WO2010053101A1 - Goutte oculaire ayant de bonnes propriétés de migration intraoculaire, agent d’imagerie fluorescent, et procédé de production associé - Google Patents

Goutte oculaire ayant de bonnes propriétés de migration intraoculaire, agent d’imagerie fluorescent, et procédé de production associé Download PDF

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WO2010053101A1
WO2010053101A1 PCT/JP2009/068851 JP2009068851W WO2010053101A1 WO 2010053101 A1 WO2010053101 A1 WO 2010053101A1 JP 2009068851 W JP2009068851 W JP 2009068851W WO 2010053101 A1 WO2010053101 A1 WO 2010053101A1
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eye
eye drop
prodrug
fluorescence
solvent
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PCT/JP2009/068851
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English (en)
Japanese (ja)
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幸二 西田
耕一 馬場
均 笠井
佑治 田中
享 久保田
俊二 横倉
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国立大学法人東北大学
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Priority to JP2010536777A priority Critical patent/JP5709523B2/ja
Publication of WO2010053101A1 publication Critical patent/WO2010053101A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A61K49/0043—Fluorescein, used in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an eye drop having high intraocular transferability and a method for producing the same.
  • Eye diseases include diseases that occur on the surface side of the eye, such as conjunctivitis, and diseases that occur in the posterior segment, such as age-related macular degeneration and (diabetic) retinopathy.
  • FIG. Fig. 1 is a partially modified horizontal cross-sectional view of the right eyeball by Kenji Honse, ophthalmic solution (Nanzandou), p169, Fig. 10-1.
  • the instilled drug is first mixed with tear fluid and stored in the tear fluid of the conjunctival sac.
  • the amount of tear fluid in the conjunctival sac in a normal person is 7-8 ml, and the maximum volume of the corneal sac is 30 ml. Therefore, if the amount of normal eye drop drops, that is, 40-50 ml, which is washed away from the punctum or eyelid margin is removed, it is partially transferred into the eyeball effectively.
  • the concentration of drugs in the conjunctival sac is rapidly decreasing within one hour immediately after instillation. Become.
  • the actual rate of decrease depends on drug properties such as fat solubility, water solubility, protein binding, and pH, but a significant concentration decrease occurs within one hour.
  • the molecular weight and polarity are important factors in drug penetration into the cornea. Drugs with a molecular weight of 100 or less have high permeability to the corneal epithelium. On the other hand, when the molecular weight of the drug is 500 or more, the permeability is extremely lowered.
  • the more a drug is fat-soluble the easier it is to penetrate the corneal epithelium.
  • the lipid solubility of a drug becomes high, the permeability of the hydrophilic corneal substance mainly composed of water decreases.
  • the more water-soluble the drug the lower the permeability of the corneal epithelium and the easier it is to pass through the corneal stroma with water as the main component. That is, the corneal permeability of the drug is contradictory between the corneal epithelium and the substance.
  • Lipid solubility is an important factor for improving the corneal epithelial permeability of drugs, but for ordinary eye drops, it is necessary to dissolve the drug in an eye drop base (which is a hydrophilic liquid such as water). For this reason, the lipophilicity of drugs is set low. Therefore, by chemically modifying hydrophilic drugs in advance, the liposolubility is increased, drug distribution to the corneal epithelium is increased, and then converted to the original hydrophilic drug mainly by enzymatic reactions that occur in the corneal epithelium. There has been reported a technique for improving the corneal permeability of a drug by facilitating permeation through the corneal stroma.
  • DPE dipivalial epinephrine
  • epinephrine a prodrug of epinephrine
  • Non-Patent Document 1 This DPE was obtained by esterifying the phenolic hydroxyl group of epinephrine, which has a strong hydrophobicity, increased migration to the epithelium, and at the same time is less susceptible to oxidative degradation. Stabilization is also planned. It has been reported that this DPE undergoes hydrolysis in the corneal epithelium to become epinephrine, appears in the anterior chamber, and exhibits the same efficacy as epinephrine at doses of 1/5 or less of conventional epinephrine.
  • a compound having a property of enhancing lipophilicity by chemically modifying a hydrophilic drug in advance and being converted into the original drug by an enzymatic reaction in aqueous humor after permeation of the corneal epithelium When the hydrophobicity of the compound is strong, aggregates are easily formed in water and become particles. Since the particle size is usually on the order of micrometers, when used as an eye drop, penetration of the drug into the corneal epithelial layer is difficult due to the size factor of the drug particle.
  • the drug that has passed through the cornea and reached the anterior chamber after instillation diffuses in the anterior chamber water and reaches the lens and iris.
  • the drug penetration into the iris parenchyma is very easy and the drug has an immediate effect on the iris.
  • the transuveal scleral flow loss system which is one of the anterior aqueous humor flow pathways, plays an important role in reaching the ciliary body of drugs in the anterior chamber.
  • the maximum drug concentration in each tissue is, for example, the concentration of eye drops in the cornea (generally about 0.1%, 1,000 mg / L). 1/100, about 1 / 5,000 in aqueous humor. Drug concentrations in iris tissue are often considered the same as aqueous humor concentrations.
