Moxidectin-containing microparticles and sustained-release injection composition containing same

Abstract

The present invention relates to microparticles containing moxidectin and a method for preparing the same, and more particularly, to microparticles containing moxidectin and a method for preparing the same, which can maintain the effect of preventing cardiofilmy because moxidectin is continuously released for 3 months or more when microparticles containing moxidectin are administered, unlike existing cardiofilmy preventing drugs which have a short half-life and thus require administration every day or month, and to a microparticle containing moxidectin and a method for preparing the microparticles containing moxidectin. Furthermore, by preparing microparticles having a certain average particle diameter and a narrow diameter distribution span, the initial burst release of moxidectin can be prevented even when the microparticles are administered, the concentration of moxidectin which is effective for 3 months or more can be constantly maintained by controlling the release of the drug, and foreign body sensation and pain can be reduced when the microparticles are used as an injection.

Description

Technical Field

[0001] The present invention relates to microparticles containing moxidectin and a sustained-release injection composition containing the microparticles. Background Art

[0002] Heartworm Disease (HWD) is a parasite called Dirofilaria immitis that is transmitted by mosquitoes and infects dogs, cats, and weasels. As the name implies, heartworms live in the hearts of mammals.

[0003] Adult heartworms can grow up to 30 cm and mainly parasitize in the pulmonary artery and right ventricle. Mature female and male heartworms produce very small larvae, called microfilariae (L1). These larvae parasitize in the blood of infected animals and are transmitted to other animals by mosquitoes. L1 that enters the mosquito's body becomes infective two weeks later, and the infective larvae are again transmitted to other animals by mosquitoes. The larvae that infect other animals will go through several growth stages and migrate to the pulmonary artery after 3 to 4 months. These mature heartworm adults live an average of 5 to 7 years, and female and male heartworms produce a large number of larvae through reproduction.

[0004] Infected animals may have as few as one and as many as 200 heartworms living in the heart and pulmonary arteries. The infection causes the pulmonary arteries to thicken and become inflamed, requiring the heart to work harder to keep the worms away and pump blood to the lungs. Inflammation may also occur in the lungs. When the number of heartworms infected is small, there may be no specific symptoms, but animals with heartworms may show early signs such as reluctance to move, coughing, and weight loss. When the infection is severe, symptoms such as severe coughing, difficulty breathing, and heart failure may occur. When animals with heartworms show these symptoms, they may also die from heart failure.

[0005] If the diagnosis confirms the infection of heartworm, arsenic drugs (caparsolate) can be used to kill the adult heartworms, or melarsomine can be used for treatment. However, these therapeutic agents all have side effects, such as severe irritation at the injection site and a certain degree of damage to the liver and kidneys.

[0006] Therefore, it is economical and safe to prevent heartworm infection before it occurs. Prevention is performed between 6 and 8 weeks of age. Heartworm prevention drugs include diethylcarbamazine (DEC) taken daily or ivermectin, milbemycin, moxidectin, and selamectin taken monthly. If the preventive drugs are used correctly, the preventive effect is significant, but since they need to be taken every day or every month, the risk of infection may be exposed if a few doses are accidentally missed.

[0007] Therefore, there is a need to develop a heartworm preventive drug that uses moxidectin that can prevent heartworms and maintains the drug efficacy for more than three months after a single administration, thereby improving the convenience of administration.

[0008] Prior art literature

[0009] Patent Literature

[0010] Patent Document 1KR10-2006-0005472A1 Summary of the invention

[0011] Problem that the invention aims to solve

[0012] The object of the present invention is to provide microparticles containing moxidectin and a sustained-release injection composition containing the microparticles.

[0013] Another object of the present invention is to provide microparticles containing moxidectin. Unlike existing heartworm preventive drugs that have a short half-life and therefore require regular monthly administration, when the microparticles containing moxidectin are administered, the heartworm preventive effect can be maintained because moxidectin is continuously released for more than 3 months.

[0014] Another object of the present invention is to provide a sustained-release injection composition comprising moxidectin, wherein even when the microparticles are administered, the initial burst release of moxidectin can be prevented, the effective concentration of moxidectin can be constantly maintained for more than 3 months by controlling the release of the drug, and when used as an injection, foreign body sensation and pain can be reduced.

[0015] Means used to solve problems

[0016] To achieve the above object, the microparticles containing moxidectin of the present invention may be microparticles containing moxidectin and a biodegradable polymer, the intrinsic viscosity of the biodegradable polymer may be 0.1 dl / g to 1 dl / g, and the average diameter of the microparticles may be 60 μm to 110 μm.

[0017] The microparticles may be spherical, and moxidectin may be uniformly contained in the microparticles.

[0018] The coefficient of variation (CV) of the microparticles may be 5% to 20%.

[0019] The microparticles may include the biodegradable polymer and moxidectin in a weight ratio of 2:1 to 12:1.

[0020] The microparticles can continuously release moxidectin for more than 3 months.

[0021] The biodegradable polymer may be selected from the group consisting of polylactide (PLA), polylactide-co-glycolide (PLGA), polyphosphazene, polyimidocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid and mixtures thereof.

[0022] The value of the microparticle according to the following formula 1 may be 0.3 to 3,

[0023] [Formula 1]

[0024] C max-peak n / C max―peak n+1

[0025] wherein microparticles containing moxidectin are mixed in a suspension to prepare an injection, the injection is administered to beagle dogs and the blood concentration of moxidectin is measured, C max-peak n is the nth C after the injection max Value, C max-peak n+1 is the C max After the value, the blood concentration of moxidectin increases again for the n+1th time. max value.

[0026] A sustained-release injection composition comprising moxidectin according to another embodiment of the present invention may comprise: microparticles comprising moxidectin; and a suspension.

[0027] Effects of the Invention

[0028] In the present invention, unlike the existing heartworm preventive drugs which have a short half-life and thus require regular monthly administration, when microparticles containing moxidectin are administered, the heartworm preventive effect can be maintained because moxidectin is continuously released for more than 3 months.

[0029] In addition, by preparing fine particles with smooth particle shape, uniform average particle diameter and narrow diameter distribution span, the initial burst release of moxidectin can be prevented even when the fine particles are administered, and the effective concentration of moxidectin can be constantly maintained for more than 3 months by controlling the release of the drug, and when used as an injection, the foreign body sensation and pain can be reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is the experimental result of the release pattern of moxidectin from the microparticles according to one embodiment of the present invention.

[0031] Figure 2 This is the experimental result of the release pattern of moxidectin from the microparticles according to one embodiment of the present invention.

[0032] Figure 3 This is the experimental result of the release pattern of moxidectin from the microparticles according to one embodiment of the present invention.

[0033] Figure 4 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0034] Figure 5 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0035] Figure 6 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0036] Figure 7 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0037] Figure 8 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0038] Fig. 9 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0039] Fig.10 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0040] Fig.11 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0041] Fig.12 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0042] Fig.13 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0043] Fig.14 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0044] Fig.15 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0045] Fig.16 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0046] Fig.17 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0047] Fig.18 This is a SEM measurement picture of the microparticles according to one example of the present invention.

[0048] Fig.19 These are the results of administering an injection containing microparticles of one example of the present invention to beagle dogs and measuring the moxidectin concentration in the blood. DETAILED DESCRIPTION

[0049] The present invention relates to microparticles containing moxidectin. The microparticles may be microparticles containing moxidectin and a biodegradable polymer. The intrinsic viscosity of the biodegradable polymer may be 0.1 dl / g to 1 dl / g. The average diameter of the microparticles may be 60 μm to 110 μm. Specific embodiments

[0051] Hereinafter, the embodiments of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein.

[0052] The microparticles containing moxidectin according to an embodiment of the present invention may be microparticles containing moxidectin and a biodegradable polymer. The intrinsic viscosity of the biodegradable polymer may be 0.1 dl / g to 1 dl / g, and the average diameter of the microparticles may be 60 μm to 110 μm.

[0053] Moxidectin of the present invention is a compound represented by the following Chemical Formula 1, which refers to a substance used as a heartworm preventive drug for animals.

[0054] [Chemical formula 1]

[0055]

[0056] The microparticles are characterized by being spherical and having a smooth surface.

