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WO2018038267A1 - Nanoparticules copolymères de poly(lactide-co-glycolide), et leur procédé de production - Google Patents

Nanoparticules copolymères de poly(lactide-co-glycolide), et leur procédé de production Download PDF

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Publication number
WO2018038267A1
WO2018038267A1 PCT/JP2017/030625 JP2017030625W WO2018038267A1 WO 2018038267 A1 WO2018038267 A1 WO 2018038267A1 JP 2017030625 W JP2017030625 W JP 2017030625W WO 2018038267 A1 WO2018038267 A1 WO 2018038267A1
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Prior art keywords
glycolide copolymer
drug
polylactide glycolide
nanoparticles
ferulic acid
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English (en)
Japanese (ja)
Inventor
榎村　眞一
宏太郎 福田
望嘉 尾形
綾乃 金城
英樹 池元
タケル 松尾
敏夫 原
秀孝 森永
晋吾 葛西
和代 ジャークス
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Sentan Pharma Inc
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Sentan Pharma Inc
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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

Definitions

  • the present invention relates to a method for producing polylactide glycolide copolymer nanoparticles and polylactide glycolide copolymer nanoparticles.
  • DDS Drug delivery system
  • PLGA polylactide glycolide copolymer
  • Patent Document 1 a mixture of acetone and ethanol as a good solvent solution in which at least a drug and PLGA are dissolved is added to a polyvinyl alcohol aqueous solution as a poor solvent, and the PLGA nanoparticle formulation encapsulating the drug A method of generating is disclosed.
  • Patent Document 2 discusses stabilization of a liquid composition in which PLGA nanoparticles containing a drug are dispersed in a dispersion.
  • the method for producing PLGA nanoparticles disclosed in Patent Document 1 and Patent Document 2 is a batch system employing an underwater emulsion method (ESD method). For this reason, it was difficult to obtain a PLGA nanoparticle formulation having a uniform particle size due to the temperature gradient and concentration gradient in the reaction vessel. Furthermore, in the method disclosed in the above-mentioned Patent Document 1, it is necessary to make the concentration of PLGA containing a good solvent or poor solvent or PLGA containing a drug contained within a predetermined concentration or less.
  • ESD method underwater emulsion method
  • the particle size distribution in the dispersion varies, and it is difficult to increase the drug content in the PLGA nanoparticles. For this reason, there existed inconveniences that the absorption efficiency of the medicine to the living body was low.
  • nanoparticles produced by the conventional batch method often become coarse, coalesced or aggregated when freeze-dried.
  • the dispersibility that is, the uniformity of the nanoparticles is not high, it is difficult to control the absorption efficiency into the living body.
  • Patent Document 3 discloses a method for producing nanoparticles using processing surfaces disposed opposite to each other.
  • a thin film fluid is formed between the processing surfaces by rotating at least one of the processing surfaces with respect to the other.
  • Patent Document 3 Although there is a suggestion regarding the PLGA nanoparticles in the above-mentioned Patent Document 3, there is no indication regarding the point of including the drug in PLGA. Moreover, the above Patent Document 3 does not discuss how to make the particle diameter of the PLGA nanoparticles encapsulating the drug uniform.
  • the present invention has been made in view of the above circumstances, and provides a PLGA nanoparticle having a more uniform particle size of the PLGA nanoparticle and increasing the drug content, and a method for producing the PLGA nanoparticle. For the purpose.
  • the polylactide glycolide copolymer nanoparticles according to the first aspect of the present invention are: A polylactide glycolide copolymer nanoparticle encapsulating a drug, The drug content is It is 20 weight% or more with respect to the weight of the said polylactide glycolide copolymer nanoparticle.
  • the value of D 50 of the polylactide glycolide copolymer nanoparticles is: 200 nm or less
  • the span value of the particle size of the polylactide glycolide copolymer nanoparticles is: 2.0 or less, It is good as well.
  • the drug is Brown rice germ extract, ⁇ -oryzanol, ferulic acid, cycloartanol ferulic acid ester, 24-methylenecycloartanol ferulic acid ester, campesterol ferulic acid ester, ⁇ -sitosterol ferulic acid ester, 2-deoxy-D-glucose, Selected from the group consisting of indocyanine green and vitamin C; It is good as well.
  • the dissolution rate of the drug from the polylactide glycolide copolymer nanoparticles in intestinal fluid 20% by weight or more, It is good as well.
  • the amount of the drug absorbed into the blood via the digestive system when administered to a living body 5 times or more compared to the drug substance, It is good as well.
  • a precipitation step of precipitating polylactide glycolide copolymer nanoparticles encapsulating the drug in the thin film fluid including.
  • the concentration of the polylactide glycolide copolymer in the raw material solution is Higher than 0.6% by weight with respect to the weight of the raw material solution, It is good as well.
