the silicon wafer, a small number of microchannels are formed, and when manufacturing microparticles simultaneously using the seven microchannels, it was possible to manufacture microparticles of the same size by adjusting the hydraulic pressure of the oil phase solution and the aqueous phase solution.

[0102] However, as the number of microchannels formed in the chip increased, there was a problem in that it became difficult to produce microparticles of uniform size by adjusting the hydraulic pressure of the oil phase solution and the aqueous phase solution.

[0103] In other words, when forming 10 or more microchannels on a single plane, it is not easy to supply the same hydraulic pressure to the aqueous and oil phase solutions from the 1st to the 10th channel. This results in problems where the size and particle size distribution of the manufactured microparticles differ due to the non-uniformity of the hydraulic pressure distribution within each microchannel.

[0104] Therefore, in order to enable the production of microparticles of uniform size even on chips in which 10 or more microchannels are formed, the present invention is characterized by maintaining the flow rate ratio of the fluids flowing into the channels of the oil phase solution and the aqueous phase solution at 1:45 or higher.

[0105] Specifically, when the flow rate of the oil phase solution is adjusted to 110 μl / min, and the flow rate of the aqueous phase solution is 5,000 μl / min, it is possible to produce a uniform emulsion at the intersection.

[0106] As described above, the production of microparticles using microchannels utilizes microfluidics, a technique that uses microfluidic engineering technology to produce microparticles with a homogeneous diameter distribution. This technique utilizes the polarity difference between the oil phase solution and the aqueous phase solution to generate an emulsion due to the repulsive force between the fluids as they pass through micro-sized channels.

[0107] When using existing single-channel or approximately 10-channel chips, flow rate control was possible by adjusting the pressure (pneumatic) ratio of the oil-phase and aqueous-phase solutions injected into the channels. However, when using integrated chips with multiple channels, it is important to adjust the flow rate ratio of the oil-phase and aqueous-phase solutions, rather than the pressure of the oil-phase and aqueous-phase solutions injected into the channels.

[0108] The flow rate ratio of the oil phase solution and the aqueous phase solution determines whether or not microparticles can be produced using microchannels. When the fluid flowing through the microchannel forms a laminar flow and is uniformly cut off at the junction where the channels meet due to the repulsive force of the fluid, it exhibits a dripping condition. However, if the flow rate ratio of the oil phase solution and the aqueous phase solution exceeds the range of the present invention, a jetting phenomenon occurs instead of dripping, resulting in an emulsion that is not uniformly produced.

[0109] Figure 1 is a photograph of an emulsion formed when the aqueous and oil phase solutions according to one embodiment of the present invention are contained within a flow rate ratio range and exhibit dripping conditions at the intersection where the channels meet.

[0110] The emulsion shown in Figure 1 demonstrates that the particles are uniformly distributed with a size of 170-190 μm, are perfectly spherical, and have a smooth surface.

[0111] In contrast, Figure 2 shows the case where the dripping condition is shown at the intersection where channels meet, and is a conceptual diagram of the emulsion that can be formed by the jetting phenomenon.

[0112] As described above, when the material is dripped, it can be confirmed that an emulsion with a uniform diameter is formed as shown in Figure 1, but when it is jetted, it can be confirmed that an emulsion with different diameters is formed.

[0113] The flow rate ratio of the oil phase solution to the aqueous phase solution is 1:45 or greater, and may be between 1:45 and 1:125. If the ratio is less than 1:45, the oil phase will jettison and a uniform size distribution of CV 10% or less cannot be achieved. If the proportion of the aqueous phase is greater than 1:45 and exceeds 1:125, all of the oil phase will be dripped, resulting in a suitable size distribution. However, as the proportion of the aqueous phase increases, the amount of aqueous phase solution used increases, which may cause problems in terms of production quantity.

[0114] More specifically, the microchannels may be formed on a material selected from the group consisting of a glass substrate, a silicon wafer, or a polymer film, but the examples of the material are not limited to those mentioned above, and any material on which microchannels can be formed can be used.

[0115] The polymer film may be selected from the group consisting of polyimide, polyethylene, fluorinated ethylene propylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polysulfone, and mixtures thereof, but is not limited to the above examples.