[0057] In addition, the microparticles are characterized in that they contain a biodegradable polymer and moxidectin, the biodegradable polymer and moxidectin are uniformly mixed, and moxidectin is uniformly distributed in the microparticles.

[0058] The microparticles can be used in the form of injections, and the microparticles can be injected into an animal and injected into the body. The microparticles injected into the animal body can slowly release moxidectin as the biodegradable polymer decomposes.

[0059] Upon release of moxidectin from the microparticles of the present invention, the biodegradable polymer on the surface decomposes and begins to release moxidectin, and then, when a plurality of holes are formed inside the microparticles, the moxidectin contained in the microparticles can be released into the animal body.

[0060] Due to the release of moxidectin as described above, the microparticles of the present invention can release moxidectin in the animal body for more than 3 months, preferably, can continuously release moxidectin for 6 months or 12 months.

[0061] The release of moxidectin may be above the concentration range for treating or preventing heartworms. That is, this does not simply mean that moxidectin is continuously released for a long time, but that it is continuously released to a blood concentration above the blood concentration at which moxidectin can actually exert its medicinal effect.

[0062] As described above, the sustained release of moxidectin and the heartworm preventive effect of the microparticles of the present invention are based on the average diameter of the microparticles, the coefficient of variation (CV) described below, and the intrinsic viscosity of the biodegradable polymer.

[0063] The mean diameter (MV) of the microparticles of the present invention may be 60 μm to 110 μm, 60 μm to 100 μm, or 70 μm to 100 μm. When used within the above range, the release effect of moxidectin can be exhibited over a desired period of time, there is no foreign body sensation when injected, and absorption by macrophages in the body can be prevented.

[0064] The coefficient of variation (CV) of the microparticles may be 5% to 20%, 6% to 19%, 7% to 18.5%, or 8% to 18.5%. The coefficient of variation is a value indicating the monodispersity of the particle size distribution. The smaller the CV value, the more uniform the particle size.

[0065] The coefficient of variation can be calculated by the following formula 2.

[0066] [Formula 2]

[0067] (Standard deviation of diameter / mean value of diameter)*100

[0068] By including microparticles having a coefficient of variation within the above range, the release pattern of moxidectin can be controlled. In addition, as described below, when prepared by the microparticle preparation method of the present invention, microparticles having a uniform size can be prepared, thereby preparing microparticles including different biodegradable polymers and using them by mixing them.

[0069] Microparticles containing a drug such as moxidectin, as described above, can release the drug by decomposition of the biodegradable polymer in vivo. Thus, the microparticles should be of uniform size to allow sustained release of the drug over a desired period of time.

[0070] Specifically, when the microparticles are distributed in various sizes, there is a problem that the small microparticles are quickly decomposed in the body or cannot release the drug due to macrophages. That is, although the microparticles with small particle sizes can release the drug, they only work in the early stage in the body and cannot release the drug for a long time.

[0071] In addition, when the size of the microparticles is large, the initial drug release effect is weak and the drug release time may be too long. The microparticles can release the drug within a desired period, but if the drug release time exceeds the desired time, the drug release pattern cannot be adjusted, and thus repeated administration may be difficult.

[0072] Microparticles having various sizes, as described above, include both small-sized and large-sized microparticles. That is, it means that the size of the microparticles cannot be adjusted, which means that the release time of the drug cannot be adjusted, and continuous use rather than single use is required, which may cause difficulties.

[0073] The microparticles of the present invention are characterized in that the average particle diameter (MV) is 60 μm to 110 μm and the coefficient of variation is 5% to 20%, which means that the microparticles are distributed within the average diameter range and only microparticles with uniform diameters are included.

[0074] As described above, as it contains microparticles of uniform size, the initial burst release of moxidectin can be prevented by injection into an animal body, and the release effect of moxidectin for 3 months, 6 months or 12 months can be exhibited.

[0075] The biodegradable polymer may be selected from the group consisting of polylactide (PLA), polylactide-co-glycolide (PLGA), polyphosphazene, polyimidocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid and mixtures thereof.

[0076] Preferably, the biodegradable polymer may be selected from the group consisting of polylactide (PLA), polylactide-co-glycolide (PLGA) and a mixture thereof.

[0077] Specifically, the polylactide (PLA) or the polylactide-glycolide copolymer (PLGA) may be included, and the polylactide (PLA) and the polylactide-glycolide copolymer (PLGA) may be included.

[0078] More specifically, the microparticles may contain PLA and moxidectin, may contain PLGA and moxidectin, or may contain PLA, PLGA, and moxidectin. Microparticles containing both PLA and PLGA mean that, as described later, when a biodegradable polymer and moxidectin are dissolved in an organic solvent, both PLA and PLGA are contained, and the prepared microparticles contain both PLA and PLGA.

[0079] In addition, as described later, the microparticles of the present invention may be included in a sustained-release injection composition. In this 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.

[0080] The microparticles contained in the injection composition may contain only one biodegradable polymer, may contain two or more different biodegradable polymers, or may contain two or more different microparticles containing more than one biodegradable polymer. As mentioned above, the inclusion of multiple microparticles is used to adjust the release time of moxidectin.

[0081] 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, 0.1 dl / g to 0.6 dl / g. In addition, 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, 15 kg / mol to 65 kg / mol.

[0082] The microparticles of the present invention are used for sustained release of moxidectin for 3 months, 6 months or 12 months, preferably, sustained release of moxidectin for 6 months or 12 months in animals.

[0083] As described above, although the release of moxidectin from the microparticles is related to the average diameter of the particles, the intrinsic viscosity also has a great influence. Generally, the greater the viscosity of the biodegradable polymer, the more delayed the release of moxidectin may be, but this feature is not necessarily applicable, and the intrinsic viscosity of the biodegradable polymer and the viscosity of moxidectin affect each other, thereby affecting the decomposition of the biodegradable polymer and the release of moxidectin.

[0084] The biodegradable polymer is approved by the FDA and can also be used as a human medicine injection, and its decomposition period is specific according to the type of biodegradable polymer. That is, the biodegradation period of a specific polymer is used in various ways, such as 2 to 3 months, 6 to 9 months, 10 to 14 months, etc.

[0085] However, this refers to the biodegradation period of the biodegradable polymer, and when mixed with moxidectin and prepared into microparticles, the biodegradation period may be changed due to the influence of moxidectin on the biodegradation period of the biodegradable polymer.

[0086] Therefore, in order to sustain the release of moxidectin in the body for a desired period of time, the combination of the biodegradable polymer and moxidectin is important.

[0087] That is, in order to release moxidectin for 3 months, it is not necessary to simply use a biodegradable polymer having a biodegradation period of 3 months, but it is necessary to examine whether a combination of moxidectin and a biodegradable polymer can achieve 3-month biodegradation.

[0088] 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 release effect of moxidectin can be exhibited over a desired period of time.

[0089] The microparticles may contain the biodegradable polymer and moxidectin in a weight ratio of 2:1 to 12:1, in a weight ratio of 4:1 to 10:1, or in a weight ratio of 9:1. When the biodegradable polymer and moxidectin are contained in the above ranges, when injected into an animal body, an initial burst release can be prevented, and a sustained release effect of moxidectin can be exhibited over a desired period of time.

[0090] In general injection forms, side effects may occur due to the initial burst release of moxidectin. However, in the present invention, even when injected as an injection, the initial burst release can be prevented and the release effect of moxidectin can be continuously exhibited for a desired period of time.

[0091] In addition, as described above, the sustained release of moxidectin for 3 months, 6 months, or 12 months means that the release of moxidectin can reach a level that exhibits a preventive or therapeutic effect against heartworms.

[0092] The value of the fine particles according to the following Formula 1 may be 0.3 to 3.

[0093] [Formula 1]

[0094] C max-peak n / C max―peak n+1

[0095] wherein microparticles containing moxidectin are mixed in a suspension to prepare an injection, the injection is administered to beagle dogs and the blood concentration of moxidectin is measured, C max-peak n is the nth C after the injection max Value, C max-peak n+1 is the C max After the value, the blood concentration of moxidectin increases again for the n+1th time. max value.