  • the pH of the thin film fluid is 6-8, It is good as well.
  • the pH of the aqueous emulsifier solution is Adjusted with sodium bicarbonate, It is good as well.
  • the emulsifier is Polyvinyl alcohol, It is good as well.
  • the drug is Brown rice germ extract, ⁇ -oryzanol, ferulic acid, cycloartanol ferulic acid ester, 24-methylenecycloartanol ferulic acid ester, campesterol ferulic acid ester, ⁇ -sitosterol ferulic acid ester, 2-deoxy-D-glucose, Selected from the group consisting of indocyanine green and vitamin C; It is good as well.
  • the particle size of PLGA nanoparticles is more uniform, and the drug content can be increased.
  • FIG. 2 is a graph showing the particle size distribution of PLGA nanoparticles obtained in Example 1.
  • FIG. 1 is a diagram showing the appearance of PLGA nanoparticles obtained in Example 1.
  • FIG. 6 is a graph showing the particle size distribution of PLGA nanoparticles obtained in Example 2.
  • FIG. 6 is a diagram showing the appearance of PLGA nanoparticles obtained in Example 3.
  • FIG. 6 is a graph showing the particle size distribution of PLGA nanoparticles obtained in Example 3.
  • (A) is a graph showing changes over time in blood concentrations of components contained in ⁇ -oryzanol and ferulic acid in mice orally administered with the drug substance.
  • (B) is a graph showing changes over time in blood concentrations of components contained in ⁇ -oryzanol and ferulic acid in mice orally administered with PLGA nanoparticles containing a drug. It is a figure which shows the absorption amount in the blood of ferulic acid from the oral administration to the mouse
  • FIG. 6 is a graph showing the particle size distribution of PLGA nanoparticles obtained in Example 6.
  • FIG. 6 is a graph showing the particle size distribution of PLGA nanoparticles obtained in Example 7.
  • FIG. 6 is a graph showing the particle size distribution of PLGA nanoparticles obtained in Example 8.
  • FIG. (A) is a figure which shows the particle size distribution of the PLGA nanoparticle obtained by the rotation speed of the holder of a thin film rotary dispersion machine being 500 rpm.
  • (B) is a figure which shows the particle size distribution of the PLGA nanoparticle obtained at the said rotation speed of 1000 rpm.
  • (C) is a figure which shows the particle size distribution of the PLGA nanoparticle obtained at the said rotation speed of 3000 rpm.
  • the PLGA nanoparticles according to the present embodiment are particles mainly composed of PLGA.
  • PLGA is a lactic acid / glycolic acid copolymer, and is also called poly (lactic-co-glycolic acid).
  • the PLGA nanoparticles contain a drug.
  • the drug is not particularly limited as long as it is a composition, compound, synthetic product, natural product, peptide, protein, nucleic acid, or the like and has a medicinal effect when administered to a living body.
  • the drug is extracted from brown rice germ extract, ⁇ -oryzanol, ferulic acid, cycloartol FE, 24-methylenecycloartanol FE, campesterol FE, ⁇ -sitosterol FE, 2-deoxy-D-glucose (2 -DG), indocyanine green and vitamin C (VC).
  • Ferulic acid is a decomposition product of ⁇ -oryzanol.
  • Ferulic acid cycloartol FE, 24-methylenecycloartanol FE, campesterol FE and ⁇ -sitosterol FE are components contained in ⁇ -oryzanol.
  • the content of the drug is 20% by weight or more based on the weight of the PLGA nanoparticles.
  • the content is the weight of the drug relative to the weight of the PLGA nanoparticle calculated based on a value obtained by quantifying the concentration of the drug extracted from the PLGA nanoparticle.
  • the upper limit of the content of the drug is not particularly limited, for example, 90.0 wt% or less, 80.0 wt% or less, 70.0 wt% or less, 60.0 wt% or less, based on the weight of the PLGA nanoparticles, 50.0 wt% or less, 40.0 wt% or less, 30.0 wt% or less, 25.0 wt% or less, 23.0 wt% or less, 22.0 wt% or less, or 21.0 wt% or less .
  • the particle size of the PLGA nanoparticles is nano-order, for example, 1 to 1000 nm, 10 to 900 nm, preferably 1 to 500 nm, more preferably 1 to 200 nm.
  • the particle size of the PLGA nanoparticles can be measured by a screening method, a sedimentation method, a microscope method, a light scattering method, a laser diffraction / scattering method, an electrical resistance test, an observation with a transmission electron microscope, an observation with a scanning electron microscope, or the like.
  • the particle size may be measured with a known particle size distribution meter.
  • the particle diameter can be represented by a Stoke equivalent diameter, a circle equivalent diameter, or a sphere equivalent diameter depending on the measurement method.
