WO2019182319A1 - Procédé de préparation de composition pharmaceutique de prévention ou de traitement de maladies associées au trouble cognitif, et composition pharmaceutique de prévention ou de traitement de maladies associées au trouble cognitif, préparée par le procédé de préparation - Google Patents

Procédé de préparation de composition pharmaceutique de prévention ou de traitement de maladies associées au trouble cognitif, et composition pharmaceutique de prévention ou de traitement de maladies associées au trouble cognitif, préparée par le procédé de préparation Download PDF

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WO2019182319A1
WO2019182319A1 PCT/KR2019/003158 KR2019003158W WO2019182319A1 WO 2019182319 A1 WO2019182319 A1 WO 2019182319A1 KR 2019003158 W KR2019003158 W KR 2019003158W WO 2019182319 A1 WO2019182319 A1 WO 2019182319A1
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Prior art keywords
microparticles
preventing
pharmaceutical composition
mixture
donepezil
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PCT/KR2019/003158
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English (en)
Korean (ko)
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김주희
이상노
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(주)인벤티지랩
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Priority claimed from KR1020190030801A external-priority patent/KR102224917B1/ko
Application filed by (주)인벤티지랩 filed Critical (주)인벤티지랩
Priority to US16/652,065 priority Critical patent/US11400085B2/en
Publication of WO2019182319A1 publication Critical patent/WO2019182319A1/fr

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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
    • A61K31/13—Amines
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a method for preparing a pharmaceutical composition for preventing or treating a disease related to cognitive disorders, and to a pharmaceutical composition for preventing or treating a disease related to cognitive disorders prepared by the method, and more specifically, evenly distributed donepezil.
  • the present invention relates to a method for preparing a pharmaceutical composition for preventing or treating a disease related to cognitive disorders capable of preparing microparticles in a uniform particle size, and to a composition prepared by the method of manufacturing the same.
  • Dementia encompasses complex clinical syndromes in which the brain is temporally damaged or destroyed by various causes such as acquired trauma, disease, or genetic factors, resulting in abnormal deterioration of overall cognitive and higher mental functions such as language, learning, and intelligence. do. Dementia caused by Alzheimer's disease, dementia caused by Alzheimer's disease, dementia caused by certain brain diseases and systemic diseases accounted for more than 50% of Alzheimer's disease. Alzheimer's dementia is a protein that causes beta-amyloid, which accumulates in the brain through oligomer and fibril stages, and in the form of plaque.
  • Acetylcholine esterase is an enzyme that hydrolyzes acetylcholine into choline and acetate, and therefore, acetylcholine esterase inhibitors are used for the treatment of Alzheimer's dementia.
  • Such dementia therapeutic agents are, for example, Donepezil (Aricept), Rivastigmin (Excelon) and Galantamine (Reminil).
  • Patent Document 1 KR 10-2008-0056731 A1
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cognitive impairment-related diseases that can maintain the effect of preventing or treating cognitive impairment-related diseases for one month due to one injection. It is to provide a pharmaceutical composition for the prophylaxis or treatment of cognitive impairment-related diseases prepared by the production method and the production method thereof.
  • Another object of the present invention is to maintain the average diameter of the particles to maintain a constant micro-sized size, thereby maintaining a constant blood concentration for the target period, and also to reduce foreign body pain and pain when administered to the patient as an injection
  • a pharmaceutical composition for the prevention or treatment of cognitive disorders related diseases that can facilitate administration to an injection
  • a pharmaceutical composition for the prevention or treatment of cognitive disorders related diseases prepared by the method prepared by the method.
  • a method for producing a pharmaceutical composition for preventing or treating a disease related to cognitive impairment 1) to prepare a first mixture by dissolving the biodegradable polymer and donepezil in an organic solvent Making; 2) dissolving the surfactant in water to prepare a second mixture; 3) injecting and flowing the first mixture of step 1) into a microchannel in a linear direction; 4) injecting and flowing the second mixture of step 2) into microchannels formed on both or one sides of the first mixture of step 3) so as to form an intersection with the microchannels flowing in a linear direction.
  • step 6 Producing a microparticle in which donepezil is evenly distributed in the spherical biodegradable polymer particles by crossing the linear flow of the first mixture with the flow of the second mixture; 5) collecting the microparticles produced at the intersection of step 4); 6) stirring the microparticles collected in step 5) to remove the organic solvent present on the surface of the microparticles; And 7) washing and drying the microparticles of step 6).
  • the donepezil may be included in the form of donepezil or a pharmaceutically acceptable salt thereof.