[0096] In Formula 1, the microparticles of the present invention are administered as an injection to beagle dogs, and the blood concentration of moxidectin is measured. The value of Formula 1 may be 0.3 to 3, 0.5 to 3, 0.5 to 2.5. When the ratio of the peak blood concentration of moxidectin appears within the above range, it can be controlled so that moxidectin can be released for a long time over a desired period of time.

[0097] Depending on the microparticles contained in the injection containing different biodegradable polymers, a peak of the blood concentration of moxidectin appears, and the formula 1 refers to the relationship based thereon.

[0098] Specifically, as described above, the microparticles of the present invention can be prepared by using two or more different biodegradable polymers. A plurality of microparticles may contain only one biodegradable polymer, but may contain different biodegradable polymers. That is, microparticles containing PLGA and moxidectin and microparticles containing PLA and moxidectin may be included.

[0099] Microparticles comprising different biodegradable polymers, as described above, can exhibit the maximum plasma concentration (C) of moxidectin of the nth order as shown in Formula 1. max-peak n ), and then the maximum blood concentration of moxidectin at the n+1th time (C max-peak n+1 ).

[0100] The n-th maximum blood concentration of moxidectin is the maximum blood concentration of moxidectin after injection, which refers to the maximum value of the blood concentration of moxidectin gradually increasing and then decreasing again, and the n+1-th maximum blood concentration of moxidectin refers to the maximum value of the blood concentration of moxidectin decreasing again under the trend of increasing again after the n-th maximum blood concentration of moxidectin. The injection formulation containing the microparticles of the present invention may show multiple maximum blood concentration values. At the n-th maximum blood concentration of moxidectin (C max-peak n ) and the maximum plasma concentration of moxidectin at the n+1th time (Cmax-peak n+1 ), the maximum blood concentration of moxidectin at the nth time may show a larger value than the maximum blood concentration of moxidectin at the n+1th time, and the maximum blood concentration of moxidectin at the n+1th time may show a larger value than the maximum blood concentration of moxidectin at the nth time.

[0101] The trend of the peak blood concentration as described above varies with the different release patterns of moxidectin, wherein the release pattern of moxidectin depends on the type of biodegradable polymer. The microparticles of the present invention are characterized in that they are prepared by the preparation method described below, and the microparticles prepared by the preparation method of the present invention can be precisely adjusted so that they have a uniform particle size. For this reason, microparticles can be prepared separately by using different biodegradable polymers and mixed for use.

[0102] As described above, microparticles prepared by using different biodegradable polymers can exhibit respective intrinsic release patterns of moxidectin, and can exhibit multiple blood drug concentration peaks according to the intrinsic release patterns.

[0103] As described above, when different biodegradable polymers are used to prepare the microparticles, the biodegradation rates of the biodegradable polymers differ. When this characteristic is utilized, when administered as an injection, microparticles that can show an initial moxidectin release effect and microparticles that can show a late moxidectin release effect are mixed and used, and a long-term sustained moxidectin release effect can be exhibited.

[0104] In contrast, the microparticles of the present invention are characterized in that, after administration in vivo, the maximum blood concentration (C max ) appears after a certain time has passed.

[0105] After administration of the microparticles of the present invention, the maximum plasma concentration of moxidectin in vivo (C max ) can be affected by the average diameter of the microparticles, the size distribution of the particles and the type of biodegradable polymer.

[0106] For example, after administration in vivo, microparticles in a 3-month to 6-month dosage form may exhibit a maximum blood drug concentration (C max). Specifically, the microparticles of the present invention can suppress the initial burst release, and after being injected into the body, the release amount of moxidectin increases slowly, and after showing the maximum blood concentration in the range of 10 to 90 days, the release amount of moxidectin decreases, and moxidectin can be continuously released for 3 months or 6 months. Different from the above content, when only one biodegradable polymer is used, multiple maximum blood concentration peaks of moxidectin are not shown, and only a single maximum blood concentration peak is shown, and the maximum blood concentration can appear in the range of 10 to 90 days after injection.

[0107] In addition, as for the 12-month dosage form, the maximum blood drug concentration (C max ). However, as described above, it may be affected by the average diameter of the microparticles, the size distribution of the particles, the type of the biodegradable polymer, and the like.

[0108] The range of days for showing the maximum blood concentration may vary depending on the administration subject and the administration dose. However, as shown in the examples of the present invention, when the total content of moxidectin administered to beagle dogs is 0.2 mg / kg to 1 mg / kg, the maximum blood concentration (C max The maximum blood concentration of moxidectin (C max ), moxidectin can be released continuously for 3 months, 6 months or 12 months, preferably, moxidectin can be released continuously for 6 months or 12 months.

[0109] The microparticles containing moxidectin are mixed in a suspension to prepare an injection, and the injection is administered to a plurality of beagles. 0.2 mg / kg of moxidectin is administered to 10 beagles in the same manner as the formula 1, and as the same injection, the moxidectin concentration in the blood of the beagles is measured, and the standard deviation of the moxidectin concentration in the blood of the beagles at the same time period may be 0.01 to 10, 0.01 to 5, or 0.01 to 3.

[0110] The standard deviation value of the moxidectin concentration in the blood as described above means that the prepared microparticles have excellent uniformity, and the excellent reproducibility in the in vivo experimental results means that the effectiveness and safety of the administration of moxidectin are excellent.

[0111] Even when the same injection is administered to beagles, the concentration of moxidectin in the blood can vary depending on the beagles. This is because drug-metabolizing enzymes vary between the subjects, and even when the same injection is administered, the metabolic rate of the drug released in the body can vary.

[0112] However, in order to provide a sustained-release preparation, the moxidectin concentration value in the blood after administration to the body needs to be controlled so as not to show a large difference, and this is a factor affected by the quality of the particles containing moxidectin prepared.

[0113] The microparticles of the present invention can be prepared by the preparation method described below, and can be prepared so that the particle size is very uniform, the surface of the particle is smooth and the particle is in a complete spherical shape.

[0114] That is, when fine particles having uniform size and properties are prepared as described above and administered to beagles or the like as an injection, the moxidectin concentration in the blood may vary slightly due to individual differences, but the difference is only a slight difference.

[0115] On the contrary, unlike the present invention, in the case of microparticles having uneven particle sizes or rough texture, the sizes of microparticles contained in the injection vary. Due to the difference in texture, when the injection is administered to beagle dogs, etc., the moxidectin concentration in the blood is measured with great differences due to the differences between microparticles in addition to the differences between individuals.

[0116] The sustained-release injection composition containing moxidectin according to another embodiment of the present invention may include the microparticles and suspension containing moxidectin.

[0117] The suspension comprises an isotonic agent, a suspending agent and a solvent.

[0118] More specifically, the isotonic agent can be selected from the group consisting of D-mannitol, maltitol, sorbitol, lactitol, xylitol, sodium chloride and a mixture thereof, preferably D-mannitol, but not limited to the examples.

[0119] The suspending agent may be selected from the group consisting of sodium carboxymethylcellulose, polysorbate 80, starch, starch derivatives, polyols, chitosan, chitosan derivatives, cellulose, cellulose derivatives, collagen, gelatin, hyaluronic acid (HA), alginic acid, algin, pectin, carrageenan, chondroitin, chondroitin sulfate, dextran, dextran sulfate, polylysine, titin, fibrin, agarose, fluran, xanthan gum, and a mixture thereof, preferably sodium carboxymethylcellulose and polysorbate 80, but not limited to the examples.

[0120] As the solvent, water for injection can be used, and any solvent that can be used as water for injection can be used without limitation.

[0121] The method for preparing microparticles containing moxidectin according to another embodiment of the present invention may include: step 1), dissolving a biodegradable polymer and moxidectin in an organic solvent to prepare an oil phase solution; step 2), dissolving a surfactant in water to prepare an aqueous phase solution; step 3), injecting the oil phase solution of step 1) into a microchannel in a linear direction to make it flow; step 4), injecting the aqueous phase solution of step 2) into a microchannel formed on both sides or one side and making it flow, so as to be able to flow with the microchannel along the linear direction of the oil phase solution of step 3). The channels form intersections, and the flow of the oil phase solution and the flow of the aqueous phase solution intersect to prepare microparticles uniformly containing moxidectin; step 5), collecting the microparticles generated at the intersections of step 4); step 6), evaporating and removing the organic solvent present in the microparticles by stirring the microparticles collected in step 5); and step 7), washing and drying the microparticles of step 6), the inherent viscosity of the biodegradable polymer may be 0.1 dl / g to 1 dl / g, and the average particle diameter (MV) of the microparticles may be 60 μm to 110 μm.

