WO2007136134A1 - Procédé de production de micelles polymères destinées à contenir un médicament hydrophobe - Google Patents

Procédé de production de micelles polymères destinées à contenir un médicament hydrophobe Download PDF

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Publication number
WO2007136134A1
WO2007136134A1 PCT/JP2007/060936 JP2007060936W WO2007136134A1 WO 2007136134 A1 WO2007136134 A1 WO 2007136134A1 JP 2007060936 W JP2007060936 W JP 2007060936W WO 2007136134 A1 WO2007136134 A1 WO 2007136134A1
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Prior art keywords
hydrophobic drug
lower alcohol
hydrophobic
aqueous medium
block copolymer
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PCT/JP2007/060936
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English (en)
Japanese (ja)
Inventor
Yuko Amano
Yasuo Yamamoto
Yasuki Kato
Mitsunori Harada
Tatsuyuki Hayashi
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Nanocarrier Co., Ltd.
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Application filed by Nanocarrier Co., Ltd. filed Critical Nanocarrier Co., Ltd.
Priority to JP2008516731A priority Critical patent/JPWO2007136134A1/ja
Publication of WO2007136134A1 publication Critical patent/WO2007136134A1/fr

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • the present invention relates to a method for encapsulating a hydrophobic drug in a polymer micelle by using a lower alcohol such as ethanol as a drug introduction medium.
  • the neovascularization has a gap of about 200 nm at the tumor site, and nanometer-sized particles leak from the gap and accumulate in the tumor.
  • Drug-encapsulated polymer micelles may have a reduced particle accumulation in the tumor if the particle size is large. Therefore, the particle diameter is 200 nm or less, preferably 150 nm or less. From the viewpoint of therapeutic effect, it is desirable that the amount of drug contained in the polymer micelle is large. In addition, drugs are often expensive, and considering economic and productive efficiency, it is desirable that the drugs be encapsulated in polymer micelles in high yields. Is done.
  • the drug encapsulation rate is high.
  • the dry-solid method generally requires stirring the drug and the polymer micelle for a long time, for example, overnight.
  • the inclusion rate and particle size of the produced drug are not satisfactory.
  • organic solvents such as dichloromethane and black mouth form are commonly used in the dry-solid method, and there are concerns about its toxicity. Therefore, a simple method for encapsulating a drug in a block copolymer without using such a highly toxic organic solvent is desired. Disclosure of the invention
  • An object of the present invention is to provide a method capable of forming a drug-encapsulated polymer micelle having a small particle diameter in a short time and easily and at a high encapsulation rate.
  • the present inventor used a lower alcohol such as ethanol or methanol as a drug introduction medium, so that the drug can be easily put into a micelle made of a block copolymer having hydrophilic and hydrophobic regions. Found that it can be introduced, and completed the present invention
  • the present invention includes the following aspects.
  • a method of encapsulating a hydrophobic drug in a polymer micelle the following steps:
  • a lower alcohol solution or dispersion in which the hydrophobic drug is dissolved or dispersed is mixed with the aqueous medium containing the polymer micelle, whereby the hydrophobic drug is mixed into the polymer micelle. Encapsulating, wherein the water solubility of the hydrophobic drug is lower than the solubility in the lower alcohol.
  • the step (1-c) comprises adding a lower alcohol solution or dispersion in which the hydrophobic drug is dissolved or dispersed to the aqueous medium containing the polymer micelle. 1] method.
  • step U-c) comprises adding the aqueous medium containing the polymer micelle to a lower alcohol solution in which the hydrophobic drug is dissolved or dispersed.
  • a method of encapsulating a hydrophobic drug in a polymer micelle comprising the following steps:
  • water solubility of the hydrophobic drug is lower than the solubility in the lower alcohol.
  • the step (2-b) comprises adding a lower alcohol solution or dispersion in which both the hydrophobic drug and the block copolymer are dissolved or dispersed to the aqueous medium. [6] the method of.
  • the step (2-b) comprises adding the aqueous medium to a lower alcohol solution or dispersion in which both the hydrophobic drug and the block copolymer are dissolved or dispersed. [6] the method of.
  • step (2-b) further comprising applying energy to a mixture of an aqueous medium in which both the hydrophobic drug and the block copolymer are dissolved or dispersed and a lower alcohol, [6] ⁇ Any method of [8].
  • amino acid and / or derivative thereof is glutamic acid or aspartic acid and / or a derivative thereof, Method.
