WO2019050259A1 - Microparticles comprising moxidectin, and preparation method therefor - Google Patents

Microparticles comprising moxidectin, and preparation method therefor Download PDF

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Publication number
WO2019050259A1
WO2019050259A1 PCT/KR2018/010324 KR2018010324W WO2019050259A1 WO 2019050259 A1 WO2019050259 A1 WO 2019050259A1 KR 2018010324 W KR2018010324 W KR 2018010324W WO 2019050259 A1 WO2019050259 A1 WO 2019050259A1
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WIPO (PCT)
Prior art keywords
microparticles
mixture
moxifectin
biodegradable polymer
moxidectin
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PCT/KR2018/010324
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French (fr)
Korean (ko)
Inventor
김주희
Original Assignee
(주)인벤티지랩
김주희
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Priority claimed from KR1020180031979A external-priority patent/KR102101969B1/en
Application filed by (주)인벤티지랩, 김주희 filed Critical (주)인벤티지랩
Priority to EP18854665.9A priority Critical patent/EP3733164A4/en
Priority to CN201880010501.4A priority patent/CN110381924A/en
Priority to JP2020533631A priority patent/JP7040818B2/en
Priority to US16/771,196 priority patent/US11931461B2/en
Publication of WO2019050259A1 publication Critical patent/WO2019050259A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

  • the present invention relates to microcapsules containing moxidectin and a method for preparing the microcapsules, and more particularly, to microcapsules containing moxidectin and a biodegradable polymer capable of preventing heartworms, and a method for producing the same.
  • Heartworm Disease is a parasite called Dirofilaria immitis, which is transmitted by mosquitoes. It infects dogs, cats and weasels. As the name suggests, heartworms parasitize the heart of mammals.
  • less than one heartworm can parasitize from one to as many as 200. Infection causes the pulmonary artery to become thick and inflamed, and the heart needs to do more to send blood to the lungs from heartworms. It also causes inflammation in the lungs. When the number of infected heartworms is low, there may be no specific symptoms, but in general, animals infected with heartworms may exhibit early symptoms such as avoidance of movement, coughing, and weight loss. In severe infections, symptoms such as severe cough, dyspnea and heart failure may occur. An animal infected with heartworms can die from heart failure if these symptoms occur.
  • the heartworm can be killed with capsolate, or melarsomine can be used to treat the disease.
  • capsolate or melarsomine can be used to treat the disease.
  • all of the above therapeutic agents have serious side effects such as irritation at the injection site and damage to the liver and kidney.
  • Heartworm antitussives include diethylcarbamazine (DEC) or monthly fed ivermectin, milbemycin, moxidectin, and selamectin, which are daily diets. Preventive medicines are all effective in preventing them when administered correctly, but they can be exposed to the risk of infection just by omitting several doses of mistakenly administered daily or monthly.
  • DEC diethylcarbamazine
  • ivermectin milbemycin
  • moxidectin moxidectin
  • selamectin which are daily diets.
  • Preventive medicines are all effective in preventing them when administered correctly, but they can be exposed to the risk of infection just by omitting several doses of mistakenly administered daily or monthly.
  • Patent Document 1 KR10-2006-0005472 A1
  • the present invention relates to microcapsules comprising moxidectin and a process for their preparation.
  • the present invention is based on the finding that, unlike the prior art cardiomyopathic remedy, which had a short half-life and had to be administered daily or monthly, when administered with microparticles containing moxifloxacin, the effect of preventing heartworm infection can be maintained for 3 to 6 months It is another object of the present invention to provide sustained-release microparticles and a method for producing the same.
  • the present invention relates to sustained-release particles containing moxidetin, which can maintain a long-term drug administration effect for a period of 3 months to 6 months, and at the same time, It is another object of the present invention to reduce the foreign body sensation and pain at the time of administration of the drug by controlling the release of the drug to keep the effective drug concentration constant.
  • a microparticle comprising moxidectin and a biodegradable polymer, wherein the microparticle is uniformly dispersed in spherical biodegradable polymer microparticles Wherein the average particle diameter of the microparticles is 80 to 130 ⁇ .
  • the microparticles of the present invention may contain a biodegradable polymer and moxidectin in a weight ratio of 4: 1 to 9: 1.
  • the microparticles of the present invention are capable of sustained release of moxifloxacin for 3 to 6 months.
  • the biodegradable polymer of the present invention is at least one selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, Polyhydroxybutyrate, polyamino acid, and combinations thereof, and is preferably selected from the group consisting of polylactide-polylactide-polylactide-polylactide-polylactide-polylactide-Co-glycolide (PLGA), but is not limited to the above examples.
  • the microparticles of the present invention are prepared using microchannels, and the width w of the channel cross section ranges from 0.7 to 1.3 with respect to the average diameter d 'of the microparticles.
  • the microparticles of the present invention are prepared using microchannels, and the height (d) of the channel cross section ranges from 0.7 to 1.3 with respect to the average diameter (d ') of the microparticles.
  • the present invention relates to a pharmaceutical composition for preventing and treating heartworms comprising microparticles according to the present invention.
  • the present invention provides a method for producing a biodegradable polymer, comprising: 1) dissolving a biodegradable polymer and moxidectin in an organic solvent to prepare a first mixture; 2) dissolving the surfactant in water to prepare a second mixture; 3) injecting and flowing the first mixture of the step 1) into the microchannel in the linear direction; 4) The second mixture of step 2) is injected and flowed into the microchannels formed on both sides or one side so as to form an intersection with the microchannels flowing in the linear direction in the step 3) Preparing a microparticle wherein a linear flow of the mixture and a flow of the second mixture cross each other and moxidetin is evenly distributed on the spherical biodegradable polymer particle; 5) collecting the microparticles generated at the intersection of step 4); 6) stirring the microparticles collected in the step 5) to evaporate and remove the organic solvent present in the microparticles; And 7) washing and drying the microparticle
  • the first mixture of step 1) of the present invention may contain 15 to 60% by weight of the biodegradable polymer.
  • the first mixture of step 1) of the present invention may contain a biodegradable polymer and moxidectin in a weight ratio of 4: 1 to 9: 1.
  • the biodegradable polymer of the present invention is at least one selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate , Polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate, polyamino acid, and combinations thereof, preferably polylactide -Co-glycolide (PLGA), but is not limited to the above example.
  • PLGA polylactide -Co-glycolide
  • the organic solvent in step 1) of the present invention is at least one selected from the group consisting of dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof.
  • the second mixture of step 2) of the present invention may contain 0.2 wt% to 0.3 wt% of a surfactant.
  • the surfactant in the step 2) of the present invention is at least one selected from the group consisting of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and a mixture thereof.
  • the step 3) of the present invention may inject the first mixture into the microchannel in the linear direction at a pressure of 1000 to 1500 mbar.
  • the step 4) of the present invention injects the second mixture into the microchannels formed on both sides or one side so as to form an intersection with the microchannel in the straight direction through which the first mixture flows , And the second mixture may be injected at a pressure of 1500 to 2000 mbar.
  • the step 5) of the present invention may collect microparticles in a water bath containing a mixed solution containing 0.2 wt% to 0.3 wt% of a surfactant.
  • the step 6) of the present invention comprises the steps of: 6-1) primary stirring at a speed of 200 to 400 rpm for 1 to 2 hours at 15 to 20 ⁇ ; 6-2) After the primary stirring step, the secondary stirring is carried out at a speed of 300 to 500 rpm at 20 to 30 DEG C for 1 to 2 hours; And 6-3) third stirring at a rate of 400 to 600 rpm for 3 to 5 hours at 40 to 50 DEG C after the secondary stirring step.
  • the microchannels of steps 3) and 4) of the present invention are formed on the surface of the wafer, and the average diameter of the microchannels is 60 to 150 ⁇ , preferably 80 to 120 ⁇ And more preferably 100 ⁇ , but it is not limited to the above example.
  • the present invention relates to microcapsules containing moxidetin and a method for producing the microcapsules, and more particularly, to microcapsules containing sustained-release microparticles capable of sustaining prevention of heartworms for 3 to 6 months upon administration of microcapsules containing moxidectin And a method for producing the same.
  • the present invention can be manufactured by maintaining the average diameter of the particles at a constant micro size, thereby reducing the foreign body sensation and pain upon administration to an animal as an injection, and facilitating administration to an injection.
  • FIG. 1 is a flow chart of a method for producing microspheres comprising moxidectin of the present invention.
  • FIG. 2 is a graph showing the drug release period according to the weight ratio of the biodegradable polymer and moxidectin of the present invention.
  • FIG. 3 is a graph showing a drug release period according to the weight ratio of the biodegradable polymer and moxidectin of the present invention.
  • FIG. 5 is a SEM photograph of microparticles according to a manufacturing method according to an embodiment of the present invention.
  • FIG. 6 is a SEM photograph of microparticles according to a manufacturing method according to an embodiment of the present invention.
  • FIG. 7 is a SEM photograph of microparticles according to the manufacturing method according to an embodiment of the present invention.
  • FIG. 8 is a diagram showing the relationship between the average diameter of the microparticles and the microchannel cross section.
  • the present invention relates to microcapsules comprising moxidectin and a biodegradable polymer, wherein the microcapsules have a shape in which a moxidectin drug is uniformly distributed in a spherical biodegradable polymer, and the microparticles have an average particle diameter of 80 to 130 ⁇ m And to microparticles comprising moxidectin.
  • the moxidectin of the present invention is a compound represented by the following general formula (1), which means a substance used as an anti-cardiovirus drug for animals.
  • FIG. 1 is a flow chart of a method for producing microspheres comprising moxidectin of the present invention.
  • the production of microcrystalline particles containing goxydetin of the present invention comprises the steps of: 1) preparing a first mixture (SlOO); 2) preparing a second mixture (S200); 3) injecting the first mixture into the microchannel in the linear direction (S300); 4) injecting the second mixture into the microchannels on both sides or one side (S40O); 5) Collecting microparticles (S500); 6) stirring the collected microparticles (S600); And 7) washing and drying microparticles (S700).
  • Step S100 is a step of preparing a first mixture, which comprises dissolving a biodegradable polymer and moxidetin in an organic solvent to prepare a first mixture, wherein the biodegradable polymer is polylactic acid, polylactide, poly Polyglycolic acid, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxypoly Polyhydroxybutyrate, polyamino acid, and combinations thereof, and is preferably polylactide-co-glycolide (PLGA), but is not limited to the above examples.
  • the biodegradable polymer is polylactic acid, polylactide, poly Polyglycolic acid, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxy
  • the organic solvent is not mixed with water and is, for example, any one or more selected from the group consisting of chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof.
  • the organic solvent is preferably dichloromethane, And organic solvent capable of dissolving biodegradable polymer and moxidectin. Any organic solvent easily selectable by those skilled in the art can be used without being limited to the above examples.
  • the first step (S100) is to prepare a first mixture in which a biodegradable polymer and moxidectin are dissolved.
  • an organic solvent is used as a solvent. It dissolves completely using an organic solvent, taking advantage of the dissolution properties of moxidectin and biodegradable polymer.
  • the first mixture comprises the biodegradable polymer and moxidectin in a weight ratio of 4: 1 to 9: 1, preferably 4: 1, but is not limited to examples.
  • the weight ratio of the biodegradable polymer and the moxidectin is less than 4: 1, that is, when the weight ratio of the biodegradable polymer is less than the above weight ratio, the weight ratio of the biodegradable polymer is smaller than that of the dendritic polymer, It is difficult to produce microparticles in which the moxidetin is evenly distributed in the polymer particles.
  • the weight ratio of the biodegradable polymer and the moxidectin exceeds 9: 1, that is, when the biodegradable polymer is mixed with the weight ratio
  • the content of moxifloxacin in the microparticles may be low and a problem may arise in that a large amount of microparticles must be administered to administer a desired concentration of the drug.