[0116] As an example, aluminum is deposited onto a silicon wafer using an e-beam evaporator, and a photoresist is patterned onto the aluminum using a photolithography technique. Subsequently, the aluminum is etched using the photoresist as a mask, and after removing the photoresist, the silicon is etched using DRIE (deep ion reactive etching) with the aluminum as a mask. After removing the aluminum, glass is anodic-bonded to the wafer and sealed to produce the microchannel.

[0117] The microchannels have an average diameter of 160 to 200 μm, preferably 180 μm, but are not limited to this. If the average diameter of the microchannels is 160 μm or less, the microparticles produced may be small, with a diameter of less than 50 μm, which may affect the release and bioavailability of effective drugs. If the average diameter of the microchannels is 200 μm or more, the average size of the produced microparticles will exceed 120 μm, which may increase the feeling of foreign body sensation and pain when the injectable drug is administered. Furthermore, the larger the diameter of the microchannels, the larger the particle size distribution of the produced particles becomes, making it difficult to produce microparticles with uniform particle size.

[0118] Furthermore, the average diameter of the microchannels is closely related to the average diameter of the particles, but it is also closely related to the flow rate ratio (μl / min) of the oil phase solution and the aqueous phase solution.

[0119] Furthermore, the cross-sectional width (w) and cross-sectional height (d) of the microchannel are closely related to the average diameter (d') of the manufactured microparticles. The cross-sectional width (w) of the microchannel is in the ratio range of 0.7 to 1.3 with respect to the average diameter (d') of the microparticles, and the cross-sectional height (d) of the microchannel is in the ratio range of 0.7 to 1.3 with respect to the average diameter (d') of the microparticles.

[0120] In other words, once the average diameter (d') of the microparticles to be manufactured is determined, the width (w) and height (d) of the cross-sectional area of ​​the microchannel must be set within a ratio range of 0.7 to 1.3 of d' in order to manufacture microparticles of the desired size.

[0121] Step 3) involves flowing the oil phase solution and the aqueous phase solution through the first and second microchannels, which are formed at the intersection, under the flow rate conditions described above.

[0122] In other words, the oil phase solution flows along the first microchannel, and the aqueous phase solution flows along the second microchannel, which is shaped to intersect with the first microchannel, and meets the flow of the oil phase solution.

[0123] More specifically, when the oil phase solution is injected into the first microchannel, the flow rate is 1:45 or higher, and when the aqueous phase solution is injected into the second microchannel, the flow rate ratio of the oil phase solution to the aqueous phase solution is 1:45 or higher, and may be between 1:45 and 1:125.

[0124] As explained earlier, conventional microparticles could be manufactured by controlling hydraulic pressure to produce microparticles with a constant diameter. However, in the case of chips with 10 or more integrated microchannels, it was impossible to manufacture microparticles with a uniform diameter by controlling hydraulic pressure. Therefore, by adjusting the flow rate ratio of the oil phase solution and the aqueous phase solution, it is possible to manufacture microparticles with a uniform diameter.

[0125] As described above, when the flow rates of the oil phase solution and the aqueous phase solution are made different, the aqueous phase solution, which has a relatively larger flow rate, compresses the oil phase solution at the point where the oil phase flow and the aqueous phase flow meet. At this time, a dripping phenomenon occurs due to the repulsive force between the oil phase solution and the aqueous phase solution, generating spherical microparticles in which the biodegradable polymer and moxidectin are uniformly distributed. More specifically, these microparticles form a morphology in which moxidectin is uniformly distributed within a spherical biodegradable polymer.

[0126] Step 4) above is a step of collecting microparticles, in which the microparticles are collected in a tank containing an aqueous solution to prevent aggregation of the initially generated microparticles.

[0127] Step 4) is used to prevent clumping among the collected microparticles by using the aqueous phase solution prepared in step 2), i.e., a mixed solution of surfactant and water. After preparing the aqueous phase solution in step 2), a portion is injected into the microchannel and the other portion is moved to the water tank in step 4).

[0128] Step 5) above is a step to remove organic solvents present in microparticles collected in the water tank, and is performed by stirring at a constant temperature and stirring speed to evaporate and remove the organic solvents present inside the microparticles. At this time, the stirring conditions are 5-1) a primary stirring step of 15-350 rpm at 15-20°C for 50-70 minutes, 5-2) a secondary stirring step of 250-450 rpm at 20-30°C for 50-70 minutes, and 5-3) a tertiary stirring step of 450-650 rpm at 40-60°C for 3-9 hours.