  • the hydrophobic drug is selected from the group consisting of anticancer drugs, antibacterial drugs, antifungal drugs, antiviral drugs, antibiotics, central nervous system drugs, peripheral nervous system drugs, hormone drugs, anesthetics and analgesics.
  • the method selected from any one of [1] to [14].
  • the present invention it is possible to form a drug-encapsulated polymer micelle having a small particle size in a short time and easily and at a high encapsulation rate.
  • empty micelles used in the present invention can be prepared in large quantities. Therefore, according to the present invention, since the drug can be easily encapsulated in empty micelles prepared in large quantities, the present invention can also be used for screening drug-encapsulated micelles.
  • the present inventor uses a lower alcohol such as ethanol or methanol as a drug introduction medium, so that a drug can be placed in a micelle of a block copolymer consisting of hydrophilic and hydrophobic regions in a short time and simply.
  • a lower alcohol such as ethanol or methanol
  • the inventors have found that drug-encapsulated polymer micelles having a high encapsulation rate and a small particle size can be formed.
  • the present invention is a method that utilizes the difference in the solubility of a hydrophobic drug to be encapsulated in a lower alcohol.
  • Hydrophobic drugs have a higher solubility in organic solvents than water. Therefore, the hydrophobic drug is dissolved or dispersed in an organic solvent in advance, and then the periphery of the drug is replaced with an aqueous environment to lower the solubility of the hydrophobic drug, thereby removing the hydrophobic drug from the hydrophobic property of the polymer micelle.
  • a lower alcohol such as ethanol or methanol as the organic solvent
  • the drug was mixed in empty micelles and instantly encapsulated in the micelle. I found out.
  • one embodiment of the method of the present invention includes the following steps.
  • Dispersion of “dissolution or dispersion” in the above stage U-a) means a state in which the solute is uniformly dispersed in the lower alcohol and no precipitation occurs.
  • the formation of the polymer micelle in the above step (1-b) can be performed, for example, by stirring the solution containing the block copolymer.
  • the micelles are formed by applying energy such as ultrasonic waves, pressure and / or shear force.
  • energy such as ultrasonic waves, pressure and / or shear force.
  • Ultrasonic waves for example, Bioruptor (Nihon Seiki) can be used by irradiating at level 4, with ice cooling for 1 second, for 5 to 10 minutes.
  • a lower alcohol solution or dispersion in which a hydrophobic drug is dissolved or dispersed may be added to the aqueous medium containing polymer micelles, or the aqueous medium containing polymer micelles May be added to and mixed with the lower alcohol solution in which the hydrophobic drug is dissolved or dispersed.
  • the addition is preferably carried out gradually while stirring the solution or medium to be added.
  • the mixing may be performed by applying energy such as ultrasonic waves, pressure and / or shear force to the mixed solution or medium. When using ultrasonic waves, for example, it can be performed under the same conditions as the formation of the polymer micelles.
  • Another embodiment of the method of the present invention includes the following steps.
  • Dispersion of “dissolution or dispersion” in the above step (2-a) also means a state in which the solute is uniformly dispersed in the lower alcohol and no precipitation occurs.
  • a lower alcohol solution or dispersion in which both the hydrophobic drug and the block copolymer are dissolved or dispersed may be added to the aqueous medium, or the aqueous medium may be added to the hydrophobic drug and the block copolymer. It may be added to a lower alcohol solution or dispersion in which both monomers are dissolved or dispersed. The addition is preferably carried out gradually while stirring the solution or medium to be added.
  • the micelle formation in the above step (2-b) can also be performed, for example, by stirring a solution containing a block copolymer.
  • the micelle formation is performed using energy such as ultrasonic waves, pressure and / or shear force. Over.
  • ultrasonic waves When ultrasonic waves are used, for example, it can be carried out under the same conditions as in the polymer micelle formation method in (1-b) above.
  • the lower alcohol When the lower alcohol is removed after preparing the drug-encapsulating polymer micelle, it can be replaced with a desired aqueous medium by ultrafiltration, dialysis, etc. However, it is not limited to these methods.
  • the lower alcohol concentration can be reduced by diluting with water, buffer solution or physiological saline, but is not limited to these methods. It goes without saying that the lower alcohol can also be diluted by the above-mentioned method of removing the lower alcohol. • Lower alcohol
  • lower alcohol refers to a substance in which a hydrophobic drug has higher solubility in an aqueous medium and is miscible with water, and is not particularly limited. Is 1 to 7, more preferably 1 to 4 lower alcohols such as methanol, ethanol, propyl alcohol, iso-propyl alcohol, t-butyl alcohol and the like. Ethanol or methanol is particularly preferred.