  • the biodegradable polymer in the first mixture comprises 15 to 60 wt%, preferably 15 wt%, but is not limited to the above examples.
  • the 2) step (S200) is a step of preparing a second mixture, wherein the surfactant is dissolved in water to prepare a second mixture.
  • the surfactant can be used without limitation as long as the biodegradable polymer solution can help form stable emulsion.
  • a nonionic surfactant is at least one selected from the group consisting of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and a mixture thereof, and more specifically, methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol , Polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sodium lauryl sulfate, sodium stearate, ester amine, linear diamine, pattyamine, and mixtures thereof.
  • Polyvinyl alcohol but are not limited to examples.
  • the third step S300 and the fourth step S400 are the steps of injecting and flowing the first mixture and the second mixture into the microchannels formed on the wafer.
  • aluminum is deposited on a silicon wafer using an e-beam evaporator, and a photoresist is patterned on aluminum using a photolithography technique. Thereafter, aluminum is etched using a photoresist as a mask, the photoresist is removed, and the silicon is etched by DRIE (deep ion reactive etching) using aluminum as a mask. After the aluminum is removed, the glass is anodically bonded onto the wafer, Thereby manufacturing the above microchannel.
  • DRIE deep ion reactive etching
  • the average diameter of the microchannels is 60 to 150 ⁇ ⁇ , preferably 80 to 120 ⁇ ⁇ , more preferably 100 ⁇ ⁇ , but is not limited to the example.
  • the cross-sectional width w and the cross-sectional height d of the microchannel are closely related to the average diameter d 'of the microparticles to be produced.
  • the width w of the cross-section of the microchannel is in the range of 0.7 to 1.3 with respect to the average diameter d 'of the microparticles
  • the height d of the cross section of the microchannel is the average diameter d ') In the range of 0.7 to 1.3.
  • the length of the width w and height d of the microchannel cross section should be set in the range of 0.7 to 1.3 of d' It is possible to manufacture microparticles of desired size.
  • step S300 the first mixture is injected into the microchannel in the linear direction, and the fourth mixture is introduced into the microchannel in the linear direction.
  • step S400 Or into one side of the microchannel.
  • the first mixture flows along the microchannel in the linear direction
  • the second mixture flows along the microchannel forming the intersection with the microchannel in the linear direction on both sides or one side with respect to the linear microchannel, The flow of the first mixture is met.
  • the first mixture when the first mixture is injected into the microchannel in the linear direction, it is injected under a constant pressure condition and flowed at a constant flow rate, the pressure condition being 1000 to 1500 mbar, preferably 1500 mbar, but not limited to the example.
  • the second mixture when the second mixture is injected into the microchannels on both sides or one side, it is injected under a constant pressure condition and flowed at a constant flow rate.
  • the pressure condition is 1500 to 2000 mbar, preferably 2000 mbar, Do not.
  • the second mixture flows under higher pressure conditions to flow the flow of the second mixture, which intersects the flow of the first mixture, at a faster flow rate than the first mixture injected into the microchannel in the linear direction.
  • the flow of the first mixture and the second mixture are relatively more
  • the second mixture having a fast flow rate compresses the first mixture and the biodegradable polymer and the moxidectin in the first mixture form spherical microparticles due to the repulsive force of the first mixture and the second mixture, Specifically, microspheres in which moxidetin is uniformly distributed in a spherical biodegradable polymer are formed.
  • the step 5) collects the microparticles in the water tank containing the second mixture to prevent aggregation of the initially formed microparticles.
  • the fifth step S500 uses a second mixture prepared in the step S200, that is, a mixed solution of a surfactant and water. After the second mixture is prepared in the step S200, Is injected into the microchannel, and the other part is moved to the water tank of step S500, and a bundle between the collected micro particles is used to prevent the phenomenon.
  • a second mixture prepared in the step S200 that is, a mixed solution of a surfactant and water.
  • the step 6) S600 is a step of stirring the microparticles collected in the water tank.
  • the microparticles are stirred at a constant temperature and stirring speed to evaporate the organic solvent present on the surface of the microparticles.
  • the stirring conditions include a primary stirring at a speed of 200 to 400 rpm at 15 to 20 ° C for 1 to 2 hours; After the primary stirring step, the secondary stirring is performed at a speed of 300 to 500 rpm for 1 to 2 hours at 20 to 30 ⁇ . And the third stirring step at a speed of 400 to 600 rpm for 3 to 5 hours at 40 to 50 DEG C after the secondary stirring step.
  • the stirring speed and temperature for stirring the microparticles are characterized by gradually increasing the stirring speed and the temperature, respectively, according to the 1st, 2nd and 3rd stirring periods. As the temperature is raised stepwise, The rate of evaporation of the organic solvent present can be controlled. That is, the organic solvent present on the surface of the microparticles can be gradually evaporated to produce microparticles having a smooth surface.
  • step (S600) is firstly stirred at 15 to 20 ° C for 1 to 2 hours, preferably at 17 ° C for 1 hour. Then, the mixture is stirred at 20 to 30 ° C for 1 to 2 hours, preferably at 25 ° C for 1 hour. Then, the mixture is stirred at 40 to 50 ° C for 3 to 5 hours, preferably at 45 ° C for 4 hours.
  • the temperature at which the first mixture and the second mixture flow through the microchannel is also 15 to 20 ⁇ ⁇ , preferably 17 ⁇ ⁇ . That is, after flowing microchannels and forming crossing points to generate microparticles, the collected microparticles are kept at a low temperature of 15 to 20 DEG C constantly until the primary agitation. It is possible to manufacture and maintain spherical particles only if the temperature of the microparticles is kept low during the manufacturing process. That is, when the temperature is not low, it is difficult to produce a uniform spherical particle.
  • step (S700) is a step of washing and drying the microparticles.
  • the microparticles in which the organic solvent on the surface is completely removed by stirring are washed several times with the filtered, purified water to remove the surfactant remaining in the microparticles And then freeze-dried.
  • microparticles finally formed are spherical biodegradable polymer microparticles having a uniformly distributed moxidectin drug, the average particle diameter of the microparticles is 80 to 130 ⁇ , the biodegradable polymer and moxidectin are used in a ratio of 4: 9: 1.
  • the weight ratio of biodegradable polymer and moxidectin contained in the microparticles is equal to the weight ratio in the first mixture, which is obtained by preparing the microparticles and removing all of the organic solvent by evaporation, Microparticles containing the biodegradable polymer and moxidectin can be produced at the same ratio as the ratio of the biodegradable polymer and the moxidectin.
  • the first mixture was prepared by dissolving polylactide-co-glycolide (PLGA) and moxidectin in dichloromethane.
  • PLGA polylactide-co-glycolide
  • moxidectin moxidectin in dichloromethane.
  • the polylactide-co-glycolide in the first mixture is contained in a proportion of 15% by weight, and the weight ratio of polylactide-co-glycolide and moxydectin is 9: 1.
  • Polyvinyl alcohol as a surfactant was mixed with water to prepare a second mixture containing 0.25 wt% of polyvinyl alcohol.
  • the first mixture and the second mixture were injected into a microchannel formed on a silicon wafer and allowed to flow. At this time, in order to flow the first mixture and the second mixture at a constant flow rate, the first mixture was flowed under a pressure condition of 1000 mbar and the second mixture was flowed under a pressure condition of 2000 mbar. The temperature condition was maintained at 17 ⁇ ⁇ .
  • the microparticles generated at the intersection of the flow of the first mixture and the flow of the second mixture are collected in a water tank containing the second mixture.
  • the microparticles collected in the water tank were first stirred at 17 ° C for 1 hour at a speed of 300 rpm, then the temperature was raised to 25 ° C, the secondary stirring was carried out at 400 rpm for 1 hour, and then the temperature was raised to 45 ° C And the mixture was stirred for 3 hours at a rate of 500 rpm for 4 hours.
  • microparticles that had been stirred were washed several times with filtered water, and lyophilized to prepare microparticles.
  • the weight ratio of polylactide-co-glycolide and moxidectin was prepared in the same manner as in Example 1 except that the weight ratio was 4: 1.
  • the weight ratio of polylactide-co-glycolide and moxydectin was prepared in the same manner as in Example 1 except that the weight ratio was 2: 1.
  • the weight ratio of polylactide-co-glycolide and moxidectin was prepared in the same manner as in Example 1 except that the weight ratio was 12: 1.
  • microparticles were collected in a water tank containing the second mixture, and then stirred under the conditions shown in Table 1 below.
  • the drug release experiment is carried out by placing the sample in a 45 ° C water bath, reciprocating 4 cm of amplitude and 120 times / minute of shaking. When collecting specimens, shake well and mix 1 mL. After centrifugation at 13,000 rpm for 3 minutes, the supernatant was collected and analyzed by high performance liquid chromatography.
  • Example 2 According to Fig. 2 and Table 2, in the case of Examples 1 and 2, moxidectin drug was released to a certain level up to 25 days, and prevention or treatment effect of cardiac wasps could be exhibited. On the other hand, in Example 3, The amount of drug release is too much, and after 7 days, the release is almost completed, which is a difficult problem to exhibit a drug release effect for a long time. In addition, in the case of Example 4, the amount of initial drug release is too small, and there is a problem in that the therapeutic effect of the moxifloxacin drug is insufficient.
  • microparticles prepared under the conditions of Example 1 and Examples 5 to 10 were examined through SEM photographs to examine the properties of the microparticles according to the stirring conditions.
  • Example 5 Experiment according to agitation condition Production results of microparticles Example 5 ⁇ Example 6 ⁇ Example 7 ⁇ Example 8 ⁇ Example 9 ⁇ Example 10 ⁇ Example 1 ⁇
  • ⁇ means that the microparticles are aggregated due to the influence of the residual solvent, and the microparticles are uneven in shape.
  • Example 1 As shown in the SEM photograph of FIG. 7, it was confirmed that the properties of the microparticles were uniformly formed and no aggregation occurred.
  • the present invention relates to microcapsules containing moxidectin and a method for preparing the microcapsules, and more particularly, to microcapsules containing moxidectin and a biodegradable polymer capable of preventing heartworms, and a method for producing the same.

Abstract

The present invention relates to microparticles comprising moxidectin and a biodegradable polymer, wherein the microparticles comprising moxidectin have a shape allowing a moxidectin drug to be uniformly distributed in spherical biodegradable polymer particles, and the average particle diameter of the microparticles is 80-130 μm. The present invention relates to: extended release microparticles capable of continuously maintaining a heartworm disease prevention effect for 3-6 months by administering microparticles comprising moxidectin; and a preparation method therefor. In addition, the present invention is prepared such that the average diameters of the particles have a predetermined micrometer size, and thus reduces a foreign body sensation and pain during administration into an animal through injection, thereby enabling administration through injection to be facilitated.

Description

목시덱틴을 포함하는 마이크로 입자 및 이의 제조 방법Microcapsules containing Moxydetin and a method for producing the same
본 발명은 목시덱틴(Moxidectin)을 포함하는 마이크로 입자 및 이의 제조 방법에 관한 것으로, 보다 구체적으로 심장 사상충을 예방할 수 있는 목시덱틴 및 생분해성 고분자를 포함하는 마이크로 입자 및 이의 제조 방법에 관한 것이다. The present invention relates to microcapsules containing moxidectin and a method for preparing the microcapsules, and more particularly, to microcapsules containing moxidectin and a biodegradable polymer capable of preventing heartworms, and a method for producing the same.