[0129] The stirring speed is determined by varying the temperature conditions and stirring time for the primary and secondary stirring steps to advance the stirring process.

[0130] As described above, the method is characterized by increasing the temperature conditions in the secondary stirring step compared to the primary stirring step, and by gradually increasing the temperature, the evaporation rate of the organic solvent present inside the microparticles can be controlled. In other words, microparticles can be produced by gradually evaporating the organic solvent present inside the microparticles.

[0131] The temperature at which the oil phase solution and aqueous phase solution flow through the microchannel is 15-20°C, preferably 17°C. That is, the temperature is kept constant at 15-20°C until the collected microparticles are stirred after flowing through the microchannel and forming intersections. Maintaining a low temperature during the microparticle manufacturing process is essential for producing and maintaining spherical particles. In other words, if the conditions are not low, it becomes difficult to produce consistently spherical particles.

[0132] Subsequently, in the secondary stirring step, the temperature is gradually increased and the stirring time is increased so that the organic solvent present inside the microparticles gradually moves to the surface and evaporates from the surface, minimizing the impact on the properties of the microparticles. In other words, if the organic solvent evaporates rapidly, the surface of the microparticles may become uneven and pores may form due to the evaporation of the organic solvent. To prevent such problems, the evaporation rate of the organic solvent can be adjusted by gradually increasing the temperature conditions and the time spent in the stirring step, as described above. By adjusting the evaporation rate of the organic solvent in this way, the surface properties of the manufactured microparticles can be controlled.

[0133] The aforementioned tertiary stirring step involves extracting the organic solvent in the emulsion as an external aqueous phase, then raising the temperature of the external aqueous phase to near the boiling point of the organic solvent and stirring it to remove the saturated organic solvent from the aqueous phase, thereby facilitating the removal of residual organic solvent within the microparticles.

[0134] Finally, step 6) is a step of washing and drying the microparticles, in which the microparticles, which have been stirred to remove all organic solvents from their surface, are washed several times with purified water that has been sterilized and filtered to remove any remaining surfactants from the microparticles, and then freeze-dried.

[0135] The final microparticles consist of spherical, biodegradable polymers with moxidectin uniformly distributed within them, containing biodegradable polymers and moxidectin in a weight ratio of 2:1 to 12:1.

[0136] The weight ratio of moxidectin and biodegradable polymer contained within the microparticles is the same as that in the oil phase solution. This is because microparticles containing moxidectin and biodegradable polymer in the same weight ratio as in the oil phase solution can be produced by passing them through microchannels to create oil phase emulsion particles and removing all organic solvents from the emulsion.

[0137] Manufacturing Example 1 Production of microparticles containing moxidectin An oil phase solution was prepared by dissolving polylactide-co-glycolide (PLGA), which has a viscosity of 0.2 dl / g, contains terminal carboxylic acid groups, has a molecular weight (MW) of 17 kg / mol, and has a lactide-to-glycolide ratio of 75:25, and moxidectin in dichloromethane. At this time, the oil phase solution contained polylactide-co-glycolide at a ratio of 15% by weight, and the weight ratio of polylactide-co-glycolide to moxidectin was 9:1.

[0138] A surfactant, polyvinyl alcohol, was mixed with water to prepare an aqueous solution containing 0.25% by weight of polyvinyl alcohol.

[0139] The oil phase solution and aqueous phase solution were injected and flowed through microchannels formed on a silicon wafer. At this time, the oil phase solution and aqueous phase solution were injected into each microchannel, with a flow rate ratio of 1:50, and the temperature was maintained at 17°C.

[0140] Microparticles generated at the intersection where the oil phase solution flow and the aqueous phase solution flow meet were collected in a tank containing the second mixture. The microparticles collected in the tank were subjected to primary stirring at 17°C at a speed of 250 rpm for 1 hour, secondary stirring at 25°C at a speed of 350 rpm for 1 hour, and then tertiary stirring at 550 rpm for 4 hours after raising the temperature to 55°C.

[0141] The stirred microparticles were washed several times with purified water that had been sterilized and filtered, and then freeze-dried to produce the microparticles.