  • the microparticles have an average diameter of 30 to 70 ⁇ m.
  • the microparticles may continue to release donepezil for 1 month to maintain a prophylactic or therapeutic effect of diseases related to cognitive impairment.
  • the biodegradable polymer may be polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, Polyorthoesters, polycaprolactones, polyhydroxyvalates, polyhydroxybutyrates, polyamino acids, and combinations thereof.
  • microparticles utilize microchannels to produce microparticles, the width w of the cross section of the channel being in the range of 0.7 to 1.3 relative to the average diameter d 'of the microparticles.
  • microparticles utilize microchannels to produce microparticles, the height d of the cross section of the channel being in the range of 0.7 to 1.3 relative to the average diameter d 'of the microparticles.
  • the cognitive disorder related disease is dementia, Alzheimer's disease, forgetfulness or Parkinson's disease.
  • a pharmaceutical composition for preventing or treating a disease related to cognitive impairment includes microparticles including donepezil and a biodegradable polymer, and the microparticles are spheroidal biodegradable polymers. Evenly distributed form, the micro particles can be produced in a uniform particle size by the above production method.
  • Alzheimer's disease is the most common degenerative brain disease causing dementia, first reported in 1907 by Dr. Alois Alzheimer, a German psychiatrist. Alzheimer's disease develops slowly and progresses gradually. Initially, memory impairment of recent work is gradually accompanied by abnormalities of other cognitive functions such as language function and judgment ability and eventually lose all daily functions.
  • amyloid-beta A ⁇
  • Tau proteins amyloid-beta
  • Alzheimer's drugs currently on the market are categorized as 'AChE inhibitors' that prevent the degradation of acetylcholine, a neurotransmitter, and 'NMDA water-soluble antagonists' that prevent glutamic acid from binding to receptors.
  • donepezil is used as an 'AChE inhibitor' to prevent the degradation of acetylcholine, a neurotransmitter.
  • the donepezil is included in the form of donepezil or a pharmaceutically acceptable salt thereof, which is in the form of Alzheimer's by increasing the concentration of acetylcholine at synapses by reversibly and non-competitively inhibiting acetylcholine esterase (AChE).
  • AChE acetylcholine esterase
  • Donepezil is a compound represented by Formula 1:
  • Such a therapeutic agent has a problem that should be taken every day for the prevention or treatment of cognitive disorder-related diseases.
  • a daily therapeutic agent must be taken for the prevention or treatment of a disease related to cognitive impairment. You can solve the problem.
  • the characteristics of long-term sustained injection that is continuously released in the body prevents cognitive disorder-related diseases by maintaining effective blood concentration for a certain period of time. Or the therapeutic effect is excellent.
  • the digestive organs such as gastrointestinal disorders
  • the digestive organs may occur in some cases, and in order to prevent or treat cognitive disorder-related diseases, a certain amount of donepezil needs to be taken regularly every day. .
  • the pharmaceutical composition for the prevention or treatment of cognitive impairment-related diseases according to the present invention, it is administered to the subcutaneous fat and a wide area of muscle tissue that can feel less pain in the injection formulation, surrounding the effective ingredient is donepezil As biodegradable polymers are slowly decomposed in the body, donpezil is released continuously for 1 month, and bioavailability is high compared to oral administration, and it is recognized by high bioavailability in spite of low dosage compared to oral administration. It is excellent in preventing or treating disorder-related diseases.
  • microparticles including donepezil and biodegradable polymer are included, and the microparticles are in a form in which donepezil is evenly distributed in the spherical biodegradable polymer.
  • the donepezil may be continuously released.
  • the microparticles have an average diameter of 30 to 70 ⁇ m.
  • the average diameter of the microparticles is less than 30 ⁇ m, the possibility of predation by macrophages after injection in the human body is increased, thereby affecting the release of effective drug and absorption in vivo.
  • injection and injection of the foreign body feeling and pain may be increased and the particle size distribution of the prepared particles is large, there is a problem that it is difficult to produce a micro particle of a uniform particle size.
  • the drug release in the body may be constantly controlled to help maintain an effective blood concentration.
  • micro particles having a uniform particle size is essential as manufactured according to the production method of the present invention to be described later.
  • the solvent evaporation method has been used as a method for preparing microparticles using a biodegradable polymer, but the microparticles prepared by the solvent evaporation method have a particle size of 20 to 200 ⁇ m so that the average diameter of the particles is not uniform. As it is prepared, aggregation between particles is likely to occur, and when administered as an injection, it is difficult to use as an injection formulation as it contains microparticles having a size that increases foreign body feeling and pain.