심장사상충(Heartworm Disease; HWD)은 모기에 의해 전염되는 Dirofilaria immitis라는 기생충으로 개, 고양이, 족제비에 감염된다. 이름에서 알 수 있듯이 심장사상충은 포유동물의 심장에 기생한다. Heartworm Disease (HWD) is a parasite called Dirofilaria immitis, which is transmitted by mosquitoes. It infects dogs, cats and weasels. As the name suggests, heartworms parasitize the heart of mammals.
심장사상충의 성충은 30cm까지 성장하며 주로 폐동맥과 우심실에 기생합니다. 성숙한 암컷, 수컷 심장사상충은 마이크로 필라리아(microfilariae, L1)라고 불리는 매우 작은 유충을 생산한다. 이러한 유충들이 감염된 동물의 혈액 속에 기생하며 모기를 통해 다른 동물에 감염된다. 모기의 몸 속으로 들어간 L1은 2주 후에는 감염능력을 가지게 되며, 감염 능력을 가진 유충은 다시 모기를 통해 다른 동물로 전해지게 된다. 다른 동물에 감염된 유충은 몇 단계 성장을 거쳐 3 내지 4달 후에는 폐동맥으로 이주하게 된다. 이렇게 성숙한 심장사상충 성충은 평균 5 내지 7년간 생존하며 암컷, 수컷 심장사상충은 생식을 통해 수 많은 유충을 생산한다.Adult adults of the heartworm grow up to 30 cm and are parasitized mainly in the pulmonary artery and right ventricle. Mature female, male heartworms produce very small larvae called microfilariae (L1). These larvae parasitize in the blood of infected animals and infect other animals through mosquitoes. L1 entering the body of the mosquito becomes infectious after 2 weeks, and the infecting larva is transmitted again to another animal through the mosquito. Larvae infected with other animals grow through several stages and migrate to the pulmonary arteries after 3 to 4 months. Adult adult heartworms survive for an average of 5 to 7 years, and female and male heartworms produce numerous larvae through reproduction.
감염된 동물의 심장과 폐동맥에는 심장사상충이 적게는 1마리부터 많게는 200마리까지 기생할 수 있다. 감염에 의해 폐동맥은 두꺼워지고 염증이 생겨 심장사상충을 피해 폐에 혈액을 보내기 위해 심장은 더 많은 일을 해야 한다. 또한 폐에도 염증이 발생한다. 감염된 심장사상충의 수가 적을 때는 특별한 증상이 없을 수 있지만 일반적으로 심장사상충에 감염된 동물은 초기 증상으로 운동 기피, 기침, 체중감소 등을 보일 수 있다. 감염이 심한 경우에는 심한 기침, 호흡 곤란, 심부전 등의 증상이 나타날 수 있다. 심장사상충에 감염된 동물이 이런 증상들을 보이면 심부전으로 인해 죽는 경우도 발생한다.In the heart and pulmonary arteries of an infected animal, less than one heartworm can parasitize from one to as many as 200. Infection causes the pulmonary artery to become thick and inflamed, and the heart needs to do more to send blood to the lungs from heartworms. It also causes inflammation in the lungs. When the number of infected heartworms is low, there may be no specific symptoms, but in general, animals infected with heartworms may exhibit early symptoms such as avoidance of movement, coughing, and weight loss. In severe infections, symptoms such as severe cough, dyspnea and heart failure may occur. An animal infected with heartworms can die from heart failure if these symptoms occur.
진단을 통해 심장사상충에 감염된 것으로 확인될 경우, 비소계 약물(caparsolate)로 심장사상충 성충을 죽이거나, melarsomine을 이용하여 치료를 진행할 수 있다. 다만, 상기 치료제 모두, 주사 부위에 자극이 심하고 간과 신장에 어느 정도 손상을 입히는 부작용이 있다. If the diagnosis is confirmed to be infecting the heartworm, the heartworm can be killed with capsolate, or melarsomine can be used to treat the disease. However, all of the above therapeutic agents have serious side effects such as irritation at the injection site and damage to the liver and kidney.
이에, 심장사상충의 감염 전에 예방하는 것이 경제적이며 안전하다. 예방은 생후 6 내지 8주에 시행한다. 심장사상충 예방약에는 매일 먹이는 디에틸카바마진(diethylcarbamazine, DEC) 또는 매달 먹이는 이버멕틴(ivermectin), 밀베마이신(milbemycin), 목시덱틴(moxidectin), 세라멕틴(selamectin) 등이 있다. 예방약들은 올바르게 투여 되면 모두 예방효과가 뛰어나지만, 매일 또는 매달 먹여야 하는 점에서, 실수로 몇 번 투여하는 것을 빼먹는 것만으로도 감염의 위험성에 노출될 수 있다.　Therefore, it is economical and safe to prevent heartworm infection. Prevention is performed 6 to 8 weeks after birth. Heartworm antitussives include diethylcarbamazine (DEC) or monthly fed ivermectin, milbemycin, moxidectin, and selamectin, which are daily diets. Preventive medicines are all effective in preventing them when administered correctly, but they can be exposed to the risk of infection just by omitting several doses of mistakenly administered daily or monthly.
이에, 심장사상충을 예방할 수 있는 목시덱틴을 이용하여, 한번 투여로 인해 3개월 내지 6개월 동안 약효를 유지시켜 투여 편의성을 개선한 심장사상충 예방약의 개발이 시급한 실정이다.Therefore, it is urgent to develop a preventive drug for cardiac canker disease which improves the convenience of administration by maintaining the medicinal effect for 3 months to 6 months by once using moxidetine to prevent heartworms.
[선행기술문헌][Prior Art Literature]
[특허문헌][Patent Literature]
(특허문헌 1) KR10-2006-0005472 A1(Patent Document 1) KR10-2006-0005472 A1
본 발명은 목시덱틴을 포함하는 마이크로 입자 및 이의 제조 방법에 관한 것이다.The present invention relates to microcapsules comprising moxidectin and a process for their preparation.
본 발명은 종래 반감기가 짧아, 매일 또는 매달 투여해야 했던 종래의 심장사상충 예방약과 달리, 목시덱틴을 포함하는 마이크로 입자를 투여할 경우, 3개월 내지 6개월 동안 지속적으로 심장사상충 예방 효과를 유지할 수 있는 서방성 마이크로 입자 및 이의 제조 방법을 제공하는 것을 목적으로 한다.The present invention is based on the finding that, unlike the prior art cardiomyopathic remedy, which had a short half-life and had to be administered daily or monthly, when administered with microparticles containing moxifloxacin, the effect of preventing heartworm infection can be maintained for 3 to 6 months It is another object of the present invention to provide sustained-release microparticles and a method for producing the same.
본 발명은 목시덱틴을 포함하는 서방성 입자로, 3개월 내지 6개월의 기간 동안 장기간 약물 투여 효과를 유지함과 동시에, 입자의 평균 직경을 일정한 마이크로 크기의 사이즈로 제조함에 따라, 마이크로 입자로부터 약물의 방출을 제어하여 유효한 약물 농도를 일정하게 유지될 수 있도록 하며, 주사제로 적용 시 균일한 크기의 마이크로 입자를 포함하여 약물 투여 시에 이물감 및 통증을 감소시키는 것을 또 다른 목적으로 한다.The present invention relates to sustained-release particles containing moxidetin, which can maintain a long-term drug administration effect for a period of 3 months to 6 months, and at the same time, It is another object of the present invention to reduce the foreign body sensation and pain at the time of administration of the drug by controlling the release of the drug to keep the effective drug concentration constant.
상기의 목적을 달성하기 위하여, 본 발명의 일 구체예로, 본 발명은 목시덱틴 및 생분해성 고분자를 포함하는 마이크로 입자이며, 상기 마이크로 입자는 구형의 생분해성 고분자 마이크로 입자에 목시덱틴 약물이 고르게 분포되어 있는 형상이며, 상기 마이크로 입자의 입자 평균 직경은 80 내지 130㎛인 목시덱틴을 포함하는 마이크로 입자에 관한 것이다. In order to achieve the above object, according to one embodiment of the present invention, there is provided a microparticle comprising moxidectin and a biodegradable polymer, wherein the microparticle is uniformly dispersed in spherical biodegradable polymer microparticles Wherein the average particle diameter of the microparticles is 80 to 130 탆.
본 발명의 일 구체예로, 본 발명의 마이크로 입자는 생분해성 고분자 및 목시덱틴을 4:1 내지 9:1의 중량 비율로 포함할 수 있다.In one embodiment of the present invention, the microparticles of the present invention may contain a biodegradable polymer and moxidectin in a weight ratio of 4: 1 to 9: 1.
본 발명의 일 구체예로, 본 발명의 마이크로 입자는 목시덱틴을 3개월 내지 6개월 동안 지속적으로 방출할 수 있다.In one embodiment of the invention, the microparticles of the present invention are capable of sustained release of moxifloxacin for 3 to 6 months.
본 발명의 일 구체예로, 본 발명의 생분해성 고분자는 폴리락트산, 폴리락타이드, 폴리락틱-코-글리콜산, 폴리락타이드-코-글리콜라이드(PLGA), 폴리포스파진, 폴리이미노카보네이트, 폴리포스포에스테르, 폴리안하이드라이드, 폴리오르쏘에스테르, 폴리카프로락톤, 폴리하이드록시발레이트, 폴리하이드록시부티레이트, 폴리아미노산 및 이들의 조합으로 이루어진 군으로부터 선택되며, 바람직하게는 폴리락타이드-코-글리콜라이드(PLGA)이지만, 상기 예시에 국한되는 것은 아니다.In one embodiment of the present invention, the biodegradable polymer of the present invention is at least one selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, Polyhydroxybutyrate, polyamino acid, and combinations thereof, and is preferably selected from the group consisting of polylactide-polylactide-polylactide-polylactide-polylactide-polylactide- Co-glycolide (PLGA), but is not limited to the above examples.
본 발명의 일 구체예로, 본 발명의 마이크로 입자는 마이크로 채널을 이용하여 제조하며, 상기 채널 단면의 폭(w)은 마이크로 입자의 평균 직경(d')에 대해 0.7 내지 1.3의 비율 범위이다.In one embodiment of the present invention, the microparticles of the present invention are prepared using microchannels, and the width w of the channel cross section ranges from 0.7 to 1.3 with respect to the average diameter d 'of the microparticles.
본 발명의 일 구체예로, 본 발명의 마이크로 입자는 마이크로 채널을 이용하여 제조하며, 상기 채널 단면의 높이(d)는 마이크로 입자의 평균 직경(d')에 대해 0.7 내지 1.3의 비율 범위이다.In one embodiment of the present invention, the microparticles of the present invention are prepared using microchannels, and the height (d) of the channel cross section ranges from 0.7 to 1.3 with respect to the average diameter (d ') of the microparticles.
본 발명의 일 구체예로, 본 발명의 따른 마이크로 입자를 포함하는 심장사상충 예방 및 치료용 약제학적 조성물에 관한 것이다.In one embodiment of the present invention, the present invention relates to a pharmaceutical composition for preventing and treating heartworms comprising microparticles according to the present invention.