  • the transfer of the drug in the anterior chamber to the posterior chamber is limited to some extent. Therefore, as described above, the eye drops move from the cornea to the anterior chamber, iris, ciliary body, and crystalline lens, and from the conjunctiva to the sclera, and partly to the retina and the surrounding tissues.
  • the eye drops move from the cornea to the anterior chamber, iris, ciliary body, and crystalline lens, and from the conjunctiva to the sclera, and partly to the retina and the surrounding tissues.
  • the main action site of the eye drops must be concentrated on the ocular surface and the anterior eye segment.
  • oral administration of drugs intravenous injection, subcutaneous injection, intramuscular injection, or local administration such as vitreous injection is selected.
  • Examples of methods for applying eye drops to the vitreous body and retina of deep intraocular tissues include local vitreous injection, retinal injection (see Patent Document 1), intra-Tenon sac injection, and vitreous implantable preparation. .
  • the drug is limited to a gene DNA, but an eye drop containing a specific liposome encapsulating an expression vector incorporating the gene DNA has been developed (patent) Reference 2). Furthermore, eye drops including liposomes that can deliver various drugs to the posterior eye segment as well as gene DNA have been developed (see Non-Patent Document 2).
  • JP 2006-507368 A Japanese Patent No. 3963506
  • an object of the present invention is to provide an eye drop that does not contain a special carrier such as a liposome and has a high intraocular drug transfer property and a method for producing the same.
  • the present inventors have previously made a hydrophilic or water-soluble drug (compound) into a prodrug to make it hydrophobic or fat-soluble, and this is performed by a method called a reprecipitation method. It was found that high intraocular transferability of the drug can be achieved by dispersing in the eye drop as particles having a particle size of the order of nanometer, and the present invention has been completed.
  • the gist of the present invention is as follows.
  • An eye drop comprising particles comprising a prodrug that changes from hydrophobic or fat-soluble to hydrophilic or water-soluble upon hydrolysis, wherein the particle size of the particles is 10 nm or more and less than 1 ⁇ m. Eye drops.
  • the particle size of the particles is preferably 10 nm or more and 500 nm or less.
  • the prodrug is dissolved in the solvent 1 in which the prodrug dissolves, and the resulting solution A is mixed with the solvent 2 in which the prodrug does not dissolve, so that the prodrug exists as nanoparticles. And can be produced by mixing with an eye drop base.
  • a fluorescent imaging agent for observing the eye at the cellular level is provided.
  • the fluorescent imaging agent of the present invention comprises particles comprising a prodrug that undergoes a hydrolysis reaction to change from hydrophobic or fat-soluble to hydrophilic or water-soluble and emits fluorescence, and the particle size of the particles is It is characterized by being 10 nm or more and less than 1 ⁇ m.
  • the particle size of the particles is preferably 10 nm or more and 500 nm or less.
  • the fluorescent imaging agent of the present invention is administered to the eyes of animals other than humans, the eyes are removed, and the extracted eyes are separated into respective parts, There is a method of observing fluorescence emitted from a site by optical means.
  • the present invention it is possible to effectively transport the compound to the intraocular tissue in the form of eye drops.
  • effective transfer of compounds to the cornea, conjunctiva, anterior aqueous humor, ciliary body, lens, sclera, choroid, and retina is possible.
  • FIG. 1 is a schematic diagram showing the structure of an eye.
  • aa ′ indicates the eyeball axis
  • bb ′ indicates the line of sight
  • cc ′ indicates the equator.
  • FIG. 2 is a diagram showing the results of fluorescence spectrum evaluation in Example 1 and Comparative Examples 1 to 3.
  • the curve with the whole marker is the fluorescence spectrum of fluorescein diacetate nanoparticles
  • the dotted curve with the triangular marker is the fluorescence spectrum of fluorescein diacetate microparticles
  • the dotted line without the marker The curve is the fluorescence spectrum of sodium fluorescein
  • the curve consisting of the solid line without the marker is the fluorescence spectrum of fluorescein.
  • FIG. 3 is a diagram showing the results of time-dependent evaluation of eyeball fluorescence spectra in Examples 2 to 5 and Comparative Example 4.
  • the curve with a round marker is a fluorescence spectrum using a rat eye as a sample 0.5 hours after administration of the eye drop, and is a dotted line with a triangular marker pointing upwards.
  • the curve is a fluorescence spectrum in which the eye of a rat 1 hour after administration of eye drops is used as a sample, and the dotted curve with a square marker is a curve of a rat 2 hours after administration of eye drops.
  • Fluorescence spectrum of eye sample, dotted curve with downward marker marker is a fluorescence spectrum of rat eye sample 3 hours after administration of eye drops.
  • FIG. 4 is a graph showing the results of evaluation over time of fluorescence spectra of fluorescein diacetate transferred to an aqueous humor in Examples 6 to 8 and Comparative Example 5.
  • the curve with a round marker is a fluorescence spectrum using a rat eye 10 minutes after administration of the eye drops
  • the dotted curve with a triangular marker is the eye drop.
  • It is a fluorescence spectrum using a rat eye 30 minutes after administration as a sample
  • a dotted curve with a square marker is a fluorescence spectrum using a rat eye 60 minutes after administration of eye drops as a sample.
  • the dotted curve without the marker, which is the spectrum is the control.