[0122] The step 1) is a step of preparing an oil phase solution, wherein moxidectin and a biodegradable polymer are dissolved in an organic solvent to prepare an oil phase solution. The biodegradable polymer is polylactide (PLA), preferably polylactide-co-glycolide (PLGA) or polylactide (PLA), but is not limited to the examples.

[0123] In addition, the organic solvent is immiscible with water, for example, one or more selected from the group consisting of chloroform, ethyl chloride, dichloroethane, dichloromethane, trichloroethane and mixtures thereof, preferably dichloromethane, but not limited to the examples. The organic solvent that can dissolve the biodegradable polymer and moxidectin is not limited to the examples, and any organic solvent that can be easily selected by a person skilled in the art can be used.

[0124] In the step 1), an oil phase solution for dissolving moxidectin and a biodegradable polymer is prepared. As mentioned above, an organic solvent is used as the solvent. This is to utilize the solubility characteristics of moxidectin and a biodegradable polymer and completely dissolve them by using an organic solvent. More specifically, moxidectin and a biodegradable polymer are dissolved in an organic solvent to prepare an oil phase solution.

[0125] In the oil phase solution, the weight ratio of the biodegradable polymer to moxidectin can be 2: 1 to 12: 1, 4: 1 to 10: 1, 9: 1. When mixed and used within the above range, moxidectin can be released continuously for a long time through the decomposition of the biodegradable polymer.

[0126] When the weight ratio of moxidectin to the biodegradable polymer is less than 1:2, that is, when the content of the biodegradable polymer is lower than the weight ratio, it may be difficult to prepare microparticles in which moxidectin is uniformly distributed in spherical biodegradable polymer particles due to the small weight ratio of the biodegradable polymer compared to the weight of moxidectin. When the weight ratio of the biodegradable polymer to moxidectin exceeds 1:12, that is, when the content of the biodegradable polymer exceeds the weight ratio, due to the small content of moxidectin in the sustained-release particles, in order to achieve the desired drug concentration, a large amount of sustained-release particles may need to be administered.

[0127] More specifically, the biodegradable polymer in the oil phase solution comprises 10 wt % to 20 wt %, preferably 15 wt %, but is not limited to the example.

[0128] The step 2) is a step of preparing an aqueous phase solution, wherein a surfactant is dissolved in water to prepare an aqueous phase solution. The surfactant can be used without restriction as long as it helps the biodegradable polymer solution to form a stable emulsion. Specifically, the surfactant is selected from one or more of the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants and mixtures thereof, more specifically, methylcellulose, polyvinyl pyrrolidone, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, sodium lauryl sulfate, sodium stearate, esteramine, linear diamine, fatty amine and mixtures thereof, preferably polyvinyl alcohol, but not limited to the examples.

[0129] The surfactant contained in the aqueous phase solution may be contained in an amount of 0.1 to 1.0 wt %, 0.2 to 0.5 wt %, or 0.25 wt %. The rest is water.

[0130] The step 3) is a step of injecting the oil phase solution and the water phase solution into the microchannel formed on the wafer or the organic substrate and allowing them to flow.

[0131] In the prior art, the microchannels used to prepare the same microparticles as those of the present invention are prepared by forming seven microchannels on a silicon wafer. The microchannels may include: a channel for the flow of an aqueous phase solution; a channel for the flow of an oil phase solution; and a channel for the movement of an emulsion generated after the aqueous phase solution and the oil phase solution form an intersection.

[0132] However, in the prior art chip in which a total of seven channels are formed on the silicon wafer, since a small number of microchannels are formed, when microparticles are simultaneously prepared using seven microchannels, microparticles of the same size can be prepared by adjusting the hydraulic pressures of the oil phase solution and the water phase solution.

[0133] However, as the number of microchannels formed in the chip increases, there is a problem that it is difficult to prepare microparticles of uniform size by adjusting the hydraulic pressures of the oil phase solution and the water phase solution.

[0134] That is, when more than 10 microchannels are formed on a plane, it is difficult to supply the hydraulic pressure of the aqueous solution and the oil solution equally from channel 1 to channel 10. Due to the uneven distribution of hydraulic pressure in each microchannel, the size and particle size distribution of the prepared microparticles are different.

[0135] Therefore, the present invention is characterized in that the flow ratio of the fluid flowing into the channel of the oil phase solution and the aqueous phase solution is maintained at 1:45 or more in order to prepare microparticles of uniform size even in a chip having more than 10 microchannels.

[0136] Specifically, when the flow rate of the oil phase solution was adjusted to 110 μl / min, and the water phase solution exhibited a flow rate of 5000 μl / min, a uniform emulsion could be prepared at the intersection point.

[0137] The use of microchannels to prepare microparticles as described above utilizes microfluidics, which is a technology that utilizes microfluidic engineering technology to prepare microparticles with a uniform diameter distribution. It is a technology that utilizes the polarity difference between an oil phase solution and an aqueous phase solution to generate an emulsion by the repulsive force between fluids when passing through a microunit channel.

[0138] When using an existing single-channel or approximately 10-channel chip, the flow rate can be controlled by adjusting the pressure (air pressure) ratio of the oil phase solution and the aqueous phase solution injected into the channel. However, when an integrated chip with multiple channels is used, it is important to adjust the flow ratio of the oil phase solution and the aqueous phase solution injected into the channel, rather than the pressure of the oil phase solution and the aqueous phase solution.

[0139] There are differences in whether microparticles can be prepared using microchannels according to the flow rate ratio of the oil phase solution to the water phase solution. When the fluid flowing in the microchannel forms a laminar flow and is disconnected in a certain manner at the intersection (junction) part where the channels intersect by the repulsive force of the fluid, a dripping condition is exhibited, and when the flow rate ratio of the oil phase solution to the water phase solution deviates from the scope of the present invention, an emulsion cannot be uniformly prepared by a jetting phenomenon other than a dripping phenomenon.

[0140] Figure 1 This is a photograph of an emulsion formed when the aqueous phase solution and the oil phase solution are included in a range of flow ratios and exhibit dripping conditions at the intersection point where the channels intersect according to an embodiment of the present invention.

[0141] It can be confirmed. Figure 1 The particle size of the emulsion shown in FIG. 5 is 170 μm to 190 μm, the particle size is uniformly distributed, the particle size is completely spherical, and the particle size is smooth.

[0142] On the contrary, Figure 2 A conceptual diagram showing dripping conditions at the intersection of channels and the emulsion that can be formed by the jetting phenomenon.

[0143] As mentioned above, when dripping, Figure 1 As shown, it was confirmed that an emulsion having a uniform diameter was formed, whereas when jetting, it was confirmed that emulsions having different diameters were formed.

[0144] The flow ratio of the oil phase solution to the water phase solution may be 1:45 or more, and may be 1:45 to 1:125. When the flow ratio is less than 1:45, jetting is formed, and the uniform size distribution with a CV of less than 10% is not obtained. When the water phase ratio becomes greater than 1:45 and reaches 1:125 or more, dripping is formed and the size distribution is appropriate. As the water phase ratio increases, the amount of the water phase solution used increases, so a problem in the preparation quantity may occur.

[0145] More specifically, the microchannel may be formed in a material selected from the group consisting of a glass substrate, a silicon wafer, or a polymer film, but examples of the material are not limited to the examples, and any material capable of forming a microchannel may be used.

[0146] The polymer film may be selected from the group consisting of polyimide, polyethylene, fluorinated ethylene propylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polysulfone and a mixture thereof, but is not limited to the examples.

[0147] As an example, aluminum is deposited on a silicon wafer using an e-beam evaporator, and a photoresist is patterned on the aluminum using photolithography. The photoresist is then used as a mask to etch the aluminum, and after removing the photoresist, the aluminum is used as a mask to etch the silicon using deep ion reactive etching (DRIE), and after removing the aluminum, glass is anodically bonded to the wafer and sealed to prepare the microchannels described above.