[0142] Manufacturing Example 2-1 Microparticles were produced in the same manner as in Production Example 1, except that polylactic acid with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 17 kg / mol was used instead of polylactide-coglycolide.

[0143] Manufacturing Example 2-2 Microparticles were produced in the same manner as in Production Example 1, except that polylactic acid with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 17 kg / mol was used instead of polylactide-coglycolide, and the polylactic acid in the oil phase solution was contained at a ratio of 10% by weight.

[0144] Manufacturing Example 3-1 Microparticles were produced in the same manner as in Production Example 1, except that polylactic acid with a viscosity of 0.4 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 45 kg / mol was used instead of polylactide-coglycolide.

[0145] Manufacturing Example 3-2 Microparticles were produced in the same manner as in Production Example 1, except that polylactic acid with a viscosity of 0.4 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 45 kg / mol was used instead of polylactide-coglycolide, and the polylactic acid in the oil phase solution was included at a ratio of 10% by weight.

[0146] Manufacturing Example 4 Microparticles were produced in the same manner as in Production Example 1, except that polylactic acid with a viscosity of 0.4 dl / g, containing terminal ester groups, and a molecular weight (MW) of 45 kg / mol was used instead of polylactide-coglycolide, and the polylactic acid in the oil phase solution was contained at a ratio of 10% by weight.

[0147] Manufacturing Example 5 Microparticles were produced in the same manner as in Production Example 1, except that polylactic acid with a viscosity of 0.5 dl / g, containing terminal ester groups, and a molecular weight (MW) of 61 kg / mol was used instead of polylactide-coglycolide, and the polylactic acid in the oil phase solution was included at a ratio of 10% by weight.

[0148] Manufacturing Example 6 As biodegradable polymers, polylactide-co-glycolide (PLGA) with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, a molecular weight (MW) of 17 kg / mol, and a lactide-to-glycolide ratio of 75:25 was used, and polylactide (PLA) with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 17 kg / mol was used, with a weight ratio of 1:1 between PLGA and PLA. At this time, the polylactide-co-glycolide and polylactic acid in the oil phase solution were included in a ratio of 10% by weight, except that the microparticles were produced in the same manner as in Production Example 1.

[0149] Manufacturing Example 7-1 Microparticles were produced in the same manner as in Production Example 1, except that two polylactide (PLA) polymers were used as biodegradable polymers: one with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 17 kg / mol, and another with a viscosity of 0.4 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 45 kg / mol, with a weight ratio of 1:1 between the two different PLA polymers.

[0150] Manufacturing Example 7-2 As biodegradable polymers, polylactide (PLA) with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 17 kg / mol, and polylactide (PLA) with a viscosity of 0.4 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 45 kg / mol were used. The weight ratio of the two different PLAs was 1:1, and the total polylactic acid in the oil phase solution was 10% by weight. Microparticles were produced in the same manner as in Production Example 1, except that.

[0151] Manufacturing Example 8 As biodegradable polymers, polylactide (PLA) with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 17 kg / mol, and polylactide (PLA) with a viscosity of 0.4 dl / g, containing terminal ester groups, and a molecular weight (MW) of 45 kg / mol were used. The weight ratio of the two different PLAs was 1:1, and the total polylactic acid in the oil phase solution was 10% by weight. Microparticles were produced in the same manner as in Production Example 1, except that.

[0152] Manufacturing Example 9-1 Microparticles were produced in the same manner as in Production Example 1, except that two polylactide (PLA) polymers were used as biodegradable polymers: one with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 17 kg / mol, and another with a viscosity of 0.4 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 45 kg / mol, with a weight ratio of 1:3 between the two different PLA polymers.

[0153] Manufacturing Example 9-2 As biodegradable polymers, polylactide (PLA) with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 17 kg / mol, and polylactide (PLA) with a viscosity of 0.4 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 45 kg / mol were used. The weight ratio of these two different PLAs was 1:3, and the total polylactic acid in the oil phase solution was 10% by weight. Microparticles were produced in the same manner as in Production Example 1, except that.

[0154] Manufacturing Example 10 As biodegradable polymers, polylactide (PLA) with a viscosity of 0.4 dl / g, containing terminal ester groups, and a molecular weight (MW) of 45 kg / mol, and polylactide (PLA) with a viscosity of 0.5 dl / g, containing terminal ester groups, and a molecular weight (MW) of 61 kg / mol were used, with a weight ratio of 1:1 between the two different PLAs. At this time, the total polylactic acid in the oil phase solution was contained at a ratio of 10% by weight, except that the microparticles were produced in the same manner as in Production Example 1.