  • non-uniform average diameter of the particles would mean that the release period of the drug cannot be controlled as desired.
  • microparticles having various particle sizes when an injection containing microparticles having various particle sizes is administered to subcutaneous fat and muscle tissue, the microparticles having small particle sizes are decomposed in a short time to release all the drugs contained in the particles into the body. The larger the microparticles, the longer the drug releases.
  • microparticles prepared through the solvent evaporation method are unable to precisely control the size of the microparticles by the manufacturing method, which makes it difficult to control the drug release period to a degree suitable for the treatment of the actual patient.
  • the microparticles of the present invention are prepared according to the production method described below, wherein the microchannels are used.
  • the width length (w) and the height length (d) of the microchannel cross section should be adjusted within the range of the average diameter and the constant length ratio of the microparticles to be prepared.
  • the width (w) of the channel cross section is in a ratio range of 0.7 to 1.3 with respect to the average diameter (d ') of the microparticles.
  • the width should be set at 70 to 130 mu m.
  • the height (d) of the channel cross section is in the ratio range of 0.7 to 1.3 with respect to the average diameter (d ') of the microparticles, and the height of the channel cross section in order to manufacture the average diameter (d') of the microparticles to 100 ⁇ m Should be set to 70 to 130 ⁇ m.
  • a liquid mixture must be injected into the microchannels, wherein the microparticles of the desired size are prepared by adjusting the width (w) and the height (d) of the microchannel cross section as described above. It can be manufactured.
  • the microparticles may continue to release donepezil for 1 month to maintain a prophylactic or therapeutic effect of diseases related to cognitive impairment.
  • the biodegradable polymer may be polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, Selected from the group consisting of polyorthoesters, polycaprolactones, polyhydroxyvalates, polyhydroxybutyrates, polyamino acids and combinations thereof, without being limited to the above examples.
  • the step of preparing the microparticles 1) dissolving the biodegradable polymer and donepezil in an organic solvent to prepare a first mixture; 2) dissolving the surfactant in water to prepare a second mixture; 3) injecting the first mixture of step 1) into a microchannel in a linear direction and flowing the first mixture; 4) injecting and flowing the second mixture of step 2) into microchannels formed on both or one sides of the first mixture of step 3) so as to form an intersection with the microchannels flowing in a linear direction.
  • step 6 Producing a microparticle in which donepezil is evenly distributed in the spherical biodegradable polymer particles by crossing the linear flow of the first mixture with the flow of the second mixture; 5) collecting the microparticles produced at the intersection of step 4); 6) stirring the microparticles collected in step 5) to remove the organic solvent present in the microparticles by evaporation; And 7) washing and drying the microparticles of step 6).
  • 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 flows at a constant flow rate, and the pressure condition at this time is 600 to 1000 mbar, preferably 800 mbar, but is limited to the examples. It doesn't work
  • the second mixture when the second mixture is injected into the microchannels on both sides or one side, it is injected at a constant pressure condition to flow at a constant flow rate, and the pressure condition is 1200 to 1600 mbar, preferably 1400 mbar, but not limited to the examples. Do not.
  • the second mixture is allowed to flow under higher pressure conditions so that the flow of the second mixture, which forms an intersection with the flow of the first mixture, is flowed at a higher flow rate than the first mixture injected into the linear microchannel.
  • the flow rate of the first mixture and the second mixture is relatively higher
  • a second mixture with a high flow rate compresses the first mixture, wherein the repulsive forces of the first and second mixtures cause the biodegradable polymer and donepezil in the first mixture to produce spherical microparticles, more Specifically, microparticles having a form in which Donepezil is evenly distributed in the spherical biodegradable polymer are formed.
  • collecting the microparticles may collect the microparticles in the water tank containing the second mixture to prevent aggregation between the microparticles generated initially.
  • the step of collecting the microparticles is to use a second mixture, i.e. a mixed solution of surfactant and water, after the preparation of the second mixture, some are injected into the microchannels and some are transferred to a bath to collect the microparticles. This is used to prevent agglomeration between the collected micro particles.
  • a second mixture i.e. a mixed solution of surfactant and water
  • the stirring conditions are the first step of stirring at a speed of 300 to 500 rpm for 0.5 to 2 hours at 15 to 20 °C; After the first stirring step, second stirring at a rate of 500 to 800 rpm for 2 to 4 hours at 30 to 50 ° C .; And after the second stirring step, proceeds in the order of the third step of stirring at a speed of 500 to 800 rpm for 0.5 to 1.5 hours at -1 to 2 °C.
  • the stirring speed is 500 to 800 rpm, preferably 700 rpm, but is not limited to the example.