[0148] The average diameter of the above-mentioned microchannel is 160 μm to 200 μm, preferably 180 μm, but not limited to the example. When the average diameter of the microchannel is less than 160 μm, there is a possibility that the diameter of the prepared microparticles is less than 50 μm and is prepared into small microparticles, which may affect effective drug release and in vivo absorption. When the average diameter of the microchannel is more than 200 μm, the average size of the prepared microparticles exceeds 120 μm, and when used as an injection, foreign body sensation and pain may be increased, and as the diameter of the microchannel increases, it is difficult to prepare microparticles with uniform particle size because the particle size distribution of the prepared particles becomes larger.

[0149] In addition, the average diameter of the microchannel is closely related to the average diameter of the particles and is also closely related to the flow ratio (μl / min) of the oil phase solution to the water phase solution.

[0150] In addition, the cross-sectional width (w) and cross-sectional height (d) of the microchannel are closely related to the average diameter (d') of the prepared microparticles. The ratio of the width (w) of the microchannel cross section to the average diameter (d') of the microparticles is in the range of 0.7 to 1.3, and the ratio of the height (d) of the microchannel cross section to the average diameter (d') of the microparticles is in the range of 0.7 to 1.3.

[0151] That is, when the average diameter (d') of the microparticles to be prepared is determined, the width (w) and height (d) of the microchannel cross section need to be set to a ratio range of 0.7 to 1.3 of d' in order to prepare microparticles of the desired size.

[0152] In the step 3), the oil phase solution and the water phase solution are allowed to flow in the first microchannel and the second microchannel forming the intersection under the flow conditions.

[0153] That is, the oil phase solution flows along the first microchannel, and the water phase solution flows along the second microchannel formed in such a manner as to form an intersection with the first microchannel, and intersects with the flow of the oil phase solution.

[0154] More specifically, when the oil phase solution is injected into the first microchannel, when the flow rate and the water phase solution are injected into the second microchannel, the flow rate ratio of the oil phase solution to the water phase solution may be greater than 1:45, and may be 1:45 to 1:125.

[0155] As described above, in the prior art, in order to prepare microparticles, microparticles with a certain diameter can be prepared by controlling the hydraulic pressure. However, in the case of a chip having more than 10 microchannels integrated therein, microparticles with a uniform diameter cannot be prepared by controlling the hydraulic pressure. Therefore, microparticles with a uniform diameter can be prepared by adjusting the flow ratio of the oil phase solution to the water phase solution.

[0156] As described above, if the flow rates of the oil phase solution and the aqueous phase solution are set differently, the aqueous phase solution with a larger flow rate compresses the oil phase solution at the point where the flow of the oil phase solution and the flow of the aqueous phase solution intersect, and at this time, dripping occurs due to the repulsive force between the oil phase solution and the aqueous phase solution, thereby generating spherical microparticles in which the biodegradable polymer and moxidectin are uniformly distributed. More specifically, the microparticles can be formed in the form of microparticles in which moxidectin is uniformly distributed in the spherical biodegradable polymer.

[0157] The step 4) is a step of collecting the microparticles, in which the microparticles are collected in a water tank filled with an aqueous solution to prevent aggregation of the microparticles generated at the initial stage.

[0158] The step 4) utilizes the aqueous solution (i.e., a mixed solution of a surfactant and water) prepared in the step 2). After the aqueous solution is prepared in the step 2), a portion is injected into the microchannel, and the other portion is moved to the water tank of the step 4) and used to prevent aggregation between the collected particles.

[0159] The step 5) is a step for removing the organic solvent present in the microparticles collected in the water tank, and stirring is performed according to certain temperature conditions and stirring speeds to evaporate and remove the organic solvent present inside the microparticles. At this time, the stirring conditions are: step 5-1), at a temperature of 15°C to 20°C, the first stirring is performed at a speed of 150rpm to 350rpm, and the stirring time is 50 minutes to 70 minutes; step 5-2), at a temperature of 20°C to 30°C, the second stirring is performed at a speed of 250rpm to 450rpm, and the stirring time is 50 minutes to 70 minutes; and step 5-3), at a temperature of 40°C to 60°C, the third stirring is performed at a speed of 450rpm to 650rpm, and the stirring time is 3 hours to 9 hours.

[0160] Regarding the stirring speed, the stirring process is performed by changing the temperature conditions and stirring time in the first and second stirring steps.

[0161] As described above, the present invention is characterized in that the stirring is performed by raising the temperature conditions in the second stirring step compared to the first stirring step, and the evaporation rate of the organic solvent present in the microparticles can be adjusted by stepwise temperature increase. That is, microparticles can be prepared by slowly evaporating the organic solvent present in the microparticles.

[0162] In addition, the temperature of the oil phase solution and the water phase solution when flowing through the microchannel is 15°C to 20°C, preferably 17°C. That is, after flowing through the microchannel and forming the intersection to generate microparticles, until the collected microparticles are stirred for the first time, the low temperature of 15°C to 20°C is constantly maintained. In the process of preparing microparticles, spherical particles can only be prepared and maintained by maintaining a low temperature. That is, in the case other than the low temperature condition, it is difficult to prepare certain spherical particles.

[0163] Next, the second stirring process gradually increases the temperature and the stirring time, so that the organic solvent inside the particles slowly moves to the surface, and as the organic solvent evaporates from the surface, the influence on the properties of the particles can be minimized. That is, when the organic solvent evaporates quickly, the surface of the particles may be rough and pores may be formed due to the evaporation of the organic solvent. In order to prevent this problem, as described above, the evaporation rate of the organic solvent can be adjusted by gradually increasing the temperature conditions and increasing the time for the stirring process. Due to the adjustment of the evaporation rate of the organic solvent, the surface shape of the prepared particles can be controlled.

[0164] In the third stirring process, after the organic solvent in the emulsion is extracted into the external aqueous phase, the external aqueous phase is heated to a temperature close to the boiling point of the organic solvent and stirred, thereby removing the saturated organic solvent from the aqueous phase, making it easy to remove the organic solvent remaining in the particles.

[0165] Finally, step 6) is a step of washing and drying the microparticles. The microparticles, from which all organic solvents on the surface are removed by stirring, are washed several times with sterile filtered pure water to remove the residual surfactant in the microparticles, and then freeze-dried.

[0166] The resulting microparticles are in the shape of spherical biodegradable polymer microparticles on which moxidectin is uniformly distributed, and contain the biodegradable polymer and moxidectin in a weight ratio of 2:1 to 12:1.

[0167] The weight ratio of moxidectin to the biodegradable polymer contained in the microparticles is the same as that in the oil phase solution. The oil phase emulsion particles are prepared through microchannels, and as all organic solvents in the emulsion are removed, microparticles containing moxidectin and the biodegradable polymer can be prepared in the same weight ratio as that in the oil phase solution.

[0168] Preparation Example 1

[0169] Preparation of microparticles containing moxidectin

[0170] Poly(lactide-co-glycolide) (PLGA) and moxidectin were dissolved in dichloromethane to prepare an oil phase solution, wherein the poly(lactide-co-glycolide) (PLGA) had a viscosity of 0.2 dl / g, contained a terminal carboxylic acid group, had a molecular weight (MW) of 17 kg / mol, and a ratio of lactide to glycolide of 75:25. At this time, the poly(lactide-co-glycolide) in the oil phase solution was contained at a ratio of 15 wt%, and the weight ratio of the poly(lactide-co-glycolide) to moxidectin was 9:1.

[0171] Polyvinyl alcohol as a surfactant was mixed with water, and an aqueous phase solution containing 0.25 wt % of polyvinyl alcohol was prepared.

[0172] The oil phase solution and the water phase solution were injected into the microchannels formed on the silicon wafer and allowed to flow. At this time, the oil phase solution and the water phase solution were injected into each microchannel with a flow ratio of 1:50, and the temperature condition was maintained at 17°C.

[0173] The particles formed at the intersection of the flow of the oil phase solution and the flow of the water phase solution were collected in the water tank filled with the second mixture. The particles collected in the water tank were stirred at 250 rpm for 1 hour at 17° C., stirred at 350 rpm for 1 hour at 25° C., and stirred at 550 rpm for 4 hours at 550 rpm.