본 발명의 일 구체예로, 본 발명은 1) 생분해성 고분자 및 목시덱틴을 유기 용매에 용해시켜 제1 혼합물을 제조하는 단계; 2) 계면활성제를 물에 용해시켜 제2 혼합물을 제조하는 단계; 3) 상기 1) 단계의 제1 혼합물을 직선 방향의 마이크로 채널로 주입하여, 흐르게 하는 단계; 4) 상기 2) 단계의 제2 혼합물을 상기 3) 단계의 제1 혼합물이 직선 방향으로 흐르는 마이크로 채널과 교차점을 형성할 수 있도록 양 측면 또는 일 측면에 형성된 마이크로 채널로 주입하여 흐르게 하며, 상기 제1 혼합물의 직선 방향의 흐름과 제2 혼합물의 흐름이 교차하여, 구형의 생분해성 고분자 입자에 목시덱틴이 고르게 분포되어 있는 마이크로 입자를 제조하는 단계; 5) 상기 4) 단계의 교차점에서 생성된 마이크로 입자를 수집하는 단계; 6) 상기 5) 단계에서 수집된 마이크로 입자를 교반하여, 상기 마이크로 입자에 존재하는 유기 용매를 증발시켜 제거하는 단계; 및 7) 상기 6) 단계의 마이크로 입자를 세척 및 건조하는 단계를 포함하며, 상기 마이크로 입자의 입자 평균 직경은 80 내지 130㎛인 목시덱틴을 포함하는 마이크로 입자의 제조 방법에 관한 것이다.In one embodiment of the present invention, the present invention provides a method for producing a biodegradable polymer, comprising: 1) dissolving a biodegradable polymer and moxidectin in an organic solvent to prepare a first mixture; 2) dissolving the surfactant in water to prepare a second mixture; 3) injecting and flowing the first mixture of the step 1) into the microchannel in the linear direction; 4) The second mixture of step 2) is injected and flowed into the microchannels formed on both sides or one side so as to form an intersection with the microchannels flowing in the linear direction in the step 3) Preparing a microparticle wherein a linear flow of the mixture and a flow of the second mixture cross each other and moxidetin is evenly distributed on the spherical biodegradable polymer particle; 5) collecting the microparticles generated at the intersection of step 4); 6) stirring the microparticles collected in the step 5) to evaporate and remove the organic solvent present in the microparticles; And 7) washing and drying the microparticles in the step 6), wherein the average particle diameter of the microparticles is 80 to 130 탆.
본 발명의 일 구체예로, 본 발명의 상기 1) 단계의 제1 혼합물은 생분해성 고분자를 15 내지 60 중량% 포함할 수 있다.In one embodiment of the present invention, the first mixture of step 1) of the present invention may contain 15 to 60% by weight of the biodegradable polymer.
본 발명의 일 구체예로, 본 발명의 상기 1) 단계의 제1 혼합물은 생분해성 고분자 및 목시덱틴을 4:1 내지 9:1의 중량 비율로 포함할 수 있다.In one embodiment of the present invention, the first mixture of step 1) of the present invention may contain a biodegradable polymer and moxidectin in a weight ratio of 4: 1 to 9: 1.
본 발명의 일 구체예로, 본 발명의 상기 생분해성 고분자는 폴리락트산, 폴리락타이드, 폴리락틱-코-글리콜산, 폴리락타이드-코-글리콜라이드(PLGA), 폴리포스파진, 폴리이미노카보네이트, 폴리포스포에스테르, 폴리안하이드라이드, 폴리오르쏘에스테르, 폴리카프로락톤, 폴리하이드록시발레이트, 폴리하이드록시부티레이트, 폴리아미노산 및 이들의 조합으로 이루어진 군으로부터 선택되며, 바람직하게는 폴리락타이드-코-글리콜라이드(PLGA)이지만, 상기 예시에 국한되는 것은 아니다.In one embodiment of the present invention, the biodegradable polymer of the present invention is at least one selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate , Polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate, polyamino acid, and combinations thereof, preferably polylactide -Co-glycolide (PLGA), but is not limited to the above example.
본 발명의 일 구체예로, 본 발명의 상기 1) 단계의 유기용매는 디클로로메탄, 클로로포름, 클로로에탄, 디클로로에탄, 트리클로로에탄 및 이들의 혼합물로 이루어진 군으군부터 선택된 어느 하나 이상이다. In one embodiment of the present invention, the organic solvent in step 1) of the present invention is at least one selected from the group consisting of dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof.
본 발명의 일 구체예로, 본 발명의 상기 2) 단계의 제2 혼합물은 계면활성제를 0.2 중량% 내지 0.3 중량% 포함할 수 있다.In one embodiment of the present invention, the second mixture of step 2) of the present invention may contain 0.2 wt% to 0.3 wt% of a surfactant.
본 발명의 일 구체예로, 본 발명의 상기 2) 단계의 계면활성제는 비이온성 계면활성제, 음이온성 계면활성제, 양이온성 계면활성제 및 이들의 혼합물로 이루어진 군으로부터 선택된 어느 하나 이상이다.In one embodiment of the present invention, the surfactant in the step 2) of the present invention is at least one selected from the group consisting of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and a mixture thereof.
본 발명의 일 구체예로, 본 발명의 상기 3) 단계는 제1 혼합물을 직선 방향의 마이크로 채널에 1000 내지 1500 mbar의 압력으로 주입할 수 있다.In one embodiment of the present invention, the step 3) of the present invention may inject the first mixture into the microchannel in the linear direction at a pressure of 1000 to 1500 mbar.
본 발명의 일 구체예로, 본 발명의 상기 4) 단계는 제2 혼합물을 제1 혼합물이 흐르는 직선 방향의 마이크로 채널과 교차점을 형성할 수 있도록 양 측면 또는 일 측면에에 형성된 마이크로 채널로 주입하며, 상기 제2 혼합물은 1500 내지 2000 mbar의 압력으로 주입할 수 있다.In one embodiment of the present invention, the step 4) of the present invention injects the second mixture into the microchannels formed on both sides or one side so as to form an intersection with the microchannel in the straight direction through which the first mixture flows , And the second mixture may be injected at a pressure of 1500 to 2000 mbar.
본 발명의 일 구체예로, 본 발명의 상기 5) 단계는 0.2 중량% 내지 0.3 중량%의 계면활성제를 포함하는 혼합 용액이 담긴 수조 내에 마이크로 입자를 수집할 수있다.In one embodiment of the present invention, the step 5) of the present invention may collect microparticles in a water bath containing a mixed solution containing 0.2 wt% to 0.3 wt% of a surfactant.
본 발명의 일 구체예로, 본 발명의 상기 6) 단계는, 6-1) 15 내지 20℃에서 1 내지 2 시간 동안 200 내지 400 rpm의 속도로 1차 교반하는 단계; 6-2) 상기 1차 교반 단계 이후, 20 내지 30℃에서 1 내지 2시간 동안 300 내지 500 rpm의 속도로 2차 교반하는 단계; 및 6-3) 상기 2차 교반 단계 이후, 40 내지 50℃에서 3 내지 5시간 동안 400 내지 600 rpm의 속도로 3차 교반하는 단계를 포함할 수 있다.In one embodiment of the present invention, the step 6) of the present invention comprises the steps of: 6-1) primary stirring at a speed of 200 to 400 rpm for 1 to 2 hours at 15 to 20 캜; 6-2) After the primary stirring step, the secondary stirring is carried out at a speed of 300 to 500 rpm at 20 to 30 DEG C for 1 to 2 hours; And 6-3) third stirring at a rate of 400 to 600 rpm for 3 to 5 hours at 40 to 50 DEG C after the secondary stirring step.
본 발명의 일 구체예로, 본 발명의 상기 3) 단계 및 4) 단계의 마이크로 채널은 웨이퍼의 표면에 형성된 것으로, 상기 마이크로 채널의 평균 직경은 60 내지 150㎛이며, 바람직하게는 80 내지 120㎛이며, 보다 바람직하게는 100㎛이지만, 상기 예시에 국한되지 않는다.In one embodiment of the present invention, the microchannels of steps 3) and 4) of the present invention are formed on the surface of the wafer, and the average diameter of the microchannels is 60 to 150 탆, preferably 80 to 120 탆 And more preferably 100 탆, but it is not limited to the above example.
본 발명은 목시덱틴을 포함하는 마이크로 입자 및 이의 제조 방법에 관한 것으로, 목시덱틴을 포함하는 마이크로 입자를 투여함에 따라, 3개월 내지 6개월 동안 지속적으로 심장사상충 예방 효과를 유지할 수 있는 서방성 마이크로 입자 및 이의 제조 방법에 관한 것이다.The present invention relates to microcapsules containing moxidetin and a method for producing the microcapsules, and more particularly, to microcapsules containing sustained-release microparticles capable of sustaining prevention of heartworms for 3 to 6 months upon administration of microcapsules containing moxidectin And a method for producing the same.
또한, 본 발명은 입자의 평균 직경을 일정한 마이크로 크기의 사이즈로 유지시켜 제조함에 따라, 동물에게 주사제로 투여 시의 이물감 및 통증을 감소시켜, 주사제로의 투여를 용이하게 할 수 있다.In addition, the present invention can be manufactured by maintaining the average diameter of the particles at a constant micro size, thereby reducing the foreign body sensation and pain upon administration to an animal as an injection, and facilitating administration to an injection.
도 1은 본 발명의 목시덱틴을 포함하는 마이크로 입자의 제조 방법에 대한 순서도이다.BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a flow chart of a method for producing microspheres comprising moxidectin of the present invention.
도 2는 본 발명의 생분해성 고분자 및 목시덱틴의 중량 비율에 따른 약물 방출 기간에 대한 결과 그래프이다. FIG. 2 is a graph showing the drug release period according to the weight ratio of the biodegradable polymer and moxidectin of the present invention.
도 3은 본 발명의 생분해성 고분자 및 목시덱틴의 중량 비율에 따른 약물 방출 기간에 대한 결과 그래프이다.FIG. 3 is a graph showing a drug release period according to the weight ratio of the biodegradable polymer and moxidectin of the present invention.
도 4는 본 발명의 일 실시예에 따른 제조 방법에 의한 마이크로 입자의 SEM 사진이다.4 is a SEM photograph of the microparticles according to the manufacturing method according to an embodiment of the present invention.
도 5는 본 발명의 일 실시예에 따른 제조 방법에 의한 마이크로 입자의 SEM 사진이다.FIG. 5 is a SEM photograph of microparticles according to a manufacturing method according to an embodiment of the present invention.
도 6은 본 발명의 일 실시예에 따른 제조 방법에 의한 마이크로 입자의 SEM 사진이다.FIG. 6 is a SEM photograph of microparticles according to a manufacturing method according to an embodiment of the present invention.
도 7은 본 발명의 일 실시예에 따른 제조 방법에 의한 마이크로 입자의 SEM 사진이다.7 is a SEM photograph of microparticles according to the manufacturing method according to an embodiment of the present invention.
도 8은 마이크로 입자의 평균 직경 및 마이크로 채널 단면과의 관계에 관한 도면이다.8 is a diagram showing the relationship between the average diameter of the microparticles and the microchannel cross section.
본 발명은 목시덱틴 및 생분해성 고분자를 포함하는 마이크로 입자로, 상기 마이크로 입자는 구형의 생분해성 고분자에 목시덱틴 약물이 고르게 분포되어 있는 형상이며, 상기 마이크로 입자의 입자 평균 직경은 80 내지 130㎛인 목시덱틴을 포함하는 마이크로 입자에 관한 것이다. The present invention relates to microcapsules comprising moxidectin and a biodegradable polymer, wherein the microcapsules have a shape in which a moxidectin drug is uniformly distributed in a spherical biodegradable polymer, and the microparticles have an average particle diameter of 80 to 130 μm And to microparticles comprising moxidectin.
이하, 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본 발명의 실시예에 대하여 상세히 설명한다. 그러나 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 실시예에 한정되지 않는다.Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily carry out the present invention. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.
본 발명의 목시덱틴은 하기 화학식 1로 표시되는 화합물로, 동물의 심장사상충 예방약으로 사용되는 물질을 의미한다.The moxidectin of the present invention is a compound represented by the following general formula (1), which means a substance used as an anti-cardiovirus drug for animals.
[화학식 1][Chemical Formula 1]
Figure PCTKR2018010324-appb-I000001
Figure PCTKR2018010324-appb-I000001
도 1은 본 발명의 목시덱틴을 포함하는 마이크로 입자의 제조 방법에 대한 순서도이다.BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a flow chart of a method for producing microspheres comprising moxidectin of the present invention.