  • the evaporation rate of the organic solvent present on the surface of the microparticles can be adjusted. That is, the organic solvent present on the surface of the microparticles may be evaporated through a stirring process to remove harmful solvents and to prepare microparticles having a smooth surface.
  • the temperature at which the first mixture and the second mixture flow through the microchannel is also 15 to 20 ° C, preferably 17 ° C. That is, after flowing the microchannel, forming the intersection to generate microparticles, the low temperature is constantly maintained at 15 to 20 ° C. until the collected microparticles are first stirred. It is possible to produce and maintain spherical particles only by keeping them at a low temperature during the preparation of the micro particles. That is, when it is not a low temperature condition, the problem which is difficult to manufacture a uniform spherical particle arises.
  • the microparticles which have been removed by removing all organic solvents on the surface are washed several times with sterile filtered filtered water to remove the surfactant remaining in the microparticles, and then freeze-dried.
  • the preparation of the microparticles can be made by injecting and flowing the mixture into the microchannels formed on the wafer.
  • microchannels are prepared.
  • the organic solvent of the present invention is not mixed with water, for example, at least one selected from the group consisting of chloroform, chloroethane, dichloroethane, trichloroethane and mixtures thereof, preferably dichloromethane,
  • the organic solvent is not limited thereto, and the organic solvent capable of dissolving the biodegradable polymer is not limited to the above examples, and any organic solvent that can be easily selected by those skilled in the art can be used.
  • the surfactant of the present invention can be used without limitation as long as the biodegradable polymer solution can help to form a stable emulsion.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of diseases related to cognitive impairment, including donepezil, and in order to alleviate the inconvenience that must be taken daily by a method for preparing the same.
  • the therapeutic effect can be maintained.
  • 1 is an experimental result of the drug elution amount of time of the microparticles according to an embodiment of the present invention.
  • Figure 2 is an experimental result of the drug elution amount of the microparticles according to an embodiment of the present invention.
  • Figure 3 is a SEM image of particles by stirring conditions according to an embodiment of the present invention.
  • Figure 4 is a SEM image of particles by stirring conditions according to an embodiment of the present invention.
  • Figure 5 is a SEM image of particles by stirring conditions according to an embodiment of the present invention.
  • FIG. 6 is a comparison result of blood concentrations during oral administration of the microparticles to the injection according to an embodiment of the present invention.
  • the present invention comprises the steps of 1) dissolving the biodegradable polymer and donepezil 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 step 1) into a microchannel in a linear direction; 4) injecting and flowing the second mixture of step 2) into microchannels formed on both or one sides of the first mixture of step 3) so as to form an intersection with the microchannels flowing in a linear direction.
  • the first mixture was prepared by dissolving polylactide-co-glycolide (PLGA) and donepezil base in dichloromethane. At this time, the weight ratio of polylactide-co-glycolide and donepezil base in the first mixture is 2: 1.
  • the polylactide-co-glycolide (PLGA 7502) was a biodegradable polymer having a lactide and glycolide-molar ratio of 75/25.
  • Polyvinyl alcohol which is a surfactant, was mixed with water to prepare a second mixture containing 0.25% by weight of polyvinyl alcohol.
  • the first and second mixtures were injected into a microchannel formed on a silicon wafer and flowed. 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 800 mbar, and the second mixture was flowed under a pressure condition of 1400 mbar. Temperature conditions were maintained at 17 ° C.
  • the microparticles produced at the intersection of the flow of the first mixture and the flow of the second mixture were collected in a bath containing the second mixture.
  • the microparticles collected in the water bath were first stirred at 17 ° C. at a speed of 400 rpm for 1 hour, the temperature was raised to 40 ° C., followed by a second stirring at a speed of 600 rpm for 3 hours, and then the temperature was lowered to 0 ° C. , And stirred three times at a speed of 600 rpm for 1 hour.
  • microparticles having been stirred were washed several times with sterile filtered filtered water and lyophilized to prepare microparticles.
  • the weight ratio of the polylactide-co-glycolide and donepezil base was prepared in the same manner as in Example 1 except for including 4: 1.
  • the weight ratio of polylactide-co-glycolide and donepezil base was prepared in the same manner as in Example 1 except for including 9: 1.
  • the weight ratio of polylactide-co-glycolide and donepezil base was prepared in the same manner as in Example 1 except for including 1: 1.
  • the polylactide-co-glycolide (PLGA 5002) was prepared in the same manner as in Example 1 except that a biodegradable polymer having a lactide and glycolide-molar ratio of 50/50 was used.