  • the hydrophobic drug that can be efficiently encapsulated in the polymer micelle may be any drug whose water solubility is lower than that in lower alcohol, and various pile cancer agents, antibacterial agents, Fungi, antivirals, antibiotics, central nervous system drugs, peripheral nervous system drugs, hormonal drugs, antihypertensive drugs, analgesics, etc.
  • anticancer agents include doseiyu xel, tamibarotene, exemestane, flutami and the like.
  • central nervous system drugs include Prohofur, Buko Pome, Biperiden
  • ⁇ Riazolam ketoprofen, feinine, amobarbital, ibuprofen, and indomethacin.
  • peripheral nervous system drugs include U dokine, xylocaine, and D-propion.
  • hormonal agents include oxendone, testosterone, estrogen, maxacalcitol and the like.
  • Alpros Yuzil, Pyre Yunide, Furosemi, Micona Pool, various hydrophobic bins, hinokitiol and the like can be mentioned.
  • “ ⁇ drug” is not limited to pharmaceuticals, but means any low molecular weight compound that exerts physiological action in vivo.
  • a low molecule is one having a molecular weight of 1500 or less.
  • the amount of drug to be used is not particularly limited. From 0.1 to 50%, preferably from 0.1 to 30% by weight, based on the total weight of polymer and drug is used.
  • the aqueous medium referred to in the present invention may be any aqueous medium in which the solubility of the hydrophobic drug is lower than the solubility in the lower alcohol of the present invention.
  • aqueous medium for example, water, physiological saline,
  • aqueous buffer solution include phosphate buffer solution, carbonate buffer solution, borate buffer solution, and acetate buffer solution. Particularly preferred is water.
  • the drug-containing polymer of the present invention is a block copolymer composed of a hydrophilic region and a hydrophobic region, which is used to form a micelle. These block copolymers are in accordance with the object of the present invention. In other cases, the force may include any hydrophilic region and any hydrophobic region.
  • the hydrophilic region includes, but is not limited to, the following: , Poly (ethylene glycol) [or poly (ethylene oxide)], polyslide, poly (vinyl pyrrolidone), hori (vinyl alcohol), poly (acrylamid), poly (Acrylic acid), poly (methacrylic acid), poly (methacrylic acid), poly (methacrylic acid ester), poly (acrylic acid ester), polyamino acid Or the area
  • region derived from these inducers is mentioned.
  • the police force ride there are dung, r kiss, run, fluke evening, garaku evening, and the like.
  • poly (ethylene glycol) segment ⁇ ⁇ has been provided with various functional groups at one end, and because the size of the region is controlled, it can be easily used. Is preferable.
  • the hydrophobic region includes acidic amino acids, in particular poly (aspartic acid) and Z or derivatives thereof, poly (glutamic acid) and z or their Derivatives can be mentioned. Specifically, but not limited to,
  • poly (acidic amino acid derivatives) such as U (r-aralkyldaltami doco-glucanic acid).
  • the block copolymer that can be used in the present invention comprises the above-mentioned hydrophilic region and hydrophobic region, and is composed of an aqueous medium (for example, water or buffered water or a water-miscible solvent, methanol, polyethylene glycol, saccharides). (Aqueous solution containing, etc.) All of the combinations of regions having the respective molecular weights that can form polymer micelles can be mentioned.
  • the hydrophilic region is poly (ethylene glycol).
  • the hydrophobic region is made of the above poly (amino acid) and / or a derivative thereof.
  • poly (amino acid derivative) segments are known per se.
  • Polyethylene glyceryl 3-Lucopoly benzene ester or small J-ethylene glycol-copolyglutamate can be prepared from benzyl ester.
  • Polyethylene Dali 3-Lucorpo ⁇ Benzester of J-aspartate or polyethylene glycol-polyglutamate benzyl ester is prepared in a polyethylene glycol with the shoulder end protected and the other end is an ano group.
  • the benzyl group is removed by alkaline hydrolysis to remove polyethylene glycol-corporaparaginic acid or polyethylene glycol. After the conversion to monopolydalate, benzyl is used to achieve the desired esterification rate in an organic solvent.