  • the particle size may be an average particle size, a volume average particle size, an area average particle size, or the like represented by an average with a plurality of particles as a measurement target.
  • the average particle diameter is an average particle diameter calculated from a number distribution or the like based on a measurement such as a laser diffraction / scattering method.
  • a 50% diameter (D 50 ) that is a particle diameter at which the cumulative curve becomes 50% may be used as the particle diameter.
  • the value of D 50 of the PLGA nanoparticles is 1 to 1000 nm, 10 to 900 nm, preferably 20 to 500 nm, more preferably 50 to 300, and preferably 50 to 200 nm.
  • Cumulative curve and D 50 can be determined using a commercially available particle size distribution meter. Examples of the particle size distribution meter include NIKISO Nanotrac Wave-EX150 (manufactured by Nikkiso Co., Ltd.).
  • the span value of the particle size of the PLGA nanoparticles is 2.0 or less.
  • the span value is obtained by (D 90 -D 10 ) / D 50 .
  • D 90 is a 90% diameter which is the particle diameter at which the cumulative curve becomes 90%.
  • D 10 is 10% diameter is the particle size of the point where the cumulative curve becomes 10%.
  • D 90 and D 10 represent respectively the particle diameters can be determined using a commercially available particle size distribution meter.
  • the method for producing the PLGA nanoparticles includes a mixing step and a precipitation step.
  • an aqueous emulsifier solution (hereinafter simply referred to as “liquid A”) and a raw material solution (hereinafter simply referred to as “liquid B”) are mixed in a thin film fluid.
  • liquid A aqueous emulsifier solution
  • liquid B a raw material solution
  • a liquid is demonstrated.
  • the emulsifier dissolved in the liquid A is not particularly limited as long as it improves the dispersion stability of the particles.
  • the emulsifier is surfactant, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, water-soluble resin, lecithin, saponins, sterols, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, polyglycerin. Fatty acid esters and polysorbates.
  • the emulsifier is polyvinyl alcohol (hereinafter simply referred to as “PVA”).
  • PVA polyvinyl alcohol
  • Commercially available PVA can be used as the emulsifier.
  • PVA may be industrial or pharmaceutical, but preferably has little remaining organic solvent or no organic solvent.
  • the concentration of the emulsifier in the aqueous emulsifier solution is, for example, 0.1 to 3.0% by weight, 0.1 to 2.0% by weight, preferably 0.1 to 1.0% by weight, particularly preferably 0.5% by weight. It is.
  • the pH of the thin film fluid in which the liquid A and the liquid B are mixed is preferably 6-8. For this reason, the pH of the solution A is preferably adjusted to 7 to 8, for example.
  • the pH adjuster for adjusting the pH of the liquid A is arbitrary, but for example, alkali species such as sodium carbonate, calcium hydroxide, ammonia, sodium hydroxide and potassium hydroxide may be used. Moreover, citric acid, acetic acid, etc.
  • the pH adjuster is preferably sodium bicarbonate.
  • sodium bicarbonate may be added to the emulsifier aqueous solution so as to be 0.001 to 0.1% by weight, preferably 0.033 to 0.01% by weight.
  • stirring conditions are not specifically limited, For example, it is stirring for 60 minutes at 15000 rpm using the precision emulsification disperser CLEARMIX (M technique company make). If bubbles are generated in the liquid A after stirring, the bubbles may be removed by any method such as standing, reduced pressure, or increased pressure.
  • B liquid contains the organic solvent in which a chemical
  • the organic solvent is not particularly limited, but is preferably a solvent containing acetone and ethanol.
  • the drug and PLGA are dissolved in the solvent.
  • a drug and PLGA are added to acetone, dissolved using ultrasonic waves or CLEARMIX, and further ethanol is added and mixed.
  • the ratio of PLGA: drug is 1.5: 1 to 1: 7, 1.4: 1 to 1: 6, preferably 1.3: 1 to 1: 5.
  • the ratio of acetone: ethanol is 3: 1 to 1: 1, preferably 2: 1 to 1: 1.
  • the concentration of PLGA in the B liquid is arbitrary, but is preferably higher than 0.6% by weight with respect to the weight of the B liquid.
  • the upper limit of the PLGA concentration is not particularly limited, but is, for example, 10.0% by weight or less, 5.0% by weight or less, 1.0% by weight or less, or 0.8% by weight or less.
  • concentration of PLGA may be less than 0.1 weight% with respect to the weight of B liquid.
  • the liquid A and the liquid B are disposed so as to face each other, and at least one of them is introduced between the processing surfaces rotating relative to the other. Thereby, a thin film fluid is formed between the processing surfaces, and the A liquid and the B liquid are mixed.
  • the mixed liquid A and liquid B react in the thin film fluid to form PLGA nanoparticles containing the drug.