[0155] Manufacturing Example 11 Microparticles were produced in the same manner as in Production Example 1, except that the weight ratio of each of the above-mentioned different polymers was 1:1:4. The biodegradable polymers used were: polylactide-co-glycolide (PLGA) with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, a molecular weight (MW) of 17 kg / mol, and a lactide-to-glycolide ratio of 50:50; polylactide-co-glycolide (PLGA) with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, a molecular weight (MW) of 17 kg / mol, and polylactide (PLA) with a viscosity of 0.2 dl / g, containing terminal carboxyl groups, and a molecular weight (MW) of 17 kg / mol.

[0156] Example 1 The microparticles from Production Example 1 and the microparticles from Production Example 2-1 were mixed in a 1:2 weight ratio. Using one vial as a reference, 2.0 mL of suspension solvent was added, and the mixture was uniformly suspended to prepare a composition for subcutaneous injection.

[0157] The aforementioned suspension solvent was composed of the elements shown in Table 1 below. [Table 1]

[0158] Example 2 A subcutaneous injection composition was prepared in the same manner as in Example 1, except that the microparticles from Production Example 1 and the microparticles from Production Example 2-1 were mixed in a 1:1 weight ratio.

[0159] Example 3 The experiment was carried out in the same manner as in Example 1, except that 50% of the dose administered in Example 1 was administered. The microparticles from Production Example 1 and Production Example 2-1 were mixed in a 1:2 weight ratio and administered in the same manner.

[0160] Experimental Example 1 The nature of the release To confirm the release of moxidectin from the microparticles of the above-mentioned manufacturing examples 1, 2-1, 4, and 5, release experiments were conducted.

[0161] The release test solution used in the release experiment was a solution containing 2% Tween 20 in purified water. 100 mg of microparticles were placed in a syringe containing 100 ml of the release test solution, sealed, and then stirred and shaken at 55°C and 120 rpm to confirm the difference in dissolution rates.

[0162] The experimental results are shown in Figure 1.

[0163] The microparticles in Manufacturing Example 1 release 50% of moxidectin after 15 hours and are suitable for a 3-month dosage form. The microparticles in Manufacturing Example 2-1 release 50% of moxidectin after 20 hours and are suitable for a 6-month dosage form.

[0164] The microparticles in Production Example 4 release 50% of moxidectin after 84 hours, making them suitable for dosage forms that release moxidectin over a longer period compared to Production Examples 1 and 2-1.

[0165] Furthermore, it can be confirmed that the microparticles in Production Example 5 take longer to release 50% of their moxidectin compared to the microparticles in Production Example 3.

[0166] Experimental Example 2 The nature of the release Release experiments were conducted to confirm the release of moxidectin from the microparticles of the aforementioned manufacturing examples 2-1, 3-1, 9-1, 7-1, and 11.

[0167] The release test solution used in the release experiment was a solution containing 2% Tween 20 and 0.001M sodium bicarbonate in purified water. 100 mg of microparticles were placed in a syringe containing 100 ml of the release test solution, sealed, and then stirred and shaken at 55°C and 120 rpm to check the difference in dissolution rates.

[0168] The experimental results are shown in Figure 2.

[0169] The average diameter (MV) was around 95 μm, and in release tests of microparticles of similar size, differences in release patterns were observed depending on the molecular weight of the polymer constituting the microparticles. When comparing the release rates of the microparticles in production examples 2-1, 3-1, 7-1, and 9-1, a higher proportion of polylactide with a molecular weight (MW) of 45 kg / mol compared to polylactide with a molecular weight (MW) of 17 kg / mol allowed for application to dosage forms that release moxidectin for a longer period of time.

[0170] In production examples 7-1 and 9-1, it was confirmed that the release delay time differed depending on the ratio of polylactide with a molecular weight (MW) of 17 kg / mol to polylactide with a molecular weight (MW) of 45 kg / mol, ranging from 1:1 to 1:3.

[0171] Furthermore, it can be confirmed that the microparticles in manufacturing example 11 contain polylactide-co-glycolide (PLGA) compared to the microparticles in the other manufacturing examples, resulting in a more rapid release of moxidectin.