[0174] The stirred microparticles were washed several times with sterile filtered purified water and freeze-dried to prepare microparticles.

[0175] Preparation Example 2-1

[0176] Microparticles were prepared in the same manner as in Preparation Example 1 except that polylactic acid having a viscosity of 0.2 dl / g, a terminal carboxyl group and a molecular weight (MW) of 17 kg / mol was used instead of the polylactide-glycolide copolymer.

[0177] Preparation Example 2-2

[0178] Microparticles were prepared in the same manner as in Preparation Example 1 except that polylactic acid having a viscosity of 0.2 dl / g, a terminal carboxyl group, and a molecular weight (MW) of 17 kg / mol was used instead of polylactide-glycolide copolymer, and the polylactic acid was contained in the oil phase solution at a ratio of 10 wt %.

[0179] Preparation Example 3-1

[0180] Microparticles were prepared in the same manner as in Preparation Example 1 except that polylactic acid having a viscosity of 0.4 dl / g, a terminal carboxyl group and a molecular weight (MW) of 45 kg / mol was used instead of the polylactide-glycolide copolymer.

[0181] Preparation Example 3-2

[0182] Microparticles were prepared in the same manner as in Preparation Example 1 except that polylactic acid having a viscosity of 0.4 dl / g, a terminal carboxyl group, and a molecular weight (MW) of 45 kg / mol was used instead of polylactide-glycolide copolymer, and the polylactic acid was contained in the oil phase solution at a ratio of 10 wt %.

[0183] Preparation Example 4

[0184] Microparticles were prepared in the same manner as in Preparation Example 1 except that polylactic acid having a viscosity of 0.4 dl / g, a terminal ester group, and a molecular weight (MW) of 45 kg / mol was used instead of polylactide-glycolide copolymer, and the polylactic acid was contained in the oil phase solution at a ratio of 10 wt %.

[0185] Preparation Example 5

[0186] Microparticles were prepared in the same manner as in Preparation Example 1 except that polylactic acid having a viscosity of 0.5 dl / g, a terminal ester group, and a molecular weight (MW) of 61 kg / mol was used instead of polylactide-glycolide copolymer, and the polylactic acid was contained in the oil phase solution at a ratio of 10 wt %.

[0187] Preparation Example 6

[0188] As biodegradable polymers, polylactide-glycolide copolymer (PLGA) and polylactide (PLA) were used, wherein the polylactide-glycolide copolymer (PLGA) had a viscosity of 0.2 dl / g, contained a terminal carboxyl group, had a molecular weight (MW) of 17 kg / mol, and a ratio of lactide to glycolide of 75:25, and the polylactide (PLA) had a viscosity of 0.2 dl / g, contained a terminal carboxyl group, had a molecular weight (MW) of 17 kg / mol, and a weight ratio of PLGA to PLA of 1:1. At this time, the polylactide-glycolide copolymer and polylactic acid in the oil phase solution were contained at a ratio of 10 weight %. Except for this, microparticles were prepared in the same manner as Preparation Example 1.

[0189] Preparation Example 7-1

[0190] Two different polylactides (PLA) were used as biodegradable polymers, one of which had a viscosity of 0.2 dl / g, contained a terminal carboxyl group, and had a molecular weight (MW) of 17 kg / mol, and the other had a viscosity of 0.4 dl / g, contained a terminal carboxyl group, and had a molecular weight (MW) of 45 kg / mol. The weight ratio of the two different PLAs was 1:1. Except for this, microparticles were prepared in the same manner as Preparation Example 1.

[0191] Preparation Example 7-2

[0192] Two different polylactides (PLA) were used as biodegradable polymers, one of which had a viscosity of 0.2 dl / g, contained a terminal carboxyl group, and had a molecular weight (MW) of 17 kg / mol, and the other had a viscosity of 0.4 dl / g, contained a terminal carboxyl group, and had a molecular weight (MW) of 45 kg / mol. The weight ratio of the two different PLAs was 1:1. At this time, the total amount of polylactic acid in the oil phase solution was contained at a ratio of 10 weight %. Except for this, microparticles were prepared in the same manner as Preparation Example 1.

[0193] Preparation Example 8

[0194] Two different polylactides (PLA) were used as biodegradable polymers, one of which had a viscosity of 0.2 dl / g, contained a terminal carboxyl group, and had a molecular weight (MW) of 17 kg / mol, and the other had a viscosity of 0.4 dl / g, contained a terminal ester group, and had a molecular weight (MW) of 45 kg / mol. The weight ratio of the two different PLAs was 1:1. At this time, the total amount of polylactic acid in the oil phase solution was contained at a ratio of 10 weight %. Except for this, microparticles were prepared in the same manner as Preparation Example 1.

[0195] Preparation Example 9-1

[0196] Two different polylactides (PLA) were used as biodegradable polymers, one of which had a viscosity of 0.2 dl / g, contained a terminal carboxyl group, and had a molecular weight (MW) of 17 kg / mol, and the other had a viscosity of 0.4 dl / g, contained a terminal carboxyl group, and had a molecular weight (MW) of 45 kg / mol. The weight ratio of the two different PLAs was 1:3. Except for this, microparticles were prepared in the same manner as Preparation Example 1.

[0197] Preparation Example 9-2

[0198] Two different polylactides (PLA) were used as biodegradable polymers, one of which had a viscosity of 0.2 dl / g, contained a terminal carboxyl group, and had a molecular weight (MW) of 17 kg / mol, and the other had a viscosity of 0.4 dl / g, contained a terminal carboxyl group, and had a molecular weight (MW) of 45 kg / mol. The weight ratio of the two different PLAs was 1:3. At this time, the total amount of polylactic acid in the oil phase solution was contained at a ratio of 10 weight %. Except for this, microparticles were prepared in the same manner as Preparation Example 1.

[0199] Preparation Example 10

[0200] Two different polylactides (PLA) were used as biodegradable polymers, one of which had a viscosity of 0.4 dl / g, contained a terminal ester group, and had a molecular weight (MW) of 45 kg / mol, and the other had a viscosity of 0.5 dl / g, contained a terminal ester group, and had a molecular weight (MW) of 61 kg / mol. The weight ratio of the two different PLAs was 1:1. At this time, the total amount of polylactic acid in the oil phase solution was contained at a ratio of 10 weight %. Except for this, microparticles were prepared in the same manner as Preparation Example 1.

[0201] Preparation Example 11

[0202] As biodegradable polymers, two different polylactide-glycolide copolymers (PLGA) and polylactide (PLA) were used, wherein one polylactide-glycolide copolymer (PLGA) had a viscosity of 0.2 dl / g, contained a terminal carboxyl group, had a molecular weight (MW) of 17 kg / mol, and a ratio of lactide to glycolide of 50:50, and the other polylactide-glycolide copolymer (PLGA) had a viscosity of 0.2 dl / g, contained a terminal carboxyl group, had a molecular weight (MW) of 17 kg / mol, and a ratio of lactide to glycolide of 75:25, and the polylactide (PLA) had a viscosity of 0.2 dl / g, contained a terminal carboxyl group, and had a molecular weight (MW) of 17 kg / mol. The weight ratio of the above three polymers was 1:1:4. Except for this, microparticles were prepared in the same manner as Preparation Example 1.

[0203] Example 1

[0204] The microparticles of Preparation Example 1 and the microparticles of Preparation Example 2-1 were mixed at a weight ratio of 1:2, and 2.0 mL of a suspending agent was added to one vial to uniformly suspend the mixture to prepare a composition for subcutaneous injection.

[0205] The suspension concentrate is composed of the composition shown in Table 1 below.

[0206] Table 1

[0207]

[0208] Example 2

[0209] A composition for subcutaneous injection was prepared in the same manner as in Example 1, except that the fine particles of Preparation Example 1 and the fine particles of Preparation Example 2-1 were mixed at a weight ratio of 1:1 and used.

[0210] Example 3

[0211] The experiment was conducted in the same manner as in Example 1 except that 50% of the dosage in Example 1 was used. The microparticles of Preparation Example 1 and the microparticles of Preparation Example 2-1 were mixed in the same manner (1:2 weight ratio) and applied.