  • the temperature conditions during the stirring were prepared in the same manner as in Example 1 except that the additional stirring process was performed at a speed of 600 rpm for 1 hour at 25 ° C. between the first and second stirrings.
  • Example 1 to 4 About 100 mg of the microparticles of Examples 1 to 4 are placed in a glass test container with a content of 120 mL, and 100 mL of the release test solution is filled. As an accelerated experimental condition for drug release, the solution was placed in a 45 ° C. water bath, and the drug release experiment was carried out with a round tripping amplitude of 4 cm and the number of shaking 120 times / minute. When sampling, shake the bottle well and take 1 mL. After centrifugation at 13,000 rpm for 3 minutes, the supernatant was taken and analyzed by high performance liquid chromatography.
  • Example 3 0 10.23 15.32 26.57 33.21 79.56 81.23 84.66
  • Example 2 0 14.97 22.64 32.73 44.21 80.65 82.56 83.21
  • Example 1 0 16.34 32.54 45.65 54.21 81.34 83.56 84.21
  • Example 4 X
  • Example 4 (Unit Dissolution Rate%) In Example 4, the biodegradable polymer and the drug were mixed at a ratio of 1: 1, and it was confirmed that the preparation of the microparticles was not possible according to the production method of the present invention. Therefore, it was not possible to evaluate the dissolution rate over time.
  • Example 1 not only shows the effective release amount at the beginning, but also the drug release degree can be confirmed after 72 hours, it can be confirmed that there is a long time effect.
  • Example 1 it can be used as a longer lasting long-acting formulation.
  • FIG. 3 is a case in which the stirring was carried out under the conditions of Example 6, it was confirmed that when the stirring is not carried out at 0 °C conditions as in Example 6, agglomeration between particles occurs.
  • Figure 4 is a case where the stirring was carried out under the conditions of Example 7, when the stirring time is increased as in Example 7, it was confirmed that there is a problem that pores are generated on the surface of the particles and the surface is not evenly formed. .
  • Example 1 in the case of Example 1, as well as the production of microparticles having an even particle diameter, as shown in Figure 5, it is possible to produce a microparticle that is formed evenly on the surface, the aggregation between the particles does not occur.
  • microparticles prepared in Example 1 were prepared in a long-term sustained injection formulation, which was administered to a beagle dog and a blood sample was taken to measure the concentration of donepezil in the blood over time. For comparison, blood concentrations were measured after administration of donepezil oral formulation.
  • the present invention relates to a method for preparing a pharmaceutical composition for preventing or treating a disease related to cognitive disorders, and to a pharmaceutical composition for preventing or treating a disease related to cognitive disorders prepared by the method, and more specifically, evenly distributed donepezil.
  • the present invention relates to a method for preparing a pharmaceutical composition for preventing or treating a disease related to cognitive disorders capable of preparing microparticles in a uniform particle size, and to a composition prepared by the method of manufacturing the same.

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Abstract

La présente invention concerne un procédé de préparation d'une composition pharmaceutique de prévention ou de traitement de maladies associées au trouble cognitif, et une composition pharmaceutique de prévention ou de traitement de maladies associées au trouble cognitif, préparée par le procédé de préparation, la composition pharmaceutique contenant des microparticules comprenant du donépézil et un polymère biodégradable, les microparticules étant formées de sorte que le donépézil est uniformément dispersé dans un polymère biodégradable sphérique. La présente invention peut maintenir un effet de prévention ou de traitement des maladies associées au trouble cognitif durant un mois avec une injection afin de résoudre l'inconvénient de l'administration quotidienne de médicament. De plus, dans la mesure où la préparation est conduite de sorte que le diamètre moyen des particules est maintenu dans une micro-taille prédéterminée, une sensation de corps étranger et de douleur sont réduites durant l'administration à un patient par injection, et ainsi l'administration par injection peut être facilitée.
PCT/KR2019/003158 2018-03-20 2019-03-19 Procédé de préparation de composition pharmaceutique de prévention ou de traitement de maladies associées au trouble cognitif, et composition pharmaceutique de prévention ou de traitement de maladies associées au trouble cognitif, préparée par le procédé de préparation WO2019182319A1 (fr)

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KR20180031972 2018-03-20
KR10-2018-0031972 2018-03-20
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KR1020190030801A KR102224917B1 (ko) 2018-03-20 2019-03-18 인지 장애 관련 질병의 예방 또는 치료용 약학적 조성물의 제조 방법 및 이의 제조 방법으로 제조된 인지 장애 관련 질병의 예방 또는 치료용 약학적 조성물

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