  • FIG. 5 is a diagram showing the results of evaluation of transferability of eye drops to the anterior segment / retina in Example 9 and Comparative Example 6.
  • the curve with a round marker is the fluorescence spectrum of the anterior segment after administration of eye drops
  • the dotted curve with a triangular marker is the retinal tissue after administration of eye drops.
  • the dotted curve with a square marker is the fluorescence spectrum of the anterior segment of the control
  • the dotted curve without the marker is the fluorescence spectrum of the control retinal tissue.
  • FIG. 6 is a confocal laser microscope image of retinal tissue in Example 9 and Comparative Example 6 (the left side is Example 9 and the right side is Comparative Example 6).
  • FIG. 7 is a graph showing the results of comparison of the fluorescence spectrum and fluorescence intensity in each tissue in Example 10.
  • the curve with a round marker is the fluorescence spectrum of the cornea
  • the dotted curve with a triangular marker is the fluorescence spectrum of the choroid and retina of the posterior eye.
  • FIG. 8 is a graph showing the results of evaluation of changes in fluorescence intensity over time in the cornea (right side) and the retina and choroid (left side) in Examples 11 to 14.
  • FIG. 9 is a graph showing the calibration curve used to determine the migration rate of fluorescein diacetate in Examples 11-14.
  • FIG. 10 is a diagram showing the results of fluorescence observation of corneal tissue using a confocal laser microscope in Examples 15 to 18. In FIG.
  • FIG. 11 shows an electron micrograph of the dexamethasone derivative nanoparticles produced in Example 19.
  • FIG. 12 shows the results of HPLC of the sample solution in Example 19 (right side) and the results of analyzing dexamethasone standards by HPLC (left side).
  • FIG. 13 shows the evaluation results by HPLC of the eye drop of Example 19 (nanoparticles, left side) and the eye drop of Comparative Example 7 (micro particles, right side).
  • FIG. 14 is a diagram showing the results of HPLC evaluation of intraocular transfer properties of eye drops of Example 19 and Comparative Examples 7 and 8, together with the results of controls.
  • the leftmost bar graph (a) is the result of the eye drop of Example 19
  • the second bar graph (b) from the left is the result of the eye drop of Comparative Example 7
  • the third bar graph from the left (C) is the result of the eye drop of Comparative Example 8
  • the rightmost bar graph (d) is the result of the control.
  • FIG. 15 shows a calibration curve used in Example 19 and Comparative Example 8 to calculate the amount of dexamethasone transferred into the eyeball by administration of eye drops.
  • the eye drop of the present invention is an eye drop containing particles comprising a prodrug that undergoes a hydrolysis reaction and changes from hydrophobic or fat-soluble to hydrophilic or water-soluble, and the particle size of the particles is 10 nm or more and 1 ⁇ m. It is characterized by being less than.
  • the prodrug contained in the eye drop and the fluorescent imaging agent of the present invention is excellent in intraocular transferability because the particle size of the particle composed of the prodrug is on the order of nanometers. First, a method for producing nanoparticles having such a particle size on the order of nanometers will be described.
  • Nanoparticles composed of prodrugs can be produced by a method called a reprecipitation method.
  • a prodrug is a compound that undergoes a hydrolysis reaction to change from hydrophobic or fat-soluble to hydrophilic or water-soluble as described above. That is, the prodrug is hydrophobic or fat-soluble. Specific examples of the prodrug will be described later.
  • hydrophobic or fat-soluble refers to a property that the solubility in water at 20 ° C. is less than 0.01 g / L.
  • Hydrophobic or water-soluble refers to the property that the solubility in water at 20 ° C. is 0.01 g / L or more.
  • the prodrug is dissolved in the solvent 1 in which the prodrug dissolves, and the obtained solution A is mixed with the solvent 2 in which the prodrug does not dissolve.
  • a dispersion liquid in which nanoparticles composed of the prodrug and the solvent 1 are dispersed in the solvent 2 is obtained.
  • the manufacturing method of the eye drop of the present invention is characterized by including a step of obtaining such a dispersion.
  • solvent means that 1 mg or more of prodrug dissolved in 100 g of solvent 1 at 20 ° C.
  • does not dissolve means prodrug that dissolves in 100 g of solvent 2 at 20 ° C. Say less than 1 mg.
  • the dispersion is mixed with the eye drop base. Therefore, the solvent 2 needs to be not harmful to the living body at the same time that the prodrug is not dissolved. Therefore, the most preferable as the solvent 2 is water which is the liquid most contained in the living body.
  • the solvent 2 include hydrophilic liquids such as an ethanol aqueous solution (ethanol concentration is 0.08 mL / mL or less). The amount of the solvent 2 used is usually 50 to 1,000,000 parts by weight, preferably 1000 to 100,000 parts by weight per 100 parts by weight of the solution A.
  • solvent 1 examples include alcohols such as ethanol, and organic solvents such as acetone, dimethyl sulfoxide (DMSO), 1-methyl-2-pyrrolidone, and tetrahydrofuran.
  • the amount of solvent 1 used is usually 100 to 100,000 parts by weight, preferably 1000 to 50000 parts by weight, per 100 parts by weight of the prodrug.