  • the PLGA nanoparticles are deposited in a thin film fluid.
  • FIG. 1 is a schematic cross-sectional view of a thin film rotary disperser 100.
  • the thin-film rotary disperser 100 includes a holder 10, a holder 20, an introduction unit 30, a fluid pressure application unit 40, an introduction unit 50, a fluid supply unit 60, and a case 70.
  • the holder 10 is disposed below the holder 20.
  • the holder 10 and the holder 20 hold the processing unit 11 and the processing unit 21, respectively.
  • the processing unit 11 and the processing unit 21 are each annular (ring-shaped).
  • the processing unit 11 has a processing surface 1.
  • the processing unit 21 has a processing surface 2 that faces the processing surface 1.
  • a contact pressure applying unit 22 is disposed between the holder 20 and the processing unit 21, .
  • the contact surface pressure applying unit 22 applies the pressure to the processing unit 21 (hereinafter, simply referred to as “back pressure”) to cause the processing unit 21 to approach the lower processing unit 11. For this reason, the processing surface 1 and the processing surface 2 can be brought close to and away from each other.
  • the holder 10 is rotated relative to the holder 20 about the axis of the holder 10 by a motor.
  • the processing surfaces 1 disposed opposite to each other rotate relative to the processing surface 2.
  • the fluid pressure applying unit 40 is connected to the introduction unit 30.
  • Liquid A is supplied between the processing surface 1 and the processing surface 2 when the fluid pressure applying unit 40 including a compressor pressurizes the A liquid. More specifically, the liquid A is introduced into the space inside the holder 10 and the holder 20 from the introduction unit 30 by pressurization by the fluid pressure applying unit 40. Further, the A liquid passes between the processing surface 1 and the processing surface 2 and tends to escape to the outside of the holder 10 and the holder 20. At this time, the holder 20 that has received the pressure of the A liquid resists the back pressure and moves away from the holder 10. Thereby, a minute space is formed between the processing surface 1 and the processing surface 2.
  • the liquid A may be directly supplied from the introduction unit 30 between the processing surface 1 and the processing surface 2.
  • the introduction unit 50 is a B liquid passage provided inside the processing unit 21.
  • a fluid supply unit 60 including a compressor is connected to one end of the introduction unit 50.
  • the fluid supply unit 60 supplies the B liquid between the processing surface 1 and the processing surface 2 via the introduction unit 50.
  • the B liquid is supplied from the introduction unit 50 between the processing surface 1 and the processing surface 2 and merges with the A liquid.
  • the A liquid and the B liquid merge between the processing surface 1 and the processing surface 2 with a minute interval between them to become a thin film fluid.
  • the thin film fluid mixing and reaction of the A liquid and the B liquid are promoted.
  • the product produced by the reaction between the liquid A and the liquid B encloses the drug and precipitates in the thin film fluid as relatively uniform and fine PLGA nanoparticles.
  • the precipitated PLGA nanoparticles are discharged to the outside of the holder 10 and the holder 20 while being suspended in a liquid.
  • the case 70 is disposed outside the outer peripheral surfaces of the holder 10 and the holder 20.
  • the case 70 accommodates the PLGA nanoparticle dispersion liquid discharged to the outside of the holder 10 and the holder 20.
  • ULEA SS-11 manufactured by M Technique Co., Ltd.
  • M Technique Co., Ltd. which is a forced thin film microreactor
  • the number of rotations of the holder 10 the back pressure, the flow rates and temperatures of the liquid A and the liquid B can be appropriately set.
  • the rotation speed is 1000 to 2500 rpm, preferably 1700 rpm.
  • the back pressure is 0.02 to 0.06 MPa.
  • the PLGA nanoparticles according to the present embodiment are hardly affected by the temperature gradient and concentration gradient in the reaction vessel, as shown in Examples 1 to 3 and 6 to 8 below. Have a more uniform particle size. Further, the content of the drug in the PLGA nanoparticles reaches 20% by weight or more with respect to the weight of the PLGA nanoparticles.
  • the above drugs contained in PLGA nanoparticles include brown rice germ extract, ⁇ -oryzanol, ferulic acid, cycloartanol FE, 24-methylenecycloartanol FE, campesterol FE, ⁇ -sitosterol FE, 2-DG. And may be selected from the group consisting of indocyanine green and VC. Since the PLGA nanoparticles have a uniform particle size and a high drug content, the drug efficacy can be obtained even at a low dose.
  • the elution rate of the drug in the intestinal fluid of the PLGA nanoparticles according to the present embodiment is 20% by weight or more.
  • medical agent through intestinal tracts, such as oral administration can be improved more.
  • the elution rate here is a ratio of the weight of the drug released from the PLGA nanoparticles to the weight of the drug included in the PLGA nanoparticles.