[0172] Experimental Example 3 The nature of the release Release experiments were conducted to confirm the release of moxidectin from the microparticles of the aforementioned manufacturing examples 2-2, 3-2, 4, 7-2, 8, and 9-2.

[0173] The release test solution used in the release experiment was a solution containing 2% Tween 20 and 0.001M sodium bicarbonate in purified water. 100 mg of microparticles were placed in a syringe containing 100 ml of the release test solution, sealed, and then stirred and shaken at 55°C and 120 rpm to check the difference in dissolution rates.

[0174] The experimental results are shown in Figure 3.

[0175] With an average diameter (MV) of around 85 μm, release tests of microparticles of similar size showed differences in release patterns depending on the ratio of molecular weights of the polymers constituting the microparticles and the differences in polymer end groups. When comparing the release rates of microparticles from each production example, a higher ratio of polylactide with a molecular weight (MW) of 45 kg / mol compared to polylactide with a molecular weight (MW) of 17 kg / mol in the microparticles allows for application to dosage forms that release moxidectin for a longer period of time.

[0176] Furthermore, when comparing the microparticles from production examples 3-2 and 3-4, it can be confirmed that the release of moxidectin is more delayed when the end groups include ester groups rather than carboxyl groups.

[0177] Experimental Example 4 PSA analysis results To specifically determine the diameter of the microparticles, we performed analyses on manufacturing examples 1-11 using a Microtrac particle size analyzer.

[0178] The units for D10 to D90 are in μm, and CV (%) was calculated using SD / Mean * 100.

[0179] The uniformity of the particle size distribution is calculated using Span value(D90-D10) / D50.

[0180] The results of the particle size analysis for the manufacturing examples are shown in Table 2 below. [Table 2]

[0181] According to Table 2 above, the microparticles produced by the manufacturing example of the present invention were measured to have D50 values ​​of 84.85 μm, 90.70 μm, 83.69 μm, 91.41 μm, 82.38 μm, 87.92 μm, 84.20 μm, and 79.98 μm, and their CV values ​​were 14.46%, 10.43%, 9.49%, 10.97%, 8.98%, 11.35%, 12.91%, and 11.27%, confirming a uniform particle distribution.

[0182] Furthermore, the average particle diameters (MV) of the microparticles were 90.85 μm, 93.29 μm, 85.26 μm, 96.05 μm, 86.67 μm, 89.51 μm, 87.22 μm, and 81.87 μm, confirming a uniform particle distribution within the range of 70 to 100 μm.

[0183] The results of the particle size analysis for manufacturing examples 7-1 to 7-11 are shown in Table 3 below. [Table 3]

[0184] According to Table 3 above, the microparticles produced by the manufacturing example of the present invention were measured to have a D50 of 98.5 μm, 80.46 μm, 91.23 μm, 95.64 μm, 84.5 μm, 78.52 μm, and 93.32 μm, and it can be confirmed that they exhibit a uniform particle distribution with CV values ​​of 11.13%, 6.74%, 10.53%, 10.75%, 10.64%, 10.63%, and 9.46%.

[0185] Furthermore, the average particle diameters (MV) of the microparticles were 99.63 μm, 80.54 μm, 91.22 μm, 96.96 μm, 86.72 μm, 78.61 μm, and 93.04 μm, confirming a uniform particle distribution within the range of 70 to 100 μm.

[0186] According to the PSA analysis results in Tables 2 and 3, when the polymer in the prepared oil phase solution was present at a ratio of 10% by weight, the average particle size (MV) was confirmed to be 84.96 μm with a standard deviation of 4.17. When the polymer in the oil phase solution was present at a ratio of 15% by weight, the average particle size (MV) was confirmed to be 94.97 μm with a standard deviation of 3.17. This shows that the average particle size (MV) increases as the concentration of polymer in the oil phase solution increases.

[0187] Furthermore, the particles produced in each manufacturing example have a Span value of 0.5 or less and a CV (%) within 5-20%, indicating that the particles produced by the aforementioned manufacturing method exhibit a very uniform particle size distribution.