  • the prodrug is dissolved in the solvent 1, and the obtained solution A is mixed with the solvent 2.
  • the solution A is utilized using a tubular object such as a syringe needle. Is preferably supplied as droplets in the solvent 2 and the solution A and the solvent 2 are mixed.
  • the solvent 1 and the solvent 2 can be diluted infinitely, so that the droplet of the solution A quickly diffuses and disappears in the solvent 2.
  • the solubility rapidly decreases, and the prodrug is precipitated.
  • nanoparticles having a particle size of the order of nanometers can be easily produced in a state of being uniformly dispersed in the solvent 2.
  • the particle size of the prodrug-containing particles is 10 nm or more and less than 1 ⁇ m, preferably 10 nm or more and 500 nm or less, more preferably 10 nm or more and 250 nm or less. If the particle size is not in the range of such a small value, the prodrug cannot be transferred to the posterior eye part, and high intraocular transferability cannot be achieved for the eye drop.
  • the particle size refers to the particle diameter of a particle measured by a scanning electron microscope and a dynamic light scattering method regardless of the shape of the particle.
  • the particle size is adjusted by the diameter of the tubular object such as the syringe needle, the stirring method when mixing the solution A and the solvent 2, and the temperature of the solution A and the solvent 2 when mixing the solution A and the solvent 2 can do.
  • grains (solution A) can also be raised by using surfactant, a suspending agent, etc.
  • An example of a surfactant is polysorbate 80, and an example of a suspending agent is polyvinylpyrrolidone K30.
  • the particle size varies depending on the types of the solvent 1 and the solvent 2 and the concentration of the prodrug in the solution A.
  • the droplet size of the solution A supplied into the solvent 2 is reduced by reducing the diameter of the tube, so that the particle size of the obtained nanoparticles is reduced.
  • the particle size decreases as the stirring speed is increased, and the particle size increases as the stirring speed is decreased.
  • the influence of the temperature of the solution A and the solvent 2 on the particle size depends on the prodrug used in the production of the eye drop of the present invention.
  • a prodrug that dissolves in a concentration range of 0.01 ⁇ g or more and less than 1 mg in 100 g of solvent 2 at 20 ° C. increases in particle size with increasing temperature and dissolves in solvent 2 at 20 ° C. and 100 g.
  • the particle size decreases as the temperature of Solution A and Solvent 2 increases.
  • the temperature range for forming the nanoparticles is generally 0 to 100 ° C. at 1 atm in the solution A and the solvent 2.
  • the dispersion of nanoparticles obtained by mixing the solution A and the solvent 2 is composed of a prodrug, a solvent 1 such as an organic solvent, and a solvent 2 such as water.
  • Organic solvents are harmful to living organisms and should be removed by dialysis. This removal may be performed after the dispersion is in the form of eye drops described later.
  • the eye drop of the present invention is obtained by mixing a dispersion liquid in which nanoparticles composed of the above prodrug (including solvent 1 if not removed by dialysis or the like) in solvent 2 are mixed with an eye drop base. Can be obtained. This operation is performed aseptically. Alternatively, the eye drops may be sterilized using a filter sterilization filter having a pore size of 0.22 ⁇ m and 0.45 ⁇ m.
  • the eye drop base is a liquid containing water and various additives. Further, when the nanoparticles contain the solvent 1, the solvent 1 is removed by dialysis or the like.
  • the said dispersion liquid can be freeze-dried, and this can also be mixed and used for an eye drop base at the time of use.
  • the additive examples include isotonic agents such as sodium chloride, concentrated glycerin, sorbitol, glucose; Buffering agents such as sodium hydrogen phosphate, sodium acetate, boric acid, citric acid; Surfactants such as polysorbate 80, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 60; Stabilizers such as sodium citrate, sodium edetate; Preservatives such as benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, chlorhexidine gluconate; Thickeners such as polyvinylpyrrolidone K30, hydroxyethylcellulose, propylene glycol, methylcellulose, macrogol 4000; Suspending agents such as carboxyvinyl polymer, macrogol 6000, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30; PH adjusters such as hydrochloric acid, glacial acetic acid, sodium hydroxide; Solubilizing agents such as
  • the concentration of the prodrug in the eye drop of the present invention containing the above-described additives as appropriate is appropriately determined depending on the type of the prodrug, but is usually in the range of 0.001 wt% to 10 wt%. .
  • Prodrugs are compounds that change from hydrophobic or lipophilic to hydrophilic or water-soluble upon hydrolysis, and usually become active as active ingredients in eye drops upon hydrolysis. However, there is no problem even if it is active before undergoing the hydrolysis reaction.
  • prodrugs examples include esterification, acetalization, amidation, thioesterification, or ketalization of a hydrophilic drug, which undergoes a hydrolysis reaction by a hydrolase in the corneal epithelium, and the ester group. And prodrugs in which the substituent is removed.
  • a prodrug obtained by esterifying indomethacin is shown below.
  • the solubility of indomethacin in water at 20 ° C. is changed from 0.01 g / L or more (hydrophilic or water-soluble) to less than 0.01 g / L (hydrophobic or fat-soluble).
  • the pH of the eye drop of the present invention is usually 5-9.
  • the pH of the eye drop can be adjusted with the above pH adjuster.