  • the elution rate is, for example, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60% by weight 20 wt% or more and 50 wt% or less, 20 wt% or more and 35 wt% or less, 25 wt% or more and 30 wt% or less, or 27 wt% or more and 29 wt% or less.
  • the PLGA nanoparticles according to the present embodiment have an amount of the drug absorbed into the blood via the digestive system when administered to a living body. 5 times or more. This is because the drug is appropriately dissolved from the PLGA nanoparticles by maintaining the uniformity of the PLGA nanoparticles even after lyophilization. For this reason, for example, when the PLGA nanoparticles are orally or enterally administered, the drug can be efficiently transported into the blood.
  • the absorbed amount may be the total weight of the drug taken into the blood after 1 hour, 6 hours, 12 hours, 24 hours, 36 hours, or 48 hours after administration.
  • the absorption amount is 5 to 100 times, 5 to 90 times, 5 to 80 times, 5 to 70 times, 5 to 60 times, 5 times to 5 times, compared with the drug substance 50 times or less, 5 times or more and 40 times or less, 5 times or more and 30 times or less, 5 times or more and 20 times or less, 5 times or more and 10 times or less, 6 times or more and 9 times or less, or 7 times or more and 8 times or less.
  • the living body is not particularly limited, and means an animal body, particularly a mammalian animal body including a human.
  • the blood concentration of the drug after a predetermined period of time is 5 to 100 times, 5 times or more compared to the case where the drug substance is administered. 90 times or less, 5 times or more and 80 times or less, 5 times or more and 70 times or less, 5 times or more and 60 times or less, 5 times or more and 50 times or less, 5 times or more and 40 times or less, 5 times or more and 30 times or less, 5 times or more It may be 20 times or less, 5 times or more and 10 times or less, 6 times or more and 9 times or less, or 7 times or more and 8 times or less.
  • liquid A and liquid B may be mixed.
  • the pH of the thin film fluid may be 6-8.
  • the uniformity of the PLGA nanoparticles when the A liquid and the B liquid are in contact with each other to form the PLGA nanoparticles is maintained, and aggregation before and after lyophilization can be suppressed.
  • the pH of the aqueous emulsifier solution may be adjusted with sodium bicarbonate.
  • Sodium bicarbonate can be used for medicines and foods that are ingested by the human body.
  • the pH of the said emulsifier aqueous solution can use arbitrary pH adjusters which can be ingested by a human body besides sodium hydrogencarbonate.
  • the emulsifier may be PVA.
  • PVA can be used for drugs and foods that are ingested by the human body, and is suitable for self-emulsification of PLGA nanoparticles.
  • any emulsifier that can be ingested by the human body can be used as long as it can be made into nanoparticles.
  • the organic solvent may be distilled off from the PLGA nanoparticle suspension, and the suspension may be freeze-dried.
  • the PLGA nanoparticle suspension may be pulverized by a spray drying method or solidified by a hot melt method.
  • the PLGA nanoparticles according to the present embodiment may be a PLGA nanoparticle dispersion liquid dispersed in an aqueous dispersion liquid.
  • the aqueous dispersion may be water alone or may contain water and a water-miscible solvent.
  • miscible solvents include methanol, isopropanol, and alcohols such as ethylene glycol.
  • the upper limit of the concentration of the PLGA nanoparticle is not particularly limited, but for example, 50.0% by weight or less, 40.0% by weight or less, 30. 0 wt% or less, 20.0 wt% or less, 10.0 wt% or less, 5.0 wt% or less, 3.0 wt% or less, 1.0 wt% or less, 0.9 wt% or less, 0.8 % By weight or less, 0.7% by weight or less, or 0.65% by weight or less.
  • Example 1 Using ULREA SS-11, drug-encapsulated PLGA nanoparticles were prepared as follows. First, the liquid A was filled in the liquid A tank, and the tank was pressurized to 0.3 MPa. Thereafter, solution A was fed at 167 mL / min at a set value of 43 ° C. (actual measured value of about 41 ° C.), and then solution B was fed at 100 mL / min at a set value of 40 ° C. (measured value of about 31 ° C.). A solution of 0.5 wt% PVA and 0.0033 wt% NaHCO 3 solution.
  • Liquid B is a solution having a composition of PLGA: ⁇ -oryzanol: acetone: ethanol in a weight ratio of 0.64: 3.2: 65.911: 30.255.
  • the rotation speed was 1700 rpm and the back pressure was 0.02 MPa.