[0212] Experimental Example 1

[0213] Release Mode

[0214] In order to confirm the release of moxidectin, release experiments were conducted on the microparticles of Preparation Example 1, Preparation Example 2-1, Preparation Example 4 and Preparation Example 5.

[0215] The release test solution used in the release experiment is a solution containing 2% Tween 20 in pure water. 100 mg of microparticles are placed in an injection bottle containing 100 ml of the release test solution and sealed. The bottle is then stirred and shaken at 55°C and at a stirring speed of 120 rpm to confirm the difference in elution rate.

[0216] The experimental results are as follows Figure 1 shown.

[0217] The time point at which 50% of the moxidectin of the microparticles of Preparation Example 1 is released is 15 hours later, which is suitable for a 3-month dosage form. The time point at which 50% of the moxidectin of the microparticles of Preparation Example 2-1 is released is 20 hours later, which is suitable for a 6-month dosage form.

[0218] The time point at which 50% of moxidectin is released from the microparticles of Preparation Example 4 is 84 hours. Compared with Preparation Example 1 and Preparation Example 2-1, the microparticles of Preparation Example 4 can be used as a dosage form for long-term release of moxidectin.

[0219] In addition, it was confirmed that the time required for 50% release of moxidectin from the microparticles of Preparation Example 5 was longer than that from the microparticles of Preparation Example 3.

[0220] Experimental Example 2

[0221] Release Mode

[0222] In order to confirm the release of moxidectin, release experiments were conducted on the microparticles of Preparation Example 2-1, Preparation Example 3-1, Preparation Example 9-1, Preparation Example 7-1 and Preparation Example 11.

[0223] The release test solution used in the release experiment is a solution containing 2% Tween 20 and 0.001M sodium bicarbonate in pure water. 100 mg of microparticles are placed in an injection bottle containing 100 ml of the release test solution and sealed. The bottle is then stirred and shaken at 55°C and at a stirring speed of 120 rpm to confirm the difference in elution rate.

[0224] The experimental results are as follows Figure 2 shown.

[0225] The average diameter (MV) is about 95 μm. In the release test of microparticles having similar sizes, there are differences in the release pattern according to the molecular weight of the polymer constituting the microparticles. When the release rates of the microparticles of Preparation Example 2-1, Preparation Example 3-1, Preparation Example 7-1, and Preparation Example 9-1 are compared, the higher the ratio of the polylactide having a molecular weight (MW) of 45 kg / mol in the microparticles is, the higher the possibility of applying it as a dosage form for long-term release of moxidectin.

[0226] In Preparation Example 7-1 and Preparation Example 9-1, it was confirmed that the release delay time changed according to the ratio of polylactide having a molecular weight (MW) of 17 kg / mol to polylactide having a molecular weight (MW) of 45 kg / mol of 1:1 to 1:3.

[0227] In addition, it was confirmed that the microparticles of Preparation Example 11 can release moxidectin faster than the microparticles of other Preparation Examples because the microparticles contain polylactide-glycolide copolymer (PLGA).

[0228] Experimental Example 3

[0229] Release Mode

[0230] In order to confirm the release of moxidectin, release experiments were conducted on the microparticles of Preparation Example 2-2, Preparation Example 3-2, Preparation Example 4, Preparation Example 7-2, Preparation Example 8 and Preparation Example 9-2.

[0231] The release test solution used in the release experiment is a solution containing 2% Tween 20 and 0.001M sodium bicarbonate in pure water. 100 mg of microparticles are placed in an injection bottle containing 100 ml of the release test solution and sealed. The bottle is then stirred and shaken at 55°C and at a stirring speed of 120 rpm to confirm the difference in elution rate.

[0232] The experimental results are as follows Figure 3 shown.

[0233] The average diameter (MV) is about 85 μm. In the release test of microparticles having similar sizes, the release pattern is different depending on the ratio of the molecular weight of the polymers constituting the microparticles and the difference in the polymer end groups. When the release rate of microparticles of each preparation example is compared, the higher the ratio of the polylactide having a molecular weight (MW) of 45 kg / mol in the microparticles, the higher the possibility of applying it as a dosage form for long-term release of moxidectin.

[0234] In addition, it was confirmed that when the microparticles of Preparation Example 3-2 and Preparation Example 4 were compared, the release of moxidectin was delayed more when the microparticles contained an ester group than when the microparticles contained a carboxyl group, depending on the difference in the terminal groups.

[0235] Experimental Example 4

[0236] PSA analysis results

[0237] In order to specifically confirm the diameter of the fine particles, Preparation Examples 1 to 11 were analyzed using a Microtrac particle size analyzer.

[0238] The unit of D10 to D90 is μm, and CV (%) is calculated as SD / mean value (Mean)*100.

[0239] The span value is calculated as (D90-D10) / D50 and represents the uniformity of the particle size distribution.

[0240] The particle size analysis results of the preparation examples are shown in Table 2 below.

[0241] Table 2

[0242]

[0243] According to Table 2, it can be confirmed that the D50 of the microparticles of the preparation examples of the present invention is 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 the CV values ​​are 14.46%, 10.43%, 9.49%, 10.97%, 8.98%, 11.35%, 12.91% and 11.27%, which show a uniform particle distribution. In addition, it can be confirmed that the average particle size (MV) of the microparticles is 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, showing a uniform particle distribution in the range of 70 μm to 100 μm.

[0244] The particle size analysis results of Preparation Examples 7-1 to 11 are shown in Table 3 below.

[0245] Table 3

[0246]

[0247] According to Table 3, it can be confirmed that the D50 of the microparticles of the preparation examples of the present invention is 98.5 μm, 80.46 μm, 91.23 μm, 95.64 μm, 84.5 μm, 78.52 μm and 93.32 μm, and the CV values ​​are 11.13%, 6.74%, 10.53%, 10.75%, 10.64%, 10.63% and 9.46%, which show a uniform particle distribution. In addition, it can be confirmed that the average particle size (MV) of the microparticles is 99.63 μm, 80.54 μm, 91.22 μm, 96.96 μm, 86.72 μm, 78.61 μm and 93.04 μm, showing a uniform particle distribution in the range of 70 μm to 100 μm.

[0248] According to the PSA analysis results in Tables 2 and 3, it was confirmed that when the prepared oil phase solution contained the polymer at a ratio of 10 weight %, the average particle size (MV) of each particle was 84.96 on average, and the standard deviation was 4.17. It was confirmed that when the oil phase solution contained the polymer at a ratio of 15 weight %, the average particle size (MV) of each particle was 94.97 on average, and the standard deviation was 3.17. Therefore, it can be seen that as the concentration of the polymer in the oil phase solution increases, the average particle size (MV) of the particles increases.

[0249] In addition, the span value (Span value) indicating the particle size distribution of the particles in each preparation example is less than 0.5, and the CV (%) is 5% to 20%. It can be seen that the particles prepared according to the above preparation method show a very uniform particle size distribution.

[0250] The particle size analysis results of the microparticles prepared according to the polymer content in the oil phase solution are shown in Table 4 below.

[0251] Table 4

[0252]

[0253] According to the PSA analysis results in the above table, it is confirmed that when the polymer is contained in the oil phase solution prepared from the same polymer (PLGA) at a ratio of 5 wt%, the average particle size (MV) of each particle is 57.98, when the polymer is contained in the oil phase solution at a ratio of 10 wt%, the average particle size (MV) of each particle is 76.27 on average, when the polymer is contained in the oil phase solution at a ratio of 15 wt%, the average particle size (MV) of each particle is 93.14 on average, and when the polymer is contained in the oil phase solution at a ratio of 20 wt%, the average particle size (MV) of each particle is 103.30 on average, and thus it can be seen that the average particle size (MV) of the particles increases as the concentration of the polymer in the oil phase solution increases. Therefore, when the same microchannel is used and the flow ratio of the oil phase to the water phase is kept constant as a dripping condition, microparticles of a desired particle size can be prepared by changing the weight % of the polymer constituting the oil phase solution. In this way, the drug release pattern based on the size of the suppressed microparticles, such as initial burst, can be controlled and used to set the drug retention period.