  • the osmotic pressure ratio (ratio to the osmotic pressure of 0.9% by weight physiological saline) of the eye drop of the present invention is usually 0.6 to 1.6.
  • the osmotic pressure ratio of the eye drop can be adjusted with the above-mentioned tonicity agent.
  • Such an eye drop of the present invention is an eye drop containing particles composed of a prodrug that undergoes a hydrolysis reaction and changes from hydrophobic or fat-soluble to hydrophilic or water-soluble, and the prodrug is as described above. Since it has properties and the particle size of the particles is in a specific range, it is excellent in intraocular transferability.
  • prodrugs are effectively transferred to the cornea, conjunctiva, anterior aqueous humor, ciliary body, lens, choroid, sclera, and retina.
  • the prodrug constituting the particle is hydrophobic or lipophilic, it has excellent affinity with the corneal epithelium, and when the eye drop of the present invention is instilled, the prodrug penetrates into the corneal epithelium.
  • a hydrolase such as an esterase enzyme group exists in the corneal epithelium, and the prodrug is hydrolyzed and changed to hydrophilic or water-soluble by the action of the hydrolase.
  • the next site to break through the corneal epithelium for the prodrug to enter the eye is the corneal stroma, which is hydrophilic.
  • prodrug B hydrolyzed prodrug
  • the prodrug B penetrates into the corneal stroma. After breaking through the corneal stroma, prodrug B moves into the eyeball and moves not only to the anterior segment but also to the posterior segment, ie, the anterior aqueous humor, ciliary body, crystalline lens, choroid, and retina. it is conceivable that.
  • the prodrug is considered to be delivered to the posterior segment by the route from the conjunctiva to the sclera after instillation.
  • the usage and dosage of the eye drop of the present invention are appropriately determined depending on the type of prodrug.
  • the eye drop of the present invention is excellent in intraocular transferability, neovascular macular disease (age-related macular degeneration, etc.), diabetic retinopathy, retinal artery occlusion, retinal vein occlusion, hypertensive retinopathy, central serous choroid Retinopathy, retinitis pigmentosa, acute retinitis pigmentosa, multiple disappearing white spot syndrome, retinitis pigmentosa, proliferative vitreoretinopathy, secondary retinal detachment, cancer-related retinopathy, glaucoma, metastatic choroidal tumor It can be suitably applied to diseases in which a drug needs to be administered to the posterior eye segment such as the retina for treatment.
  • neovascular macular disease age-related macular degeneration, etc.
  • diabetic retinopathy diabetic retinopathy
  • retinal artery occlusion retinal vein occlusion
  • hypertensive retinopathy central serous choroid Re
  • drugs that are hydrolyzed to treat these diseases eg, synthetic steroids, fibrinolytics, anticoagulants, platelet aggregation inhibitors, prostaglandin-related drugs, sympathetic blockers, carbonic acid Dehydrase inhibitor, sympathomimetic, parasympathomimetic, hyperosmotic, neuroprotective, vasodilator, anti-inflammatory enzyme, vitamin preparation, diuretic, calcium antagonist, anti-inflammatory, cytostatic It is preferable to select a compound obtained by esterifying, acetalizing, amidating, thioesterifying or ketalizing a drug such as a non-steroidal anti-inflammatory agent.
  • these diseases eg, synthetic steroids, fibrinolytics, anticoagulants, platelet aggregation inhibitors, prostaglandin-related drugs, sympathetic blockers, carbonic acid Dehydrase inhibitor, sympathomimetic, parasympathomimetic, hyperosmotic, neuroprotective, vasodilator, anti-inflammatory enzyme, vitamin preparation
  • the eye drop of the present invention is applied to diseases in which a drug needs to be administered to the anterior segment such as keratitis and conjunctivitis, a sufficient therapeutic effect can be obtained.
  • the eye drop of the present invention can be used not only for humans but also for the treatment of eye diseases such as monkeys, cows, horses, dogs, cats and other mammals.
  • the prodrug migrates to the posterior eye region and penetrates the entire eye.
  • the prodrug is hydrolyzed to generate fluorescence
  • the fluorescence from the eye or each part of the eye cornea, conjunctiva, anterior chamber, ciliary body, lens, vitreous body, choroid, retina, Can be observed (observed).
  • the fluorescent imaging agent of the present invention that makes it possible to observe such particles is a particle formed of a prodrug that undergoes a hydrolysis reaction to change from hydrophobic or fat-soluble to hydrophilic or water-soluble and emits fluorescence.
  • the particle size of the particles is from 10 nm to less than 1 ⁇ m, preferably from 10 nm to 500 nm, and more preferably from 10 nm to 250 nm.
  • Prodrugs satisfying the above conditions include diacetate fluorescein, 3′-O-acetyl-2 ′, 7′-bis (carboxyethyl) -4 or 5-carboxyfluorescein, diacetoxymethyl ester (BCECF-AM) and 5- or 6- (N-succinimidyloxycarbonyl) -fluorescein 3 ', 6' -diacetate (CFSE) and the like.
  • the fluorescent imaging agent is administered to the eyes of animals other than humans, the eyes are removed, the extracted eyes are separated into each part, and the part And a method of observing fluorescence emitted from the optical means.