[0188] The results of the particle size analysis of the manufactured microparticles based on the polymer content in the oil phase solution are shown in Table 4 below. [Table 4]

[0189] According to the PSA analysis results in the table above, when the polymer in the oil phase solution produced by the same polymer (PLGA) is present at a ratio of 5% by weight, the average particle size (MV) of each particle is 57.98. When the polymer in the oil phase solution is present at a ratio of 10% by weight, the average particle size (MV) of each particle is 76.27. When the polymer in the oil phase solution is present at a ratio of 15% by weight, the average particle size (MV) of each particle is 93.14. When the polymer in the oil phase solution is present at a ratio of 20% by weight, the average particle size (MV) of each particle is 103.30. This shows that the average particle size (MV) of the particles increases as the concentration of polymer in the oil phase solution increases.

[0190] Therefore, by using the same microchannel and maintaining a constant flow rate ratio between the oil phase and the aqueous phase under dripping conditions, it is possible to produce microparticles of a desired particle size by changing the weight percentage of polymers constituting the oil phase. This allows for control of the drug release pattern based on the microparticle size, such as suppressing initial burst, and can be used to set the drug retention period.

[0191] Experimental Example 5 SEM analysis results To specifically confirm the properties of the microparticles, we performed analyses on manufacturing examples 1 to 11 using a Scanning Electron Microscope (SEM).

[0192] The results of SEM analysis for Production Examples 1 to 11 are as shown in FIGS. 3 to 18 below.

[0193] According to the SEM measurement photos, it was confirmed that micro-particles with uniform particle size and smooth surface were produced into complete spherical micro-particles.

[0194] Experimental Example 6 Results of pharmacokinetic analysis The pharmacokinetic evaluation for Example 1 was confirmed.

[0195] Example 1 above was a sustained-release dosage form for 6 months or more, and it was confirmed whether moxidectin was continuously released for 6 months after injection to maintain the drug effect of moxidectin.

[0196] For the micro-particles of the present invention, the moxidectin administered to beagle dogs was 0.4 mg / kg, and a total of 5 animals were administered by SC injection.

[0197] The results of the blood concentration analysis of moxidectin are as shown in Table 5 below. [Table 5]

[0198] According to the above experimental results, it was confirmed that the blood concentration of moxidectin had no initial excessive release and showed the first Cmax at around 25 days after injection. When 25 days had passed, the blood concentration of moxidectin decreased evenly, and after 56 days had passed, the blood concentration of moxidectin increased. Thereafter, it was confirmed that the second Cmax appeared at around 91 days. Therefore, it can be confirmed that the value according to Formula 1 below is 1.35. [Formula 1] ] C max-peak n / C max―peak n+1

[0199] Here, Micro-particles containing moxidectin were mixed in a suspension solution to produce an injection, and the injection was administered to beagle dogs, and the blood concentration of moxidectin was measured. C max-peak n This is the nth-order Cmax value obtained by administering the injectable drug. C max-peak n+1 This is the (n+1)th Cmax value resulting from the increase in moxidectin blood concentration again after the nth Cmax value.

[0200] This pattern of moxidectin blood concentration is due to the production of microparticles using two types of biodegradable polymers, which are then mixed and manufactured into an injectable formulation. Differences in the viscosity, molecular weight, and combination with moxidectin of the biodegradable polymers result in differences in the rate of degradation, leading to the aforementioned pattern of blood concentration release.

[0201] Furthermore, the results of the analysis of the pharmacokinetic characteristics of Example 1 are shown in Table 6 below. [Table 6]

[0202] Experimental Example 7 Results of pharmacokinetic analysis The pharmacokinetic evaluation for Example 2 was confirmed.

[0203] The experiment was carried out in the same manner as in Example 1, except that the microparticles from Production Example 1 and the microparticles from Production Example 2-1 were mixed in a 1:1 weight ratio. [Table 7]

[0204] According to the experimental results described above, it was confirmed that there was no initial excessive release of moxidectin blood concentration, and that the primary Cmax was observed around 21 days after injection. After 21 days, the moxidectin blood concentration decreased steadily, and after 56 days, the moxidectin blood concentration increased. Subsequently, the secondary Cmax was observed around 70 days. Therefore, it can be confirmed that the value calculated using Equation 1 is 2.24.

[0205] Furthermore, 24 hours after injection, the blood concentration of moxidectin was 0.75 ng / ml, and the standard deviation of the blood concentration in the beagle dogs that participated in the experiment was 0.24.