  • Partially benzyl ester by adding an alcohol and reacting in the presence of a condensing agent, for example, N—N dicyclyl D-hexyl cal-positive (DCC) or N—N′-disopropyl cal-positive (DIPCI) It is possible to protect the block copolymer with.
  • a condensing agent for example, N—N dicyclyl D-hexyl cal-positive (DCC) or N—N′-disopropyl cal-positive (DIPCI) It is possible to protect the block copolymer with.
  • Polyethylene glycol-polyaspartate dodecy Polyester-copolyaspartic acid hexadecyl ester can be obtained by using 1-hexade diol as the ester.
  • block copolymers that are easy to produce and can be conveniently used in the present invention can be represented by the following formulas (I) and (II). Can be mentioned.
  • R and R 3 each independently represent a hydrogen atom or a lower alkyl group substituted or unsubstituted by an optionally protected functional group
  • R 2 is a hydrogen atom, saturated or saturated.
  • R 4 represents a hydroxyl group, a saturated or unsaturated C 1, to C 3 Q aliphatic oxy group or an aryl lower alkyloxy group
  • R 5 represents —O— or —NH—
  • R 6 represents a hydrogen atom, a phenyl group, — (CH 2 ) 4 —phenyl group, unsubstituted or substituted with an amino group or a carboxyl group
  • R 7 represents a methylene group or an ethylene group
  • n is an integer of 10 to 25 500
  • X is 10 to 3 0 is an integer
  • R ⁇ 6 When some R ⁇ 6 is a hydrogen atom, it is less than 60% of x + m), y represents an integer of 1 or 2, and is — NH—, — ⁇ _, -O -Z- NH—, —CO _, — CH 2 _, _ 0—Z—S—Z— and —OC ⁇ —Z—NH— (where Z is independently a C 1, C 6 alkylene group.) Represents a linking group selected from the group consisting of: O 2 — OCO—Z—CO— and one NH C0—Z _C0 _ (where Z is independently a C 1, C 6 alkylene group) ) Represents a linking group selected from Examples of the functional group that may be protected include a hydroxyl group, an acetal group, a ketal group, an aldehyde group, and a sugar residue.
  • R and R 3 represent a lower alkyl group substituted with a functional group which may be protected
  • the hydrophilic segments are, for example, W0 9 6/3 3 2 3 3 and W 0 9 6/3
  • the method described in 2 4 3 4, WO 9 7/0 6 2 0 2 can be followed.
  • Lower alkyl means a linear or branched alkyl group having, for example, 7 or less carbon atoms, preferably 4 or less carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group. included.
  • the formed drug-encapsulating polymer micelle if necessary, filter the aqueous solution containing it with a hydrophilic filter having a pore size of 0.22; m. It is known that 0.22 m fill is usually used for the preparation of injections (intravenous, arterial, intramuscular, intraperitoneal, etc.). Even if the drug-encapsulated polymer micelle aqueous solution is sterilized by filtration using a 0.22 im filter, the sterilized drug-encapsulated polymer micelle aqueous solution can be obtained in an extremely high yield. That is, according to the present invention, an injection can be provided efficiently.
  • an injection is a drug before sterilization filtration in which various sugars and / or various polyethylene glycols (macrogol) are reduced and / or removed from the lower alcohol. It can be produced by a method further comprising a step of adding to the encapsulated polymer micelle aqueous solution (or aqueous solution).
  • sugars include, but are not limited to, maltose, trehalose, xylitol, glucose, sucrose, fructose, lactose, mannitol and dextrin.
  • the molecular weight is about 1 00 0 to about 3 5 0 0 0, for example, Macrogol 1 0 0 0, 1 5 4 0, 4 0 0 0, 6 0 0 0, 2 0 0 0 0 And 3 5 0 0 0 and the like.
  • an auxiliary capable of stabilizing the drug-containing polymer micelle in the injection can be easily and safely added to the injection.
  • Such injections can be manufactured easily and safely, and when they are freeze-dried, the dry preparations can be re-dissolved or reconstituted in a solution containing drug micelles using water or an aqueous solution. However, it is possible to provide an injection solution in which aggregation between micelle particles hardly occurs.
  • the saccharide in the solution before lyophilization is added so that its final concentration is 0.1 to 15% (w / V), and polyethylene glycol is It is recommended to add so that the final concentration is 0.5 to 10% (w / V).