  • the extracted eye may be observed without being separated into each part.
  • Information obtained by observation is digitized, for example, and the digitized information is output by the output means.
  • optical means examples include a spectrofluorometer.
  • the output means means for displaying the digitized information on a display two-dimensionally or three-dimensionally, means for electrically outputting the digitized information, means for printing the digitized information, Means for recording digitized information on a recording medium can be mentioned.
  • Observing may be one, plural or all of the separated parts.
  • the fluorescent imaging agent of the present invention may be administered to the eyes of animals other than humans, the eyes may be removed, the removed eyes may be separated into each part, and the part may be observed with a confocal laser microscope. Of course, one, a plurality or all of the separated parts may be observed. Further, the eyes may be observed directly without being separated into each part. At that time, the eyes may be observed without being removed or removed.
  • the fluorescent imaging agent of the present invention dissolves the prodrug by dialysis or the like from a dispersion in which the above-mentioned prodrug nanoparticles are dispersed in the solvent 2 in which the prodrug is not dissolved. Is obtained by removing the solvent 1 Alternatively, the dispersion may be obtained by mixing with an eye drop base. Even in this case, the solvent 1 is removed.
  • this nanoparticle dispersion was dialyzed using a dialysis tube to remove acetone.
  • the individual particle size (particle diameter) was 10 nm or more and 500 nm or less.
  • Example 1 One eye of a 4-week-old male rat was instilled with 10 ⁇ l of the eye drop obtained above. After 0.5 hour, the rats were killed by anesthesia, and the eyes instilled with eye drops were sufficiently washed with physiological saline and then removed and further washed with physiological saline.
  • the washed eyes were mixed with 5 ml of a mixed solution (volume ratio 1: 1) of a sodium hydroxide aqueous solution (100 mM) and a DMSO aqueous solution.
  • a mixed solution volume ratio 1: 1 of a sodium hydroxide aqueous solution (100 mM) and a DMSO aqueous solution.
  • fluorescein diacetate was present in the state of fluorescein after hydrolysis, and the eyeball was dissolved.
  • the fluorescence spectrum of the obtained sample solution was evaluated. Specifically, the fluorescence intensity when the sample solution was excited with light having a wavelength of 488 nm was measured. The results are shown in FIG.
  • the fluorescence spectrum was evaluated twice (conditions 1 and 2) while changing the measurement conditions.
  • the measurement result in the case of the condition 1 is a diagram on the left side of FIG. 2, and the measurement result in the case of the condition 2 is a diagram on the right side of FIG.
  • Condition 2 differs from condition 1 in the slit width of the excitation side slit and the fluorescence side slit of the spectrofluorophotometer. Specifically, in condition 1, the excitation side slit and the fluorescence side slit are each 5.0 nm, and in condition 2, the excitation side slit and the fluorescence side slit are each 2.5 nm.
  • Fluorescein diacetate was recrystallized from an acetone solution in which fluorescein diacetate was dissolved to obtain a powder of fluorescein diacetate. This powder was refined in an agate bowl to obtain microparticles. The microparticles were mixed with water containing sodium chloride and polyvinylpyrrolidone K30 (PVP) to obtain an eye drop. In this eye drop, the final concentration of each component was 0.05% by weight of fluorescein diacetate, 0.9% by weight of sodium chloride, and 2% by weight of PVP. The pH of the eye drop was 7.
  • the fluorescence spectrum was evaluated in the same manner as in Condition 1 of Example 1. The results are shown in FIG.
  • this dispersion was subjected to dialysis using a dialysis tube to remove dimethyl sulfoxide.
  • the resulting dispersion is mixed with water containing salt so that the final concentration of each component is 0.05% by weight for fluorescein, 0.9% by weight for salt and 2% by weight for PVP.
  • the pH of the eye drop was 7.
  • the obtained eye drop was evaluated for the fluorescence spectrum in the same manner as in Condition 2 of Example 1. The results are shown in FIG.
  • the obtained dispersion is mixed with water containing salt so that the final concentration of each component is 0.05% by weight for sodium fluorescein, 0.9% by weight for salt and 2% by weight for PVP.
  • an eye drop was obtained.
  • the pH of the eye drop was 7.
  • the obtained eye drop was evaluated for the fluorescence spectrum in the same manner as in Condition 1 of Example 1. The results are shown in FIG.
  • fluorescein diacetate nanoparticles refers to the eye drop of Example 1
  • fluorescein diacetate microparticles refers to the eye drop of Comparative Example 1
  • fluorescein refers to the eye drop of Comparative Example 2.
  • Fluorescein sodium indicates the eye drop of Comparative Example 3.
  • the washed eyes were mixed with 5 ml of a mixed solution (volume ratio 1: 1) of a sodium hydroxide aqueous solution (100 mM) and a DMSO aqueous solution.
  • a mixed solution volume ratio 1: 1 of a sodium hydroxide aqueous solution (100 mM) and a DMSO aqueous solution.
  • fluorescein diacetate was present in the state of fluorescein after hydrolysis, and the eyeball was dissolved.