상기의 순서도에 따르면, 본 발명의 목시덱틴을 포함하는 마이크로 입자의 제조는 1) 제1 혼합물을 제조하는 단계(S100); 2) 제2 혼합물을 제조하는 단계(S200); 3) 제1 혼합물을 직선 방향의 마이크로 채널로 주입하는 단계(S300); 4) 제2 혼합물을 양 측면 또는 일 측면의 마이크로 채널로 주입하는 단계(S40O); 5) 마이크로 입자를 수집하는 단계(S500); 6) 수집한 마이크로 입자를 교반하는 단계(S600); 및 7) 마이크로 입자를 세척 및 건조하는 단계(S700)의 순으로 진행된다.According to the above flowchart, the production of microcrystalline particles containing goxydetin of the present invention comprises the steps of: 1) preparing a first mixture (SlOO); 2) preparing a second mixture (S200); 3) injecting the first mixture into the microchannel in the linear direction (S300); 4) injecting the second mixture into the microchannels on both sides or one side (S40O); 5) Collecting microparticles (S500); 6) stirring the collected microparticles (S600); And 7) washing and drying microparticles (S700).
보다 구체적으로 본 발명의 일 실시예에 따른 목시덱틴을 포함하는 마이크로 입자의 제조 방법에 대해 설명하면 하기와 같다. More specifically, a method for producing microcapsules containing moxidectin according to an embodiment of the present invention will be described below.
1) 단계(S100)는 제1 혼합물을 제조하는 단계로, 생분해성 고분자 및 목시덱틴을 유기 용매에 용해시켜 제1 혼합물을 제조하는 단계로, 상기 생분해성 고분자는 폴리락트산, 폴리락타이드, 폴리락틱-코-글리콜산, 폴리락타이드-코-글리콜라이드(PLGA), 폴리포스파진, 폴리이미노카보네이트, 폴리포스포에스테르, 폴리안하이드라이드, 폴리오르쏘에스테르, 폴리카프로락톤, 폴리하이드록시발레이트, 폴리하이드록시부티레이트, 폴리아미노산 및 이들의 조합으로 이루어진 군으로부터 선택되며, 바람직하게는 폴리락타이드-코-글리콜라이드(PLGA)이지만, 상기 예시에 국한되지 않는다. 1) Step S100 is a step of preparing a first mixture, which comprises dissolving a biodegradable polymer and moxidetin in an organic solvent to prepare a first mixture, wherein the biodegradable polymer is polylactic acid, polylactide, poly Polyglycolic acid, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxypoly Polyhydroxybutyrate, polyamino acid, and combinations thereof, and is preferably polylactide-co-glycolide (PLGA), but is not limited to the above examples.
또한, 상기 유기 용매는 물과 섞이지 않는 것으로, 예를 들면, 클로로포름, 클로로에탄, 디클로로에탄, 트리클로로에탄 및 이들의 혼합물로 이루어진 군으군부터 선택된 어느 하나 이상의 것이며, 바람직하게는 디클로로메탄이지만, 예시에 국한되는 것은 아니며, 생분해성 고분자 및 목시덱틴을 용해시킬 수 있는 유기 용매로, 상기 예시에 국한되지 않고, 당업자가 쉽게 선택할 수 있는 유기 용매라면 모두 사용 가능하다고 할 것이다. The organic solvent is not mixed with water and is, for example, any one or more selected from the group consisting of chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof. The organic solvent is preferably dichloromethane, And organic solvent capable of dissolving biodegradable polymer and moxidectin. Any organic solvent easily selectable by those skilled in the art can be used without being limited to the above examples.
상기 1) 단계(S100)는 생분해성 고분자 및 목시덱틴을 용해시킨 제1 혼합물을 제조하는 것으로, 용매는 상기에 기재한 바와 같이, 유기 용매를 사용한다. 이는 목시덱틴 및 생분해성 고분자의 용해 특성을 이용하여, 유기 용매를 사용하여 완전히 용해시킨다. 완전 용해시킨 후, 제1 혼합물은 생분해성 고분자 및 목시덱틴을 4:1 내지 9:1의 중량 비율로 포함하며, 바람직하게는 4:1 이지만 예시에 국한되지 않는다. 생분해성 고분자 및 목시덱틴의 중량 비율이 4:1 미만인 경우, 즉 생분해성 고분자를 상기 중량 비율보다 미만으로 포함하는 경우에는 목시덴틴의 중량에 비해 생분해성 고분자의 중량 비율이 적어, 구형의 생분해성 고분자 입자에 목시덱틴이 고르게 분포하여 포함되고 있는 형태의 마이크로 입자 제조가 어려운 문제가 발생하며, 생분해성 고분자 및 목시덱틴의 중량 비율이 9:1을 초과하는 경우, 즉 생분해성 고분자를 상기 중량 비율보다 초과하여 포함하는 경우에는, 마이크로 입자 내 목시덱틴의 함량이 적어 원하는 농도의 약물투여를 위해 많은 양의 마이크로 입자를 투여해야 하는 문제가 발생할 수 있다.The first step (S100) is to prepare a first mixture in which a biodegradable polymer and moxidectin are dissolved. As described above, an organic solvent is used as a solvent. It dissolves completely using an organic solvent, taking advantage of the dissolution properties of moxidectin and biodegradable polymer. After complete dissolution, the first mixture comprises the biodegradable polymer and moxidectin in a weight ratio of 4: 1 to 9: 1, preferably 4: 1, but is not limited to examples. When the weight ratio of the biodegradable polymer and the moxidectin is less than 4: 1, that is, when the weight ratio of the biodegradable polymer is less than the above weight ratio, the weight ratio of the biodegradable polymer is smaller than that of the dendritic polymer, It is difficult to produce microparticles in which the moxidetin is evenly distributed in the polymer particles. When the weight ratio of the biodegradable polymer and the moxidectin exceeds 9: 1, that is, when the biodegradable polymer is mixed with the weight ratio The content of moxifloxacin in the microparticles may be low and a problem may arise in that a large amount of microparticles must be administered to administer a desired concentration of the drug.
보다 구체적으로, 상기 제1 혼합물 내의 생분해성 고분자는 15 내지 60 중량% 포함하며, 바람직하게는 15 중량% 이지만, 상기 예시에 국한되지 않는다. More specifically, the biodegradable polymer in the first mixture comprises 15 to 60 wt%, preferably 15 wt%, but is not limited to the above examples.
상기 2) 단계(S200)는 제2 혼합물을 제조하는 단계로, 계면활성제를 물에 용해시켜 제2 혼합물을 제조한다. 상기 계면활성제는 생분해성 고분자 용액이 안정한 에멀젼 형성을 도울 수 있는 것이라면 제한 없이 사용 가능하다. 구체적으로는 비이온성 계면활성제, 음이온성 계면활성제, 양이온성 계면활성제 및 이들의 혼합물로 이루어진 군으로부터 선택된 어느 하나 이상의 것이며, 더욱 구체적으로 메틸셀룰로오스, 폴리비닐피롤리돈, 레시틴, 젤라틴, 폴리비닐알코올, 폴리옥시에틸렌 소르비탄 지방산 에스테르, 폴리옥시에틸렌 피마자유 유도체, 라우릴 황산 나트륨, 스테아르산 나트륨, 에스테르 아민, 리니어 디아민, 패티 아민 및 이들의 혼합물로 이루어진 군으로부터 선택된 어느 하나 이상의 것이며, 바람직하게는 폴리비닐알코올이지만, 예시에 국한되지는 않는다.The 2) step (S200) is a step of preparing a second mixture, wherein the surfactant is dissolved in water to prepare a second mixture. The surfactant can be used without limitation as long as the biodegradable polymer solution can help form stable emulsion. Specifically, it is at least one selected from the group consisting of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and a mixture thereof, and more specifically, methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol , Polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sodium lauryl sulfate, sodium stearate, ester amine, linear diamine, pattyamine, and mixtures thereof. Preferably, Polyvinyl alcohol, but are not limited to examples.
상기 3) 단계(S300) 및 4) 단계(S400)는 웨이퍼 상에 형성된 마이크로 채널로 제1 혼합물 및 제2 혼합물을 주입하여, 흐르게 하는 단계이다. The third step S300 and the fourth step S400 are the steps of injecting and flowing the first mixture and the second mixture into the microchannels formed on the wafer.
보다 구체적으로, 실리콘 웨이퍼에 e-beam evaporator를 이용하여 알루미늄을 증착하며, 포토리소그래피(photolithography) 기법을 이용하여 포토레지스트(photoresist)를 알루미늄 위에 패터닝한다. 이후, 포토레지스트를 마스크로 이용하여 알루미늄 식각(etching)하고, 포토레지스트를 제거한 후 알루미늄을 마스크로 하여 실리콘을 DRIE(deep ion reactive etching)로 에칭하고, 알루미늄 제거 후 웨이퍼 위에 유리를 양극 접합하여 밀봉하여, 상기의 마이크로 채널을 제조한다. More specifically, aluminum is deposited on a silicon wafer using an e-beam evaporator, and a photoresist is patterned on aluminum using a photolithography technique. Thereafter, aluminum is etched using a photoresist as a mask, the photoresist is removed, and the silicon is etched by DRIE (deep ion reactive etching) using aluminum as a mask. After the aluminum is removed, the glass is anodically bonded onto the wafer, Thereby manufacturing the above microchannel.
또한, 상기 마이크로 채널의 평균 직경은 60 내지 150㎛이며, 바람직하게는 80 내지 120㎛이며, 보다 바람직하게는 100㎛이지만, 예시에 국한되지 않는다. In addition, the average diameter of the microchannels is 60 to 150 占 퐉, preferably 80 to 120 占 퐉, more preferably 100 占 퐉, but is not limited to the example.
또한, 상기 마이크로 채널의 단면 폭(w) 및 단면의 높이(d)는 제조되는 마이크로 입자의 평균 직경(d')과 밀접한 관련이 있다. 도 8과 같이, 상기 마이크로 채널 단면의 폭(w)은 마이크로 입자의 평균 직경(d')에 대해 0.7 내지 1.3의 비율 범위이며, 마이크로 채널 단면의 높이(d)는 마이크로 입자의 평균 직경(d')에 대해 0.7 내지 1.3의 비율 범위이다.In addition, the cross-sectional width w and the cross-sectional height d of the microchannel are closely related to the average diameter d 'of the microparticles to be produced. 8, the width w of the cross-section of the microchannel is in the range of 0.7 to 1.3 with respect to the average diameter d 'of the microparticles, and the height d of the cross section of the microchannel is the average diameter d ') In the range of 0.7 to 1.3.
즉, 제조하고자 하는 마이크로 입자의 평균 직경(d')이 결정되면, 이에 따라, 마이크로 채널 단면의 폭(w) 및 높이(d)의 길이는 d'의 0.7 내지 1.3의 비율 범위로 설정해야만, 원하는 크기의 마이크로 입자 제조가 가능하다. That is, if the average diameter d 'of the microparticles to be manufactured is determined, the length of the width w and height d of the microchannel cross section should be set in the range of 0.7 to 1.3 of d' It is possible to manufacture microparticles of desired size.
상기 3) 단계(S300)는 제1 혼합물을 직선 방향의 마이크로 채널로 주입하여, 흐르게 하는 것이며, 상기 4) 단계(S400)는 제2 혼합물을 직선 방향의 마이크로 채널과 교차점을 형성하도록 형성된 양 측면 또는 일 측면의 마이크로 채널로 주입하여 흐르게 하는 것이다. In step S300, the first mixture is injected into the microchannel in the linear direction, and the fourth mixture is introduced into the microchannel in the linear direction. In step S400, Or into one side of the microchannel.