  • the ratio of block copolymer to saccharide or polyethylene glycol is 1: 1 to 1: 1 10 or 1: 0.5 to 1: 1 0 by weight, respectively. Comparative Examples and Examples The present invention will be specifically described.
  • polyethylene glycol monopoly () 8-benzyl 1) L-aspartic acid) is abbreviated as block copolymer, and polyethylene glycol-poly (a-benzyl-L-glutamic acid) block copolymer as G.
  • the average molecular weight of the PEG chain of the block copolymer is 1,200, the residue of polyamino acid chain 40, and the introduction rate of the benzyl group of the polyamino acid side chain is 60%, , .1 2 — 4 0 (6 0)
  • the average molecular weight of polyethylene glycol monopoly (j8-benzyl-1-L-aspartic acid) block copolymer has a PEG chain average molecular weight of 1,200, polyamino acid chain of 40 residues, and polyamino acid side chain
  • the introduction rate of benzyl group is 60%, it is expressed as A12-40 (60).
  • Block copolymer A12-40 (100), A12-40 (60), G12-40 (100), G12-40 (60) each weighed 20mg into each screw tube, add 3mL water, Sonication (level 4, 1 second intermittent 10 minutes, Nippon Seiki) was performed to make empty micelles. Stir 2 mL of each empty micelle solution, gradually add 200 uL of docetaxel (3.5 mg / mL) dissolved in ethanol, and perform sonication again to form docetaxel-containing micelles (polymer vs. docetaxel). Weight ratio 5 (w / w), final ethanol concentration 10 (v / v)).
  • the particle size of the prepared micelle was measured by NIC0MP (trademark) 380ZLS (PSS-NIC0 MP), and the average value of the intensity of Gaussian distribution or Nicomp distribution was used.
  • micelles were filtered with MILLEX (registered trademark) -GV PVDF, 0.22 um (Millipore), and the filtrate was ultracentrifuged (200,000 g, 1 hour, 20).
  • MILLEX registered trademark
  • -GV PVDF 0.22 um
  • the absorbance at 280 ⁇ m of the sample before filtration, the filtrate, and the supernatant after ultracentrifugation was measured with a spectrophotometer. Since the maximum absorbance of docetaxel is 280 nm and the block copolymer also has an absorbance of 280 nm, the encapsulation rate was determined by the following method.
  • the amount of docetaxel encapsulated in the micelle was determined by subtracting the amount of docetaxel in the supernatant after ultracentrifugation from the amount of docetaxel in the filtrate.
  • Table 1 shows the particle size and encapsulation rate of the prepared docetaxel-encapsulated micelles. Indicated. Table 1 (Docetaxel-encapsulated micelles prepared by ethanol method-1)
  • a micelle was prepared under the same conditions as in Example 1 except that indomethacin was used instead of docetaxel, the particle size was measured, and the inclusion rate was determined by the following method.
  • Indometin has a maximum absorbance of 320 nm, and the block copolymer also absorbs at 320 nm.Therefore, 5 (U (v / v) acetonitrile for each of the sample before filtration, the filtrate, and the empty micellar solution.
  • the polymer micelles were disintegrated by dilution 20-200 times with ril, and the absorbance at 320 ⁇ was measured in the same manner. The supernatant after ultracentrifugation was similarly performed with 50% (v / v) acetonitrile.
  • the absorbance at 320 ⁇ after dilution 200 times was measured, and the inclusion rate was determined from the calibration curve of indomethacin by the same method as in Example 1. The results are shown in Table 2.
  • Example 3 Prepare micelles under the same conditions as in Example 1 except that hytocopherol was used instead of docetaxel, and measure the particle size.
  • the inclusion rate was determined by the method. Because the maximum absorbance of hytocopherol is 29 In m and the block copolymer also absorbs at 291 nm, 50% (v / v> acetononitrile) of each sample before filtration, filtrate, and empty micellar solution. Dilute to ⁇ 200 times to disrupt polymer micelles, and measure the absorbance at 291 nm of each. Similarly, the supernatant after ultracentrifugation was 20 to 200 times with 50% (v / v) acetonitrile. And the absorbance at 291 nm was measured, and the inclusion rate was determined from the calibration curve of ⁇ _tocopherol by the same method as in Example 1. The results are shown in Table 3.