  • the fluorescence spectrum of the obtained sample solution was evaluated. Specifically, the fluorescence intensity when all sample solutions were excited with light having a wavelength of 488 nm was measured. The results are shown in FIG. 3 (the left side of FIG. 3 is the evaluation result of the fluorescence spectrum, and the right side of FIG. 3 is the measurement result of the fluorescence intensity at a wavelength of 525 nm when excited with light having a wavelength of 488 nm).
  • Fluorescence spectrum evaluation was performed on the obtained sample solution. Specifically, the fluorescence intensity when all sample solutions were excited with light having a wavelength of 488 nm was measured. The results are shown in FIG.
  • fluorescein diacetate was transferred to the anterior aqueous humor, and the transferred fluorescein diacetate (which was hydrolyzed into fluorescein when transferred) contained at least the eye drops. 30 minutes after instillation, it moves to the outside of the anterior aqueous humor over time, and in the eye drop of Comparative Example 5, the eye drop does not contain fluorescein diacetate. It turns out that the fluorescence by fluorescence was detected slightly. Therefore, it can be seen that the fluorescence detected by using the eye drops of Examples 6 to 8 is not autofluorescence such as anterior aqueous humor.
  • the washed eye is cut and separated into the anterior segment and the posterior segment, the retinal tissue is removed from the posterior segment, and each sample of the anterior segment and retinal tissue is washed with an aqueous solution of sodium hydroxide (100 mM) and DMSO.
  • the mixture was mixed with 5 ml of a mixture (volume ratio 1: 1).
  • fluorescein diacetate was present in the state of fluorescein after hydrolysis, and each sample was dissolved.
  • Fluorescence spectrum evaluation was performed on the obtained sample solution. Specifically, the fluorescence intensity when all sample solutions were excited with light having a wavelength of 488 nm was measured. The results are shown in FIG. The retinal tissue was also observed with a confocal laser microscope. The result is shown in FIG.
  • the washed eye is quickly frozen and solidified, and then the eye is cut and the cornea, anterior aqueous humor, conjunctiva, sclera (posterior eye part), ciliary body, lens, vitreous body (anterior eye part), vitreous body (Rear eye part) and retina and choroid (rear eye part) were separated, and each was mixed with 5 ml of a mixed solution of sodium hydroxide aqueous solution (100 mM) and DMSO aqueous solution (volume ratio 1: 1). In this mixed solution, fluorescein diacetate was present in the state of fluorescein after hydrolysis, and each sample was dissolved.
  • the obtained sample solution cornea, the retina of the posterior eye part and the choroid were evaluated for fluorescence spectrum. The results are shown in FIG. 7 (left side). Moreover, the fluorescence intensity in wavelength 525nm was measured about the sample solution of each structure
  • FIG. 7 shows that in the eye drop of Example 10, fluorescein diacetate migrates to both the cornea and the retina and choroid of the posterior eye (when it migrates, it is hydrolyzed into fluorescein). It can be seen that the amount is greater in the cornea.
  • FIG. 7 shows that when the eye drop of the present invention is instilled, fluorescein diacetate migrates to the entire eye including the posterior segment, although there is a difference in the migration amount.
  • the washed eye is quickly frozen and solidified, and then the eye is cut to separate the cornea and the posterior eye retina and choroid, each of which is mixed with a sodium hydroxide aqueous solution (100 mM) and a DMSO aqueous solution (volume ratio). 1: 1) Mixed with 5 ml. In this mixed solution, fluorescein diacetate was present in the state of fluorescein after hydrolysis, and each sample was dissolved.
  • FIG. 10 shows that by using the fluorescent imaging agent of the present invention, the cornea structure can be observed in a tomographic fluorescence while maintaining the shape of the eyeball of the eye.
  • Dexamethasone (the solubility is 0.035 g / L, calculated by ACD / Solubility DB (manufactured by Advanced chemistry development)) is generated after hydrolysis from the dexamethasone sorbate derivative.
  • each particle size (particle diameter) was 10 nm or more and 500 nm or less.
  • An electron micrograph of the dexamethasone derivative nanoparticles is shown in FIG.
  • ⁇ Preparation of eye drops> A 2 wt% PVP aqueous solution (1 g) was added to the obtained nanoparticle dispersion (10 g), and then freeze-dried to remove ethanol to obtain a nanoparticle powder. Subsequently, the nanoparticle powder obtained by freeze-drying was mixed with 1 g of water containing sodium chloride, and the nanoparticle powder was redispersed in water. An eye drop was obtained by adjusting the final concentration of each component to 0.2% by weight of the dexamethasone derivative, 0.9% by weight of sodium chloride, and 2% by weight of PVP.
  • the washed eyes were mixed with 500 ⁇ l of DMSO, and this solution was sonicated (60 minutes). Subsequently, this solution was passed through a syringe filter having a pore size of 0.2 ⁇ m.
  • FIG. 12 shows a chromatogram derived from a dexamethasone standard product.
  • the result (chromatogram) of Example 19 is shown in FIG. 12 (right). Also in the sample solution containing the eye instilled with the eye drop of Example 19, a peak derived from dexamethasone similar to that of the dexamethasone standard product was detected, indicating that dexamethasone was transferred into the eyeball.
  • FIG. 13 and FIG. 14 show the results of comparing nanoparticle eye drops (Example 19) and microparticle eye drops (this comparative example) with respect to dexamethasone content in the eyeball after instillation.