  • the pH of the mixed liquid (discharge liquid) was 7.85. 100 mL of discharge liquid was collect
  • Example 2 In the same manner as in Example 1, drug-encapsulated PLGA nanoparticles were prepared as follows using ULREA SS-11. Liquid A was filled into ULREA liquid tank A, and the tank was pressurized to 0.3 MPa. Thereafter, solution A was fed at 167 mL / min at 41 ° C., and then solution B was delivered at 30 ° C. at 100 mL / min. A solution of 0.5 wt% PVA and 0.01 wt% NaHCO 3 solution. In addition, the solution B is a solution having a composition of PLGA: brown rice germ extract: acetone: ethanol in a weight ratio of 0.64: 0.49: 65.91: 32.96. The rotation speed was 1700 rpm and the back pressure was 0.02 MPa.
  • the particle size distribution with a single peak, D 50 was at 200nm following 154 nm.
  • the uniformity of PLGA nanoparticles was also relatively high.
  • Example 3 Similarly to Example 2, drug-encapsulated PLGA nanoparticles were produced, and 15 L of discharge liquid was collected in a receiving tank.
  • a ribbon heater was installed on the bottom of the receiving tank and heated at 60 ° C.
  • the PLGA nanoparticle dispersion obtained by evaporating the solvent overnight under vacuum reduced pressure ( ⁇ 0.1 MPa) was frozen at ⁇ 80 ° C., and the shelf was heated to 45 ° C. with a shelf-type freeze dryer and freeze-dried for 3 days.
  • the yield of PLGA nanoparticles at this time was 97.29 g.
  • the particle size distribution of PLGA nanoparticles was measured in the same manner as in Example 1 above.
  • NIKISO Nanotrac Wave-EX150 manufactured by Nikkiso Co., Ltd.
  • a sample for TEM observation was prepared in the same manner as in Example 1 above, and the appearance of the obtained PLGA nanoparticles was imaged with a transmission electron microscope (JEM-ARM200F, manufactured by JEOL Ltd.).
  • the ⁇ -oryzanol content in PLGA nanoparticles was evaluated as follows. First, a standard solution was prepared. 10 mg of brown rice germ extract was weighed into a 100 mL volumetric flask and dissolved by adding 50 mL of acetonitrile. Next, the volume was made up to 100 mL with acetonitrile to obtain a standard stock solution (100 ⁇ g / mL). The standard stock solution was serially diluted with acetonitrile to 50, 25, 12.5, 6.25, and 3.125 ⁇ g / mL to obtain a standard solution.
  • HPLC high performance liquid chromatography
  • HPLC conditions Instrument LC-2000 plus series (manufactured by JASCO) Detection wavelength: UV320nm
  • Mobile phase: n-hexane: 2-propanol: acetic acid 470: 25: 5, preparation of mobile phase using HPLC solvent, acetic acid content 99.5% or more
  • Flow rate 1.0 mL / min
  • Injection volume 10 ⁇ L Measurement time: 10 minutes
  • ethanol and acetone were quantified as follows in the discharge liquid and the powder after freeze-drying in this example.
  • 10 mg of ethanol was weighed and dimethyl sulfoxide (DMSO) was added to make 10 g, which was used as an ethanol standard stock solution (1,000 ppm solution).
  • the ethanol standard stock solution was serially diluted with DMSO to 50, 100, 250, and 500 ppm to obtain an ethanol standard solution.
  • 10 mg of acetone was weighed, DMSO was added to make 10 g, and an acetone standard stock solution (1,000 ppm solution) was obtained.
  • the acetone standard stock solution was serially diluted with DMSO to 50, 100, 250, and 500 ppm to obtain an acetone standard solution.
  • the sample solution was prepared as follows. About 40 mg of a sample composed of the discharged liquid or powder after freeze-drying was weighed, and about 0.4 g of milli-Q water was added. After stirring for 30 seconds with a vortex mixer, the mixture was sonicated for 5 minutes and dispersed. About 1.2 g of DMSO was added to the dispersion and mixed, followed by filtration using a 0.45 ⁇ m membrane filter. The obtained filtrate was used as a sample solution. The standard solution and the sample solution were analyzed by gas chromatography (GCMS) under the following conditions, and the ethanol and acetone concentrations in the sample solution were calculated from the calibration curve of the standard solution.
  • GCMS gas chromatography
  • GCMS measurement conditions Equipment: GCMS-QP2010 (manufactured by Shimadzu Corporation) Column: DB-select 624UI for ⁇ 467>, inner diameter: 0.25 mm, length: 30 m, film thickness: 1.4 ⁇ m Column oven temperature: 40 ° C. (10 minutes) ⁇ 10 ° C./min ⁇ 200° C.
  • Vaporization chamber temperature 250 ° C
  • Injection mode Split Control mode: Linear velocity (32.0 cm / sec) Pressure: 35.0kPa Total flow rate: 14.7 mL / min Column flow rate: 0.79 mL / min, Purge flow rate: 10.0 mL / min Split ratio: 5.0 Ion source temperature: 200 ° C Interface temperature: 240 ° C Injection volume: 1 ⁇ L
  • a PLGA nanoparticle solution of 5 mg / mL was prepared with Milli-Q water, stirred with a vortex mixer for 30 seconds, and treated with ultrasonic waves for 10 minutes.