즉, 제1 혼합물은 직선 방향의 마이크로 채널을 따라 흐르며, 제2 혼합물은 상기 직선 방향의 마이크로 채널을 기준으로 양 측면 또는 일 측면에서 직선 방향의 마이크로 채널과 교차점을 형성하는 마이크로 채널을 따라 흘러, 제1 혼합물의 흐름과 만나게 된다. That is, the first mixture flows along the microchannel in the linear direction, and the second mixture flows along the microchannel forming the intersection with the microchannel in the linear direction on both sides or one side with respect to the linear microchannel, The flow of the first mixture is met.
이때, 제1 혼합물을 직선 방향의 마이크로 채널로 주입 시, 일정한 압력 조건으로 주입하여, 일정한 유속으로 흐르게 하며, 이때의 압력 조건은 1000 내지 1500mbar이며, 바람직하게는 1500mbar이지만 예시에 국한되지 않는다. 또한, 제2 혼합물을 양 측면 또는 일 측면의 마이크로 채널로 주입 시, 일정한 압력 조건으로 주입하여, 일정한 유속으로 흐르게 하며, 이때의 압력 조건은 1500 내지 2000mbar이며, 바람직하게는 2000mbar이지만 예시에 국한되지 않는다. At this time, when the first mixture is injected into the microchannel in the linear direction, it is injected under a constant pressure condition and flowed at a constant flow rate, the pressure condition being 1000 to 1500 mbar, preferably 1500 mbar, but not limited to the example. In addition, when the second mixture is injected into the microchannels on both sides or one side, it is injected under a constant pressure condition and flowed at a constant flow rate. The pressure condition is 1500 to 2000 mbar, preferably 2000 mbar, Do not.
즉, 직선 방향의 마이크로 채널로 주입되는 제1 혼합물보다 제1 혼합물의 흐름과 교차점을 형성하는 제2 혼합물의 흐름을 더 빠른 유속으로 흐르게 하기 위해, 더 높은 압력 조건 하에서 제2 혼합물을 흐르게 한다. That is, the second mixture flows under higher pressure conditions to flow the flow of the second mixture, which intersects the flow of the first mixture, at a faster flow rate than the first mixture injected into the microchannel in the linear direction.
상기와 같이, 제1 혼합물 및 제2 혼합물의 유속을 다르게 하고, 제2 혼합물의 유속을 제1 혼합물의 유속보다 빠르게 함으로써, 제1 혼합물의 흐름과 제2 혼합물의 흐름이 만나는 지점에서 상대적으로 더 빠른 유속을 가지는 제2 혼합물이 제1 혼합물을 압축하게 되고, 이때 제1 혼합물 및 제2 혼합물의 반발력으로 인해 제1 혼합물 내의 생분해성 고분자 및 목시덱틴이 구 형상의 마이크로 입자를 생성하게 되며, 보다 구체적으로, 구형의 생분해성 고분자에 목시덱틴이 고르게 분포되어 있는 형태의 마이크로 입자를 형성하게 된다.As described above, by making the flow rates of the first mixture and the second mixture different, and making the flow rate of the second mixture higher than the flow rate of the first mixture, the flow of the first mixture and the flow of the second mixture are relatively more The second mixture having a fast flow rate compresses the first mixture and the biodegradable polymer and the moxidectin in the first mixture form spherical microparticles due to the repulsive force of the first mixture and the second mixture, Specifically, microspheres in which moxidetin is uniformly distributed in a spherical biodegradable polymer are formed.
상기 5) 단계(S500)는, 마이크로 입자를 수집하는 단계로 제2 혼합물이 담긴 수조 내에서 마이크로 입자를 수집하여, 초기 생성된 마이크로 입자들 간의 뭉치는 현상(aggregation)을 방지한다. The step 5) (S500) collects the microparticles in the water tank containing the second mixture to prevent aggregation of the initially formed microparticles.
상기 5) 단계(S500)는 상기 2) 단계(S200)에서 제조한 제2 혼합물, 즉 계면활성제 및 물의 혼합 용액을 이용하는 것으로, 제2 혼합물을 상기 2) 단계(S200)에서 제조한 이후, 일부는 마이크로 채널로 주입시키고, 다른 일부는 5) 단계(S500)의 수조로 이동시켜, 수집된 마이크로 입자들간의 뭉치는 현상을 방지하는데 이용된다. The fifth step S500 uses a second mixture prepared in the step S200, that is, a mixed solution of a surfactant and water. After the second mixture is prepared in the step S200, Is injected into the microchannel, and the other part is moved to the water tank of step S500, and a bundle between the collected micro particles is used to prevent the phenomenon.
상기 6) 단계(S600)는, 수조 내에서 수집된 마이크로 입자를 교반하는 단계로, 마이크로 입자를 일정한 온도 조건 및 교반 속도로 교반하여, 마이크로 입자의 표면에 존재하는 유기 용매를 증발시켜 제거한다. 이때, 교반 조건은 15 내지 20℃에서 1 내지 2 시간 동안 200 내지 400 rpm의 속도로 1차 교반하는 단계; 상기 1차 교반 단계 이후, 20 내지 30℃에서 1 내지 2시간 동안 300 내지 500 rpm의 속도로 2차 교반하는 단계; 및 상기 2차 교반 단계 이후, 40 내지 50℃에서 3 내지 5시간 동안 400 내지 600 rpm의 속도로 3차 교반하는 단계의 순서로 진행한다.The step 6) S600 is a step of stirring the microparticles collected in the water tank. The microparticles are stirred at a constant temperature and stirring speed to evaporate the organic solvent present on the surface of the microparticles. At this time, the stirring conditions include a primary stirring at a speed of 200 to 400 rpm at 15 to 20 ° C for 1 to 2 hours; After the primary stirring step, the secondary stirring is performed at a speed of 300 to 500 rpm for 1 to 2 hours at 20 to 30 캜. And the third stirring step at a speed of 400 to 600 rpm for 3 to 5 hours at 40 to 50 DEG C after the secondary stirring step.
마이크로 입자를 교반하는 교반속도와 온도는 1, 2, 3차 교반 시기에 따라 각각 교반속도와 온도를 서서히 증가시키며 교반시키는 것을 특징으로 하며, 온도를 단계적으로 상승시킴에 따라, 마이크로 입자의 표면에 존재하는 유기 용매의 증발 속도를 조절할 수 있다. 즉, 마이크로 입자의 표면에 존재하는 유기 용매를 서서히 증발시켜, 매끄러운 표면을 가지는 마이크로 입자를 제조할 수 있다. The stirring speed and temperature for stirring the microparticles are characterized by gradually increasing the stirring speed and the temperature, respectively, according to the 1st, 2nd and 3rd stirring periods. As the temperature is raised stepwise, The rate of evaporation of the organic solvent present can be controlled. That is, the organic solvent present on the surface of the microparticles can be gradually evaporated to produce microparticles having a smooth surface.
보다 구체적으로 상기 6) 단계(S600)는, 1차로 15 내지 20℃에서 1 내지 2 시간 동안 교반하며, 바람직하게는 17℃에서 1시간 동안 교반한다. 이후 2차로 20 내지 30℃에서 1 내지 2시간 동안 교반하며, 바람직하게는 25℃에서 1시간동안 교반한다. 이후 3차로 40 내지 50℃에서 3 내지 5시간 동안 교반하며, 바람직하게는 45℃에서 4시간 동안 교반을 진행한다.More specifically, the 6) step (S600) is firstly stirred at 15 to 20 ° C for 1 to 2 hours, preferably at 17 ° C for 1 hour. Then, the mixture is stirred at 20 to 30 ° C for 1 to 2 hours, preferably at 25 ° C for 1 hour. Then, the mixture is stirred at 40 to 50 ° C for 3 to 5 hours, preferably at 45 ° C for 4 hours.
제1 혼합물 및 제2 혼합물이 마이크로 채널을 흐를 때의 온도 또한 15 내지 20℃이며, 바람직하게는 17℃이다. 즉, 마이크로 채널을 흐르고, 교차점을 형성하여 마이크로 입자를 생성한 이후, 수집된 마이크로 입자를 1차 교반할 때 까지는 일정하게 15 내지 20℃로 저온을 유지한다. 마이크로 입자의 제조 과정에서 저온을 유지해야만, 구형의 입자를 제조 및 유지가 가능하다. 즉, 저온 조건이 아닌 경우에는 일정한 구 형상의 입자를 제조하기 어려운 문제가 발생한다. The temperature at which the first mixture and the second mixture flow through the microchannel is also 15 to 20 占 폚, preferably 17 占 폚. That is, after flowing microchannels and forming crossing points to generate microparticles, the collected microparticles are kept at a low temperature of 15 to 20 DEG C constantly until the primary agitation. It is possible to manufacture and maintain spherical particles only if the temperature of the microparticles is kept low during the manufacturing process. That is, when the temperature is not low, it is difficult to produce a uniform spherical particle.
마지막으로 상기 7) 단계(S700)는, 마이크로 입자를 세척 및 건조하는 단계로, 교반하여 표면의 유기 용매를 모두 제거한 마이크로 입자를 제균 여과된 정제수로 수 차례 세척하여 마이크로 입자에 잔존하는 계면활성제를 제거하고, 이후 동결 건조한다. Finally, the 7) step (S700) is a step of washing and drying the microparticles. The microparticles in which the organic solvent on the surface is completely removed by stirring are washed several times with the filtered, purified water to remove the surfactant remaining in the microparticles And then freeze-dried.
최종적으로 생성된 마이크로 입자는 구형의 생분해성 고분자 마이크로 입자에 목시덱틴 약물이 고르게 분포되어 있는 형태이며, 마이크로 입자의 입자 평균 직경은 80 내지 130㎛이고, 생분해성 고분자 및 목시덱틴을 4:1 내지 9:1의 중량 비율로 포함한다. 마이크로 입자 내에 포함된 생분해성 고분자 및 목시덱틴의 중량 비율은 제1 혼합물에서의 중량 비율과 동일한데, 이는 마이크로 입자를 제조하고, 유기 용매를 모두 증발시켜 제거함에 따라, 제1 혼합물 내에서의 중량 비율과 동일한 비율로 생분해성 고분자 및 목시덱틴을 함유한 마이크로 입자를 제조할 수 있다. Finally, the microparticles finally formed are spherical biodegradable polymer microparticles having a uniformly distributed moxidectin drug, the average particle diameter of the microparticles is 80 to 130 탆, the biodegradable polymer and moxidectin are used in a ratio of 4: 9: 1. The weight ratio of biodegradable polymer and moxidectin contained in the microparticles is equal to the weight ratio in the first mixture, which is obtained by preparing the microparticles and removing all of the organic solvent by evaporation, Microparticles containing the biodegradable polymer and moxidectin can be produced at the same ratio as the ratio of the biodegradable polymer and the moxidectin.
[제조예:[Preparation Example: 목시덱틴을 포함하는 마이크로 입자의 제조]Preparation of Microparticles Containing Moxydetin]
실시예 1Example 1
폴리락타이드-코-글리콜라이드(PLGA) 및 목시덱틴을 디클로로메탄(dichloromethane)에 용해하여 제1 혼합물을 제조하였다. 이때, 제1 혼합물 내의 폴리락타이드-코-글리콜라이드는 15 중량%의 비율로 포함하며, 폴리락타이드-코-글리콜라이드 및 목시덱틴의 중량 비율은 9:1이다. The first mixture was prepared by dissolving polylactide-co-glycolide (PLGA) and moxidectin in dichloromethane. Here, the polylactide-co-glycolide in the first mixture is contained in a proportion of 15% by weight, and the weight ratio of polylactide-co-glycolide and moxydectin is 9: 1.