[0254] Experimental Example 5

[0255] SEM analysis results

[0256] In order to specifically confirm the properties of the microparticles, Preparation Examples 1 to 11 were analyzed using a scanning electron microscope (SEM).

[0257] The SEM analysis results of Preparation Examples 1 to 11 are as follows Figures 3 to 18 shown.

[0258] The SEM measurement images confirmed that the prepared particles had uniform particle sizes, smooth surfaces, and perfect spherical shapes.

[0259] Experimental Example 6

[0260] Pharmacokinetic analysis results

[0261] The pharmacokinetic evaluation of Example 1 was confirmed.

[0262] The Example 1 is a sustained release dosage form for more than 6 months. After injection, moxidectin is continuously released for 6 months to confirm whether the efficacy of moxidectin is maintained.

[0263] The microparticles of the present invention were used to administer 0.4 mg / kg of moxidectin to beagle dogs, which was administered to a total of 5 beagle dogs by subcutaneous injection.

[0264] The results of the blood concentration analysis of moxidectin are shown in Table 5 below.

[0265] Table 5

[0266]

[0267] According to the experimental results, it was confirmed that the blood concentration of moxidectin did not show an initial burst release, and the first C max At the time point of 25 days, the blood concentration of moxidectin was constantly decreasing, and after 56 days, the blood concentration of moxidectin increased. Then, it was confirmed that the second C max It appears around day 91. From this, it can be confirmed that the value according to the following formula 1 is 1.35.

[0268] [Formula 1]

[0269] C max-peak n / C max-peak n+1

[0270] wherein microparticles containing moxidectin are mixed in a suspension to prepare an injection, the injection is administered to beagle dogs and the blood concentration of moxidectin is measured, C max-peak n is the nth C after the injection max Value, C max-peak n+1 is the C max After the value, the blood concentration of moxidectin increases again for the n+1th time. max value.

[0271] The blood drug concentration pattern of moxidectin as described above is obtained by using two biodegradable polymers to prepare each microparticle, and mixing them to prepare an injectable dosage form. The viscosity, molecular weight and combination of the biodegradable polymer with moxidectin result in differences in degradation rates, thereby resulting in the above-mentioned blood drug concentration release pattern.

[0272] In addition, the analysis results of the pharmacokinetic characteristics of Example 1 are shown in Table 6 below.

[0273] Table 6

[0274] Example 1 average Standard Deviation AUC final (ng·hr / ml) 25084.66 6983.41 AUCinf (ng·hr / ml) 26028.26 7034.78 Cmax(ng / ml) 16.73 4.32 Tmax(hr) 916.80 708.39 T1 / 2 466.89 121.18

[0275] Experimental Example 7

[0276] Pharmacokinetic analysis results

[0277] The pharmacokinetic evaluation of Example 2 was confirmed.

[0278] An experiment was conducted in the same manner as in Example 1, except that the fine particles of Preparation Example 1 and the fine particles of Preparation Example 2-1 were mixed at a weight ratio of 1:1 and used.

[0279] Table 7

[0280]

[0281] According to the experimental results, it was confirmed that the blood concentration of moxidectin did not show an initial burst release, and the first C max At the time point of 21 days, the blood concentration of moxidectin decreased steadily, and after 56 days, the blood concentration of moxidectin increased. Then, it was confirmed that the second C max It appears around day 70. From this, it can be confirmed that the value according to the above formula 1 is 2.24.

[0282] In addition, 24 hours after the injection, the blood concentration of moxidectin was 0.75 ng / ml, and the standard deviation of the blood concentration of the beagle dogs subjected to the experiment was 0.24.

[0283] The analysis results of the pharmacokinetic characteristics of Example 2 are shown in Table 8 below.

[0284] Table 8

[0285] Example 2 average Standard Deviation AUC final (ng·hr / ml) 17701.36 3301.50 AUCinf (ng·hr / r / ml) 18717.96 3736.92 Cmax (ng / ml) 13.66 4.61 Tmax(hr) 576.00 124.71

[0286] Experimental Example 8

[0287] Pharmacokinetic analysis results

[0288] The pharmacokinetic analysis of Example 3 was performed.

[0289] The experiment was conducted in the same manner as in Example 1 except that 50% of the dosage applied in Example 1 was applied. The microparticles of Preparation Example 1 and the microparticles of Preparation Example 2-1 were mixed in the same manner (1:2 weight ratio) and applied.

[0290] Table 9

[0291]

[0292] According to the experimental results, it was confirmed that the blood concentration of moxidectin did not show an initial burst release, and the first C max At the time point of 35 days, the blood concentration of moxidectin decreased steadily, and after 77 days, the blood concentration of moxidectin increased. Then, it was confirmed that the second C max It appears around day 105. From this, it can be confirmed that the value according to the above formula 1 is 0.56.

[0293] Experimental Example 9

[0294] Pharmacokinetic analysis results

[0295] In the in vivo experiment, an experiment was conducted to confirm the reproducibility when the same test drug was administered by comparing the moxidectin concentration in the blood of each administered individual.

[0296] For comparison, the currently commercially available ProHeartSR-12 was administered to three beagle dogs, and the moxidectin concentration in the blood was measured over 180 days.

[0297] The microparticles of the present invention are those of Example 3. The dosage of moxidectin was 0.2 mg / kg and administered to a total of 10 beagle dogs. The moxidectin concentration in the blood was measured over 180 days.

[0298] The experimental results are shown in Table 10, Table 11 and Fig.19 shown.

[0299] Table 10

[0300]

[0301] (Unit: ng / ml)

[0302] Table 11

[0303]

[0304] (Unit: ng / ml)

[0305] According to the experimental results, it can be confirmed that the commercially available ProHeartSR-12 shows a large difference in blood concentration among beagle dogs, while in Example 1 of the present invention, the results of measuring the moxidectin concentration in the blood of 10 beagle dogs showed a deviation of 0.2 to 2.39, so there was almost no difference.

[0306] Although the preferred embodiments of the present invention are described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concepts of the present invention defined in the claims also fall within the scope of the present invention.

[0307] Industrial Applicability

[0308] The present invention relates to microparticles containing moxidectin and a sustained-release injection composition containing the microparticles.

Claims

1. A microparticle comprising moxidectin, wherein: The microparticles are microparticles containing moxidectin and a biodegradable polymer, The inherent viscosity of the biodegradable polymer is 0.1 dl / g to 1 dl / g, The average diameter of the microparticles is 60 μm to 110 μm.

2. The microparticles containing moxidectin according to claim 1, wherein The microparticles are spherical, The microparticles uniformly contain moxidectin.

3. The microparticles containing moxidectin according to claim 1, wherein The coefficient of variation of the microparticles was between 5% and 20%.

4. The microparticles containing moxidectin according to claim 1, wherein The microparticles contain a biodegradable polymer and moxidectin in a weight ratio of 2:1 to 12:

1.

5. The microparticles containing moxidectin according to claim 1, wherein The microparticles continuously release moxidectin for more than 3 months.

6. The microparticles containing moxidectin according to claim 1, wherein The biodegradable polymer is selected from the group consisting of polylactide, polylactide-co-glycolide, polyphosphazene, polyimidocarbonate, polyphosphate, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid and a mixture thereof.

7. The microparticles containing moxidectin according to claim 1, wherein The value of the microparticles according to the following formula 1 is 0.3 to 3, [Formula 1] C max-peakn / C max―peakn+1 wherein microparticles containing moxidectin are mixed in a suspension to prepare an injection, the injection is administered to beagle dogs and the blood concentration of moxidectin is measured, C max-peakn is the nth C after the injection max Value, C max-peakn+1 is the C max After the value, the blood concentration of moxidectin increases again for the n+1th time. max value.

8. The microparticles containing moxidectin according to claim 7, wherein Using the injection, 0.2 mg / kg of moxidectin was administered to a plurality of beagle dogs, and the moxidectin concentration in the blood was measured, and the standard deviation of the moxidectin concentration in the blood of each beagle dog to which the injection was administered was 0.01 to 10.

9. A sustained-release injection composition comprising moxidectin, wherein: Include: Microparticles comprising the moxidectin of claim 1; and Suspension.

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