  • the zeta potential of the obtained sample was measured using Nanotrac Wave-UZ152 (Nikkiso Co., Ltd.).
  • the ethanol concentration of the discharged liquid was 1686 ppm / mL, but the ethanol concentration of the powder after lyophilization was 123 ppm / mL.
  • the acetone concentration of the discharged liquid was 272 ppm / mL, but the acetone concentration of the powder after lyophilization was below the detection limit.
  • the residual ethanol concentration in the powder of PLGA nanoparticles according to this example could be reduced to 1/10 or less of the discharge liquid.
  • acetone was able to be removed from the powder of PLGA nanoparticles.
  • Example 4 Regarding the PLGA nanoparticles prepared in Example 3 above, the elution rate of ⁇ -oryzanol from the PLGA nanoparticles in the intestinal fluid was evaluated as follows. First, an artificial intestinal fluid was prepared to reproduce the fasting intestinal fluid. 2.18 g of artificial intestinal fluid preparation reagent (manufactured by Celeste), 6.19 g of NaCl, 3.44 g of NaH2PO4, and 0.42 g of NaOH were dissolved in 1000 mL of purified water. Subsequently, the pH of the solution was adjusted to 6.5 using 1N NaOH or 1N HCl aqueous solution, and this solution was used as an artificial intestinal fluid.
  • artificial intestinal fluid preparation reagent manufactured by Celeste
  • 6.19 g of NaCl, 3.44 g of NaH2PO4, and 0.42 g of NaOH were dissolved in 1000 mL of purified water. Subsequently, the pH of the solution was adjusted to 6.5 using 1N NaOH or 1N HC
  • FIG. 7 shows the change over time in the amount of ⁇ -oryzanol in artificial intestinal fluid having a PLGA nanoparticle concentration of 1 mg / mL.
  • the amount of ⁇ -oryzanol in the artificial intestinal fluid after 24 hours was 75 ⁇ g / mL (7.5% relative to the concentration of 1 mg / mL of PLGA nanoparticles in the artificial intestinal fluid).
  • the dissolution rate was 28.6% by weight.
  • the collected blood was centrifuged to obtain supernatant plasma.
  • Isopropanol was added to the obtained plasma, stirred with a vortex mixer, further sonicated, and centrifuged to obtain a supernatant.
  • the supernatant was applied to a 0.2 ⁇ m filter to obtain a sample for LCMS measurement.
  • the blood concentrations of cycloartol FE, 24-methylenecycloartanol FE, campesterol FE, ⁇ -sitosterol FE, and ferulic acid were analyzed by liquid chromatography mass spectrometry (LC / MS) under the following conditions. And measured.
  • Table 1 shows the transitions of substances to be measured in LC / MS.
  • FIG. 8 (A) and FIG. 8 (B) show the blood concentrations of components and ferulic acid contained in ⁇ -oryzanol in mice to which the drug substance and PLGA nanoparticles were orally administered, respectively.
  • the blood concentration of ferulic acid and cycloartol FE was maintained higher than that of the drug substance until 48 hours after administration. More specifically, the blood concentration of ferulic acid 1 hour after administration was 17.6 ng / mL for the drug substance, compared with 119.4 ng / mL for the PLGA nanoparticles.
  • the blood concentration of cycloartol FE 4 hours after administration was 15 ng / mL for PLGA nanoparticles, while it was below the detection limit for the drug substance.
  • the area under the curve (AUC) from 0 to 6 hours after calculation from FIGS. 8 (A) and 8 (B) was calculated.
  • the AUC of the drug substance was 17.6.
  • the AUC of PLGA nanoparticles was 191.7.
  • AUC from 0 to 48 hours was calculated for cycloartol FE, as shown in FIG. 10, the AUC of the original was 0, whereas the AUC of PLGA nanoparticles was 593. 1
  • Example 3 it was shown that the PLGA nanoparticles prepared in Example 3 described above significantly increased the amount of ⁇ -oryzanol encapsulated in the blood when compared to the original when administered orally.
  • ICG Indocyanine green
  • ULREA SS-11 manufactured by M Technique
  • solution A was fed at a set value of 43 ° C.
  • solution B was fed at a set value of 41 ° C. (actual measured value of about 29 ° C.) at 100 mL / min.
  • Liquid A is a 0.5 wt% PVA aqueous solution.
  • Liquid B contains 0.82% by weight of PLGA and 0.05% by weight of ICG in a mixed solvent of acetone and ethanol in a weight ratio of 2: 1.
  • the rotation speed was 1700 rpm and the back pressure was 0.02 MPa.