계면활성제인 폴리비닐알콜을 물에 혼합하여, 폴리비닐알콜을 0.25 중량% 포함하는 제2 혼합물을 제조하였다. Polyvinyl alcohol as a surfactant was mixed with water to prepare a second mixture containing 0.25 wt% of polyvinyl alcohol.
상기 제1 혼합물 및 제2 혼합물을 실리콘 웨이퍼 상에 형성된 마이크로 채널에 주입하여 흐르게 하였다. 이때, 제1 혼합물 및 제2 혼합물을 일정한 유속으로 흐르게 하기 위해, 제1 혼합물은 1000mbar의 압력 조건 하에서, 제2 혼합물은 2000mbar의 압력 조건 하에서 흐르게 하였다. 온도 조건은 17℃로 유지하였다.The first mixture and the second mixture were injected into a microchannel formed on a silicon wafer and allowed to flow. At this time, in order to flow the first mixture and the second mixture at a constant flow rate, the first mixture was flowed under a pressure condition of 1000 mbar and the second mixture was flowed under a pressure condition of 2000 mbar. The temperature condition was maintained at 17 占 폚.
상기 제1 혼합물의 흐름 및 제2 혼합물의 흐름이 만나는 교차점에서 생성된 마이크로 입자를 제2 혼합물이 담긴 수조 내에서 수집하였다. 상기 수조 내에 수집된 마이크로 입자를 17℃에서 1시간 동안 300rpm의 속도로 1차 교반하고, 25℃로 온도를 상승시켜, 1시간 동안 400rpm의 속도로 2차 교반하고, 이후 45℃로 온도를 상승시키고, 4시간 동안 500rpm의 속도로 3차 교반하였다.The microparticles generated at the intersection of the flow of the first mixture and the flow of the second mixture are collected in a water tank containing the second mixture. The microparticles collected in the water tank were first stirred at 17 ° C for 1 hour at a speed of 300 rpm, then the temperature was raised to 25 ° C, the secondary stirring was carried out at 400 rpm for 1 hour, and then the temperature was raised to 45 ° C And the mixture was stirred for 3 hours at a rate of 500 rpm for 4 hours.
교반을 완료한 마이크로 입자를 제균 여과된 정제수로 수 차례 세척하고, 동결 건조하여 마이크로 입자를 제조하였다.The microparticles that had been stirred were washed several times with filtered water, and lyophilized to prepare microparticles.
실시예 2Example 2
폴리락타이드-코-글리콜라이드 및 목시덱틴의 중량 비율은 4:1로 제조한 것을 제외하고 실시예 1과 동일하게 제조하였다.The weight ratio of polylactide-co-glycolide and moxidectin was prepared in the same manner as in Example 1 except that the weight ratio was 4: 1.
실시예 3Example 3
폴리락타이드-코-글리콜라이드 및 목시덱틴의 중량 비율은 2:1로 제조한 것을 제외하고 실시예 1과 동일하게 제조하였다.The weight ratio of polylactide-co-glycolide and moxydectin was prepared in the same manner as in Example 1 except that the weight ratio was 2: 1.
실시예 4Example 4
폴리락타이드-코-글리콜라이드 및 목시덱틴의 중량 비율은 12:1로 제조한 것을 제외하고 실시예 1과 동일하게 제조하였다.The weight ratio of polylactide-co-glycolide and moxidectin was prepared in the same manner as in Example 1 except that the weight ratio was 12: 1.
실시예 5 내지 실시예 10Examples 5 to 10
실시예 1과 동일하게 제조하였으나, 마이크로 입자를 제2 혼합물이 담긴 수조 내에서 수집한 이후, 교반 조건을 하기 표 1과 같은 조건으로 교반 공정을 진행하였다.The microparticles were collected in a water tank containing the second mixture, and then stirred under the conditions shown in Table 1 below.
교반 조건Stirring condition 교반 온도Stirring temperature 교반 시간Stirring time 교반 속도Stirring speed
실시예 5Example 5 1One 15℃15 ℃ 1시간1 hours 300rpm300rpm
22 1시간1 hours 400rpm400rpm
33 4시간4 hours 500rpm500rpm
실시예 6Example 6 1One 30℃30 ℃ 1시간1 hours 300rpm300rpm
22 1시간1 hours 400rpm400rpm
33 4시간4 hours 500rpm500rpm
실시예 7Example 7 1One 45℃45 ° C 1시간1 hours 300rpm300rpm
22 1시간1 hours 400rpm400rpm
33 4시간4 hours 500rpm500rpm
실시예 8Example 8 1One 15℃15 ℃ 1시간1 hours 300rpm300rpm
22 30℃30 ℃ 1시간1 hours
33 45℃45 ° C 4시간4 hours
실시예 9Example 9 1One 15℃15 ℃ 1시간1 hours 400rpm400rpm
22 30℃30 ℃ 1시간1 hours
33 45℃45 ° C 4시간4 hours
실시예10Example 10 1One 15℃15 ℃ 1시간 1 hours 500rpm500rpm
22 30℃30 ℃ 1시간1 hours
33 45℃45 ° C 4시간4 hours
[실험예 1: 목시덱틴을 포함하는 마이크로 입자의 약물 방출 실험]1. In-vitro 약물 방출 실험 [Experimental Example 1: Drug release test of microparticles containing moxifloxacin] 1. In-vitro drug release experiment
실시예 1 내지 4의 마이크로 입자 약 100 mg을 내용량 120 mL의 유리제 시험용기에 넣고 방출시험액을 100 mL를 채운다. 약물 방출에 대한 가속 실험 조건으로서 45℃ 수욕조에 넣고, 진폭 4 cm 및 진탕 횟수 120회/분 왕복하여 약물 방출 실험을 진행한다. 검체 채취 시, 병을 잘 흔들어 섞은 후 1 mL를 취한다. 13,000 rpm, 3분간 원심분리 후, 상층액을 취하여 고성능 액체 크로마토그래피로 분석하였다.About 100 mg of the microparticles of Examples 1 to 4 are placed in a 120 mL glass test container and 100 mL of the release test solution is filled. As an accelerated experimental condition for drug release, the drug release experiment is carried out by placing the sample in a 45 ° C water bath, reciprocating 4 cm of amplitude and 120 times / minute of shaking. When collecting specimens, shake well and mix 1 mL. After centrifugation at 13,000 rpm for 3 minutes, the supernatant was collected and analyzed by high performance liquid chromatography.
dayday 1One 22 33 44 77 1010 1414 1616 2121 2525
실시예 3Example 3 28.128.1 42.542.5 57.257.2 69.369.3 92.592.5 94.294.2 94.394.3 95.195.1 95.195.1 96.396.3
실시예 2Example 2 12.712.7 22.322.3 34.234.2 43.843.8 66.866.8 88.288.2 94.594.5 94.394.3 94.594.5 95.095.0
실시예 1Example 1 6.56.5 12.312.3 20.120.1 28.128.1 50.250.2 72.072.0 86.286.2 93.193.1 93.593.5 96.296.2
실시예 4Example 4 2.22.2 7.37.3 12.112.1 18.618.6 35.735.7 56.356.3 72.572.5 78.678.6 88.388.3 93.993.9
(단위 %)(unit %)
도 2 및 표 2에 따르면, 실시예 1 및 2의 경우에 25일까지 목시덱틴 약물이 일정 수준으로 방출되어, 심장 사상충의 예방 또는 치료 효과가 나타날 수 있는 반면, 실시예 3의 경우에는 초반에 약물 방출의 양이 너무 많고, 7일 이후에는 방출이 거의 완료되어, 장 시간 약물 방출 효과를 나타내기에는 어려운 문제가 있다. 뿐만 아니라, 실시예 4의 경우에는 초기 약물 방출 양이 너무 미비하여, 목시덱틴 약물의 치료 효과가 미비한 문제가 있다.According to Fig. 2 and Table 2, in the case of Examples 1 and 2, moxidectin drug was released to a certain level up to 25 days, and prevention or treatment effect of cardiac wasps could be exhibited. On the other hand, in Example 3, The amount of drug release is too much, and after 7 days, the release is almost completed, which is a difficult problem to exhibit a drug release effect for a long time. In addition, in the case of Example 4, the amount of initial drug release is too small, and there is a problem in that the therapeutic effect of the moxifloxacin drug is insufficient.
2. In-vivo PK 2. In vivo PK
실시예 1 및 2의 마이크로 입자에 대해 상기 1의 실험과 동일한 방식으로 실험을 진행하여, In-vivo PK 데이터를 분석하여, 3개월까지의 지속적인 약물 방출 효과를 확인하였다. Experiments were carried out on the microparticles of Examples 1 and 2 in the same manner as in Experiment 1 described above, and the in vivo PK data were analyzed to confirm sustained drug release effect up to 3 months.
그 결과는 도 3과 같다. 도 3에 나타낸 바와 같이, 실시예 1 및 2의 경우에 최대 3개월(90일)까지 목시덱틴이 방출됨을 확인할 수 있다. 해당 결과를 바탕으로, 본 발명의 마이크로 입자는 3개월 동안 지속적인 목시덱틴 방출 효과를 나타냄을 확인하였다.The results are shown in FIG. As shown in FIG. 3, it can be confirmed that moxidetine is released up to 3 months (90 days) in the case of Examples 1 and 2. Based on the results, it was confirmed that the microparticles of the present invention showed sustained release of moxidectin for 3 months.
[실험예 2: 마이크로 입자의 성상 검토][Experimental Example 2: Examination of properties of microparticles]
교반 조건에 따른 마이크로 입자의 성상을 검토하기 위하여, 실시예 1 및 실시예 5 내지 10의 조건 하에서 제조된 마이크로 입자의 성상을 SEM 사진을 통해 검토하였다. The microparticles prepared under the conditions of Example 1 and Examples 5 to 10 were examined through SEM photographs to examine the properties of the microparticles according to the stirring conditions.
결과는 하기 표 3과 같다. The results are shown in Table 3 below.
교반 조건에 따른 실험Experiment according to agitation condition 마이크로 입자의 제조결과Production results of microparticles
실시예 5Example 5 △△
실시예 6Example 6 △△
실시예 7Example 7 △△
실시예 8Example 8 △△
실시예 9Example 9 △△
실시예 10Example 10 △△
실시예 1Example 1 ○○
△는 도 4 및 도 5의 SEM 사진과 같이, 잔류 용매의 영향으로 마이크로 입자의 뭉침 현상이 발생하고, 마이크로 입자의 성상이 고르지 못한 것을 의미한다.반면, 실시예 1의 경우에는 도 6 및 도 7의 SEM 사진과 같이, 마이크로 입자의 성상이 고르게 형성되고, 뭉침 현상이 발생하지 않는 것을 확인하였다. As shown in the SEM photographs of FIGS. 4 and 5, Δ means that the microparticles are aggregated due to the influence of the residual solvent, and the microparticles are uneven in shape. On the other hand, in the case of Example 1, As shown in the SEM photograph of FIG. 7, it was confirmed that the properties of the microparticles were uniformly formed and no aggregation occurred.
이상에서 본 발명의 바람직한 실시예에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고 다음의 청구범위에서 정의하고 있는 본 발명의 기본 개념을 이용한 당업자의 여러 변형 및 개량 형태 또한 본 발명의 권리범위에 속하는 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, Of the right.
본 발명은 목시덱틴(Moxidectin)을 포함하는 마이크로 입자 및 이의 제조 방법에 관한 것으로, 보다 구체적으로 심장 사상충을 예방할 수 있는 목시덱틴 및 생분해성 고분자를 포함하는 마이크로 입자 및 이의 제조 방법에 관한 것이다. The present invention relates to microcapsules containing moxidectin and a method for preparing the microcapsules, and more particularly, to microcapsules containing moxidectin and a biodegradable polymer capable of preventing heartworms, and a method for producing the same.