[0206] The results of the analysis of the pharmacokinetic characteristics for Example 2 are shown in Table 8 below. [Table 8]

[0207] Experimental Example 8 Results of pharmacokinetic analysis Pharmacokinetic evaluation was carried out for Example 3.

[0208] The experiment was carried out in the same manner as in Example 1, except that 50% of the dose administered in Example 1 was administered. The microparticles from Production Example 1 and Production Example 2-1 were mixed in a 1:2 weight ratio and administered in the same manner. [Table 9]

[0209] According to the experimental results described above, it was confirmed that there was no initial excessive release of moxidectin blood concentration, and that the primary Cmax was observed around 35 days after injection. After 35 days, the moxidectin blood concentration decreased steadily, and after 77 days, the moxidectin blood concentration increased. Subsequently, the secondary Cmax was observed around 105 days. Therefore, it can be confirmed that the value calculated using Equation 1 above is 0.56.

[0210] Experimental Example 9 Results of pharmacokinetic analysis In in vivo experiments, we compared the blood moxidectin concentrations in individual subjects to confirm the reproducibility of the results when the same test drug was administered.

[0211] For comparison, three beagle dogs were administered the currently available ProHeart SR-12, and their blood moxidectin levels were measured for 180 days.

[0212] In Example 3, the microparticles of the present invention were administered to a total of 10 beagle dogs at a dose of 0.2 mg / kg of moxidectin, and the blood moxidectin concentration was measured for 180 days.

[0213] The experimental results are shown in Tables 10, 11, and Figure 19 below. [Table 10] [Table 11]

[0214] According to the experimental results described above, commercially available ProHeart SR-12 shows a large difference in blood concentration among beagle dogs, whereas in Example 1 of the present invention, when measuring the blood moxidectin concentration in 10 beagle dogs, the deviation was 0.2 to 2.39, confirming that there was no significant difference.

[0215] Although preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements by those skilled in the art that utilize the basic concepts of the present invention as defined in the following claims also fall within the scope of the present invention. [Industrial applicability]

[0216] The present invention relates to microparticles containing moxidectin and sustained-release injectable compositions containing the same.

Claims

1. These are microparticles containing moxidectin and biodegradable polymers. The intrinsic viscosity of the biodegradable polymer is 0.2 dl / g to 1 dl / g. The average diameter of the aforementioned microparticles is 60 to 110 μm. The biodegradable polymer is selected from the group consisting of polylactide (PLA), polylactide-coglycolide (PLGA), and mixtures thereof. Microparticles containing moxidectin.

2. The microparticles are spherical, The microparticles uniformly contain moxidectin. Microparticles containing moxidectin as described in claim 1.

3. The coefficient of variation (CV) of the aforementioned microparticles is between 5% and 20%. Microparticles containing moxidectin as described in claim 1.

4. The microparticles contain a biodegradable polymer and moxidectin in a weight ratio of 2:1 to 12:

1. Microparticles containing moxidectin as described in claim 1.

5. The aforementioned microparticles continuously release moxidectin for more than three months. Microparticles containing moxidectin as described in claim 1.

6. The aforementioned microparticles are 0.3 to 3 according to the following formula 1. Microparticles containing moxidectin as described in claim 1: [Formula 1] C ｍａｘ－ｐｅａｋ ｎ / C ｍａｘ―ｐｅａｋ ｎ＋１ Here, Microparticles containing moxidectin were mixed with a suspension solution to prepare an injectable preparation, and the injectable preparation was administered to beagle dogs, and the blood concentration of moxidectin was measured. C ｍａｘ－ｐｅａｋ ｎ This is the nth-order Cmax value obtained by administering the injectable drug. C ｍａｘ－ｐｅａｋ ｎ＋１ This is the (n+1)th Cmax value resulting from the increase in moxidectin blood concentration again after the nth Cmax value.

7. Multiple beagle dogs were administered 0.2 mg / kg of moxidectin as the aforementioned injectable agent, and the blood concentration of moxidectin was measured. The standard deviation of blood moxidectin concentration among beagle dogs administered the aforementioned injectable agent is 0.01 to 10. Microparticles containing moxidectin as described in claim 6.

8. Microparticles containing moxidectin as described in claim 1, Includes a suspension solution, A sustained-release injectable composition containing moxidectin.

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