  • 133.5 mL of the discharge liquid was collected, and the solvent was distilled off from the discharge liquid by an evaporator for 35 minutes.
  • the obtained ICG-containing PLGA nanoparticle aqueous dispersion 46.5 mL was lyophilized to obtain 0.49 g of ICG-containing PLGA nanoparticles.
  • ICG-containing PLGA nanoparticles prepared above were weighed into a tube, and 5.8 mL of milli-Q water was added. After stirring for 30 seconds with a vortex mixer, sonication was performed for 5 minutes. Using Milli-Q water as a control, the particle size distribution of ICG-containing PLGA nanoparticles was measured with NIKKISO Nanotrac Wave-EX150 (manufactured by Nikkiso Co., Ltd.).
  • the particle size distribution with a single peak, D 50 was 250 nm.
  • the span value of the ICG-containing PLGA nanoparticles was 1.7, and the standard deviation SD of the particle diameter was 4.7 nm.
  • 2-DG-containing PLGA nanoparticles were prepared as follows. First, the liquid A was filled in the liquid A tank, and the tank was pressurized to 0.3 MPa. Thereafter, solution A was fed at a set value of 43 ° C., and then solution B was fed at a set value of 41 ° C. (actual measured value of about 29 ° C.) at 100 mL / min. Liquid A is an aqueous solution containing 0.05 wt% PVA and 0.02 wt% mannitol.
  • Liquid B contains 0.083 wt% PLGA and 0.033 wt% 2-DG in a mixed solvent of acetone and methanol in a weight ratio of 2: 1.
  • the rotation speed was 3000 rpm, and the back pressure was 0.02 MPa.
  • the discharge liquid 300 mL was collected, and the solvent was distilled off from the discharge liquid with an evaporator for 60 minutes.
  • 60 mL of the obtained 2-DG-containing PLGA nanoparticle aqueous dispersion was lyophilized to obtain 0.085 g of 2DG-containing PLGA nanoparticles.
  • the particle size distribution of 2DG-containing PLGA nanoparticles, a single peak, D 50 was 52 nm.
  • the span value of the 2DG-containing PLGA nanoparticles was 1.77, and the standard deviation SD of the particle diameter was 4.7 nm.
  • VC nanoparticles were prepared as follows. First, the liquid A was filled in the liquid A tank, and the tank was pressurized to 0.3 MPa. Thereafter, the liquid A was fed at a set value of 40 ° C., and then the liquid B was fed at a set value of 40 ° C. at 100 mL / min.
  • Liquid A is an aqueous solution containing 0.05 wt% PVA and 0.02 wt% mannitol.
  • Liquid B contains 0.08 wt% PLGA and 0.03 wt% VC in a mixed solvent of acetone and methanol in a weight ratio of 2: 1.
  • the rotation speed of the holder was 500, 1000 or 3000 rpm, and the back pressure was 0.02 MPa.
  • the discharge liquid 300 mL was collected, and the solvent was distilled off from the discharge liquid with an evaporator for 60 minutes.
  • 60 mL of the obtained VC nanoparticle aqueous dispersion was freeze-dried, about 0.085 g of VC nanoparticles were obtained at 500 rpm, 1000 rpm, and 3000 rpm, respectively.
  • each VC nanoparticle prepared above was weighed into a tube, and 2.1 mL of milli-Q water was added. After stirring for 30 seconds with a vortex mixer, sonication was performed for 5 minutes. Using Milli-Q water as a control, the particle size distribution of PLGA nanoparticles was measured with NIKKISO Nanotrac Wave-EX150 (Nikkiso Co., Ltd.).
  • FIGS. 13A to 13C show the particle size distribution of VC nanoparticles at the rotation speeds of 500 rpm, 1000 rpm, and 3000 rpm, respectively. If the rotational speed is 500 rpm, the 1000rpm and 3000 rpm, D 50 of VC nanoparticles, respectively 69 nm, at 93nm and 94 nm, span value of each 1.7,1.4 and 2.0.
  • the present invention is suitable for drug DDS.

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Abstract

Cette invention concerne des nanoparticules copolymères de poly(lactide-co-glycolide) renfermant un médicament à l'état encapsulé. La teneur en médicament est de 20 % en poids ou plus par rapport au poids des nanoparticules copolymères de poly(lactide-co-glycolide). La valeur de mesure des diamètres de particules des nanoparticules copolymères de poly(lactide-co-glycolide) peut être de 2,0 ou moins.
PCT/JP2017/030625 2016-08-26 2017-08-25 Nanoparticules copolymères de poly(lactide-co-glycolide), et leur procédé de production Ceased WO2018038267A1 (fr)

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EP3646875A4 (fr) * 2017-06-28 2020-07-15 Sentan Pharma Inc. Composition pharmaceutique et promoteur d'immunoactivité tumorale

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