Claims (20)

  1. 목시덱틴 및 생분해성 고분자를 포함하는 마이크로 입자로,Microcapsules containing moxidectin and a biodegradable polymer,
    상기 마이크로 입자는 구형의 생분해성 고분자에 목시덱틴 약물이 고르게 분포되어 있는 형상이며,The microparticles have a shape in which the moxidectin drug is uniformly distributed in the spherical biodegradable polymer,
    상기 마이크로 입자의 입자 평균 직경은 80 내지 130㎛인 The microparticles have an average particle diameter of 80 to 130 mu m
    목시덱틴을 포함하는 마이크로 입자.Microparticles containing moxifectin.
  2. 제 1항에 있어서,The method according to claim 1,
    상기 마이크로 입자는 생분해성 고분자 및 목시덱틴을 4:1 내지 9:1의 중량 비율로 포함하는 Wherein the microparticles comprise a biodegradable polymer and moxidectin in a weight ratio of 4: 1 to 9: 1
    목시덱틴을 포함하는 마이크로 입자. Microparticles containing moxifectin.
  3. 제 1항에 있어서,The method according to claim 1,
    상기 마이크로 입자는 목시덱틴을 3개월 내지 6개월 동안 지속적으로 방출하는 The microparticles continuously release the moxifloxacin for 3 to 6 months
    목시덱틴을 포함하는 마이크로 입자.Microparticles containing moxifectin.
  4. 제 1항에 있어서,The method according to claim 1,
    상기 생분해성 고분자는 폴리락트산, 폴리락타이드, 폴리락틱-코-글리콜산, 폴리락타이드-코-글리콜라이드(PLGA), 폴리포스파진, 폴리이미노카보네이트, 폴리포스포에스테르, 폴리안하이드라이드, 폴리오르쏘에스테르, 폴리카프로락톤, 폴리하이드록시발레이트, 폴리하이드록시부티레이트, 폴리아미노산 및 이들의 조합으로 이루어진 군으로부터 선택되는 Wherein the biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, Polyhydroxybutyrate, polyamino acid, and combinations thereof. ≪ RTI ID = 0.0 > polyol < / RTI >
    목시덱틴을 포함하는 마이크로 입자.Microparticles containing moxifectin.
  5. 제 4항에 있어서,5. The method of claim 4,
    상기 생분해성 고분자는 폴리락타이드-코-글리콜라이드(PLGA)인 The biodegradable polymer may be polylactide-co-glycolide (PLGA)
    목시덱틴을 포함하는 마이크로 입자.Microparticles containing moxifectin.
  6. 제 1항에 있어서, The method according to claim 1,
    상기 마이크로 입자는 마이크로 채널을 이용하여 제조하며, The microparticles are prepared using microchannels,
    상기 채널 단면의 폭(w)은 마이크로 입자의 평균 직경(d')에 대해 0.7 내지 1.3의 비율 범위인The width w of the channel cross-section is in the range of 0.7 to 1.3 with respect to the average diameter d 'of the microparticles
    목시덱틴을 포함하는 마이크로 입자. Microparticles containing moxifectin.
  7. 제 1항에 있어서, The method according to claim 1,
    상기 마이크로 입자는 마이크로 채널을 이용하여 제조하며, The microparticles are prepared using microchannels,
    상기 채널 단면의 높이(d)는 마이크로 입자의 평균 직경(d')에 대해 0.7 내지 1.3의 비율 범위인The height (d) of the channel cross-section is in the range of 0.7 to 1.3 with respect to the average diameter (d ') of the microparticles
    목시덱틴을 포함하는 마이크로 입자. Microparticles containing moxifectin.
  8. 제 1항에 따른 마이크로 입자를 포함하는Comprising microparticles according to claim < RTI ID = 0.0 > 1,
    심장사상충 예방 및 치료용 약제학적 조성물.A pharmaceutical composition for prevention and treatment of heartworm.
  9. 1) 생분해성 고분자 및 목시덱틴을 유기 용매에 용해시켜 제1 혼합물을 제조하는 단계;1) preparing a first mixture by dissolving a biodegradable polymer and moxidectin in an organic solvent;
    2) 계면활성제를 물에 용해시켜 제2 혼합물을 제조하는 단계;2) dissolving the surfactant in water to prepare a second mixture;
    3) 상기 1) 단계의 제1 혼합물을 직선 방향의 마이크로 채널로 주입하여, 흐르게 하는 단계;3) injecting and flowing the first mixture of the step 1) into the microchannel in the linear direction;
    4) 상기 2) 단계의 제2 혼합물을 상기 3) 단계의 제1 혼합물이 직선 방향으로 흐르는 마이크로 채널과 교차점을 형성할 수 있도록 양 측면 또는 일 측면에 형성된 마이크로 채널로 주입하여 흐르게 하며,4) The second mixture of step 2) is injected and flowed into the microchannels formed on both sides or one side so that the first mixture of step 3) can form an intersection with the microchannels flowing in a linear direction,
    상기 제1 혼합물의 직선 방향의 흐름과 제2 혼합물의 흐름이 교차하여, 구형의 생분해성 고분자 입자에 목시덱틴 약물이 고르게 분포되어 있는 형태인 마이크로 입자를 제조하는 단계;Preparing a microparticle in which a linear mixture of the first mixture and a second mixture cross each other and the moxidectin drug is uniformly distributed on the spherical biodegradable polymer particles;
    5) 상기 4) 단계의 교차점에서 생성된 마이크로 입자를 수집하는 단계; 5) collecting the microparticles generated at the intersection of step 4);
    6) 상기 5) 단계에서 수집된 마이크로 입자를 교반하여, 상기 마이크로 입자에 존재하는 유기 용매를 증발시켜 제거하는 단계; 및6) stirring the microparticles collected in the step 5) to evaporate and remove the organic solvent present in the microparticles; And
    7) 상기 6) 단계의 마이크로 입자를 세척 및 건조하는 단계를 포함하며,7) washing and drying the microparticles of step 6)
    상기 마이크로 입자의 입자 평균 직경은 80 내지 130㎛인 The microparticles have an average particle diameter of 80 to 130 mu m
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  10. 제 9항에 있어서,10. The method of claim 9,
    상기 1) 단계의 제1 혼합물은 생분해성 고분자를 15 내지 60 중량% 포함하는 The first mixture of step 1) comprises 15 to 60% by weight of the biodegradable polymer
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  11. 제 9항에 있어서,10. The method of claim 9,
    상기 1) 단계의 제1 혼합물은 생분해성 고분자 및 목시덱틴을 4:1 내지 9:1의 중량 비율로 포함하는 Wherein the first mixture in step 1) comprises a biodegradable polymer and moxidectin in a weight ratio of 4: 1 to 9: 1
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  12. 제 9항에 있어서,10. The method of claim 9,
    상기 생분해성 고분자는 폴리락트산, 폴리락타이드, 폴리락틱-코-글리콜산, 폴리락타이드-코-글리콜라이드(PLGA), 폴리포스파진, 폴리이미노카보네이트, 폴리포스포에스테르, 폴리안하이드라이드, 폴리오르쏘에스테르, 폴리카프로락톤, 폴리하이드록시발레이트, 폴리하이드록시부티레이트, 폴리아미노산 및 이들의 조합으로 이루어진 군으로부터 선택되는 Wherein the biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, Polyhydroxybutyrate, polyamino acid, and combinations thereof. ≪ RTI ID = 0.0 > polyol < / RTI >
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  13. 제 9항에 있어서,10. The method of claim 9,
    상기 1) 단계의 유기 용매는 디클로로메탄, 클로로포름, 클로로에탄, 디클로로에탄, 트리클로로에탄 및 이들의 혼합물로 이루어진 군으군부터 선택된 어느 하나 이상인 The organic solvent in step 1) may be any one selected from the group consisting of dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof.
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  14. 제 9항에 있어서,10. The method of claim 9,
    상기 2) 단계의 제2 혼합물은 계면활성제를 0.2 중량% 내지 0.3 중량% 포함하는 것인 Wherein the second mixture in step 2) comprises 0.2 wt% to 0.3 wt% of a surfactant
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  15. 제 9항에 있어서,10. The method of claim 9,
    상기 2) 단계의 계면활성제는 비이온성 계면활성제, 음이온성 계면활성제, 양이온성 계면활성제 및 이들의 혼합물로 이루어진 군으로부터 선택된 어느 하나 이상인 The surfactant in the step 2) may be any one or more selected from the group consisting of a nonionic surfactant, an anionic surfactant, a cationic surfactant,
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  16. 제 9항에 있어서,10. The method of claim 9,
    상기 3) 단계는 제1 혼합물을 직선 방향의 마이크로 채널에 1000 내지 1500 mbar의 압력으로 주입하는 것인 The step 3) is a step of injecting the first mixture into a linear microchannel at a pressure of 1000-1500 mbar
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  17. 제 9항에 있어서,10. The method of claim 9,
    상기 4) 단계는 제2 혼합물을 제1 혼합물이 흐르는 직선 방향의 마이크로 채널과 교차점을 형성할 수 있도록 양 측면 또는 일 측면에 형성된 마이크로 채널로 주입하며,In the step 4), the second mixture is injected into the microchannels formed on both sides or one side so as to form an intersection with the microchannel in the linear direction through which the first mixture flows,
    상기 제2 혼합물은 1500 내지 2000 mbar의 압력으로 주입하는 것인 And the second mixture is injected at a pressure of 1500 to 2000 mbar.
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  18. 제 9항에 있어서,10. The method of claim 9,
    상기 5) 단계는 제2 혼합물이 담긴 수조 내에 마이크로 입자를 수집하는 것인 The step 5) is a step of collecting the microparticles in the water tank containing the second mixture
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  19. 제 9항에 있어서,10. The method of claim 9,
    상기 6) 단계는,The step (6)
    6-1) 15 내지 20℃에서 1 내지 2 시간 동안 200 내지 400 rpm의 속도로 1차 교반하는 단계;6-1) primary stirring at 15 to 20 DEG C for 1 to 2 hours at a rate of 200 to 400 rpm;
    6-2) 상기 1차 교반 단계 이후, 20 내지 30℃에서 1 내지 2시간 동안 300 내지 500 rpm의 속도로 2차 교반하는 단계; 및6-2) After the primary stirring step, the secondary stirring is carried out at a speed of 300 to 500 rpm at 20 to 30 DEG C for 1 to 2 hours; And
    6-3) 상기 2차 교반 단계 이후, 40 내지 50℃에서 3 내지 5시간 동안 400 내지 600 rpm의 속도로 3차 교반하는 단계를 포함하는 6-3) After the second stirring step, the third stirring is carried out at a speed of 400 to 600 rpm at 40 to 50 DEG C for 3 to 5 hours
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
  20. 제 10항에 있어서,11. The method of claim 10,
    상기 3) 단계 및 4) 단계의 마이크로 채널은 웨이퍼의 표면에 형성된 것으로, The microchannels of steps 3) and 4) are formed on the surface of the wafer,
    상기 마이크로 채널의 평균 직경은 60 내지 150㎛인 The microchannels have an average diameter of 60 to 150 mu m
    목시덱틴을 포함하는 마이크로 입자의 제조 방법.A method for producing microparticles comprising moxifectin.
PCT/KR2018/010324 2017-09-06 2018-09-05 Microparticles comprising moxidectin, and preparation method therefor WO2019050259A1 (en)

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JP2020533631A JP7040818B2 (en) 2017-09-06 2018-09-05 Microparticles containing moxidectin and methods for producing them
US16/771,196 US11931461B2 (en) 2017-09-06 2018-09-05 Microparticles containing moxidectin, and preparation method therefor

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