  • the particle size and inclusion rate of the prepared micelles were determined in the same manner as in Example 1. However, ultracentrifugation is 200, OOOg, 1 hour, 20 for the final ethanol concentration s'5% (v / v) and 20 and 30% (v / v) for the final ethanol concentration. 500, 000g, 1 hour, 20 hours. The results are shown in Table 4.
  • a micelle was prepared under the same conditions as in Example 4 except that indomethacin was used instead of docetaxel, the particle size was measured, and the encapsulation rate was determined by the method described in Example 2. The results are shown in Table 5.
  • Table 5 (Effect of ethanol concentration of indometain-encapsulated micelles)
  • a micelle was prepared under the same conditions as in Example 6 except that indomethacin was used in place of docetaxel, the particle size was measured, and the inclusion rate was determined by the method described in Example 2. The results are shown in Table 7.
  • a micelle was prepared under the same conditions as in Example 8 except that indomethacin was used instead of docetaxel, the particle size was measured, and the inclusion rate was determined by the method described in Example 2. The results are shown in Table 9.
  • a micelle was prepared under the same conditions as in Comparative Example 1 except that indomethacin was used instead of docetaxel, the particle size was measured, and the inclusion rate was determined by the method described in Example 2. The results are shown in Table 11.
  • a micelle was prepared under the same conditions as in Comparative Example 3 except that indomethacin was used in place of docetaxel, the particle size was measured, and the inclusion rate was determined by the method described in Example 2. The results are shown in Table 13.

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Abstract

L'invention concerne un procédé permettant d'enfermer un médicament hydrophobe dans une micelle polymère. Le procédé comprend les étapes consistant à (1-a) dissoudre ou à disperser un médicament hydrophobe dans un alcool inférieur ; (1-b) fournir un milieu aqueux contenant des micelles polymères constituées d'un copolymère séquencé comportant une région hydrophile et une région hydrophobe ; et (1-c) mélanger la solution ou la dispersion d'alcool inférieur dans laquelle est dissous ou dispersé le médicament hydrophobe avec le milieu aqueux contenant les micelles polymères pour que les micelles polymères enferment le médicament. La solubilité dans l'eau du médicament hydrophobe est inférieure à sa solubilité dans l'alcool.
PCT/JP2007/060936 2006-05-23 2007-05-23 Procédé de production de micelles polymères destinées à contenir un médicament hydrophobe WO2007136134A1 (fr)

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Cited By (5)

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WO2011025036A1 (fr) * 2009-08-31 2011-03-03 ナノキャリア株式会社 Composition particulaire et composition médicamenteuse comprenant celle-ci
JP2011162512A (ja) * 2010-02-12 2011-08-25 Nano Career Kk 粒子状医薬組成物
WO2015002078A1 (fr) 2013-07-03 2015-01-08 日本化薬株式会社 Nouvelle préparation à base d'un composé d'acide boronique
WO2017086392A1 (fr) 2015-11-18 2017-05-26 日本化薬株式会社 Composition comprenant un nouveau dérivé de l'acide glutamique et un copolymère à blocs, et utilisation de cette dernière
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EP2474306A1 (fr) * 2009-08-31 2012-07-11 NanoCarrier Co., Ltd. Composition particulaire et composition médicamenteuse comprenant celle-ci
EP2474306A4 (fr) * 2009-08-31 2013-11-27 Nanocarrier Co Ltd Composition particulaire et composition médicamenteuse comprenant celle-ci
CN102481255B (zh) * 2009-08-31 2015-04-22 那野伽利阿株式会社 颗粒组合物和含有其的医药组合物
WO2011025036A1 (fr) * 2009-08-31 2011-03-03 ナノキャリア株式会社 Composition particulaire et composition médicamenteuse comprenant celle-ci
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JP2011162512A (ja) * 2010-02-12 2011-08-25 Nano Career Kk 粒子状医薬組成物
US9795563B2 (en) 2010-02-12 2017-10-24 Nanocarrier Co., Ltd. Particulate pharmaceutical composition
WO2015002078A1 (fr) 2013-07-03 2015-01-08 日本化薬株式会社 Nouvelle préparation à base d'un composé d'acide boronique
WO2017086392A1 (fr) 2015-11-18 2017-05-26 日本化薬株式会社 Composition comprenant un nouveau dérivé de l'acide glutamique et un copolymère à blocs, et utilisation de cette dernière
US11951153B2 (en) 2016-02-29 2024-04-09 Sun Pharmaceutical Industries Limited Topical cyclosporine-containing formulations and uses thereof

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