  • the leftmost bar graph “a” shows the result of Example 19
  • the second bar graph “b” from the left shows the result of this comparative example.
  • the dexamethasone content was expressed as the area of the spectrum obtained by HPLC measurement.
  • nanoparticle eye drops have higher intraocular mobility than microparticle eye drops. From these examples and comparative examples, it was shown that the eye drop of the present invention having enhanced intraocular transferability was effective.
  • Example 8 The dexamethasone derivative was mixed with an aqueous solution containing sodium chloride and containing 2% by weight of PVP, and an aqueous microparticle dispersion was obtained by ultrasonic treatment. In this dispersion, the final concentration of each component was 0.2% by weight of the dexamethasone derivative, 0.9% by weight of sodium chloride, and 2% by weight of PVP to obtain an eye drop.
  • the obtained eye drop (the particle size (particle diameter) of each particle in the eye drop is 1 ⁇ m or more and 100 ⁇ m or less) was instilled into a rat in the same manner as in Example 19 and evaluated by HPLC.
  • the dexamethasone content in the eyeball after instillation was estimated from the area of the spectrum obtained by HPLC measurement using a calibration curve (see FIG. 15).
  • a sufficient amount of dexamethasone that can be calibrated was not transferred into the eye.
  • intraocular transferability was observed, and the amount was 1.06 ⁇ 0.34 ⁇ g / g tissue. .
  • cornea 11 cornea 12 iris 13 ciliary body 14 sclera 15 choroid 16 retina 17 fovea 18 optic nerve 19 disc recess 20 vitreous 21 lens 22 eyeball conjunctiva 23 posterior chamber 24 anterior chamber

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Abstract

La présente invention concerne une goutte oculaire qui peut permettre une grande migration intraoculaire d’un agent médical contenu à l’intérieur de celle-ci sans qu’un vecteur tel qu’un liposome ne soit nécessaire. La présente invention concerne également un procédé de production de la goutte oculaire. La goutte oculaire est caractérisée par le fait qu’elle comprend des particules composées d’un promédicament hydrophobe ou liposoluble qui peut devenir hydrophile ou soluble dans l’eau sous l’effet d’une hydrolyse, les particules ayant une taille de particules qui supérieure ou égale à 10 nm et inférieure à 1 µm.
PCT/JP2009/068851 2008-11-06 2009-11-04 Goutte oculaire ayant de bonnes propriétés de migration intraoculaire, agent d’imagerie fluorescent, et procédé de production associé WO2010053101A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011155501A1 (fr) * 2010-06-11 2011-12-15 独立行政法人科学技術振興機構 Particules multimères pharmaceutiques et leur procédé de fabrication
WO2013161778A1 (fr) 2012-04-24 2013-10-31 国立大学法人大阪大学 Procédé de production d'une dispersion aqueuse de nanoparticules de médicament et son utilisation
JP2016132616A (ja) * 2015-01-15 2016-07-25 大内新興化学工業株式会社 眼疾患治療用ナノ粒子製剤
CN110461311A (zh) * 2016-08-26 2019-11-15 奥野哲治 微细纳米化药剂及其应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10215894A (ja) * 1997-02-06 1998-08-18 Mitsubishi Chem Corp 生細胞の検出方法
JP2004528267A (ja) * 2000-07-13 2004-09-16 ファルマシア・アンド・アップジョン・カンパニー 選択的シクロオキシゲナーゼ−２阻害性薬物の眼処方
JP2004530458A (ja) * 2001-01-24 2004-10-07 ヴィクター ジェイ． ドハーティ， 携帯型眼用イルミネーター
JP2005238342A (ja) * 2004-02-24 2005-09-08 Japan Science & Technology Agency 有機化合物の超微粒子の製造方法
JP2007119456A (ja) * 2005-09-30 2007-05-17 Toyama Chem Co Ltd 難溶性薬物のナノ微粒子を含有する水性懸濁液剤
JP2007518804A (ja) * 2004-01-20 2007-07-12 アラーガン、インコーポレイテッド トリアムシノロンアセトニドおよびヒアルロン酸を好ましく含有する眼局所治療用組成物
JP2008526352A (ja) * 2005-01-06 2008-07-24 ジーイー・ヘルスケア・アクスイェ・セルスカプ 光学イメージング

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000247871A (ja) * 1999-02-25 2000-09-12 Santen Pharmaceut Co Ltd 網膜または硝子体への薬物放出制御システム
JP2002138036A (ja) * 2000-08-24 2002-05-14 Santen Pharmaceut Co Ltd 薬物放出制御システム
JP4921750B2 (ja) * 2005-09-14 2012-04-25 株式会社日本点眼薬研究所 ピレノキシンまたは薬理学的に許容される塩を含有する懸濁性医薬組成物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10215894A (ja) * 1997-02-06 1998-08-18 Mitsubishi Chem Corp 生細胞の検出方法
JP2004528267A (ja) * 2000-07-13 2004-09-16 ファルマシア・アンド・アップジョン・カンパニー 選択的シクロオキシゲナーゼ−２阻害性薬物の眼処方
JP2004530458A (ja) * 2001-01-24 2004-10-07 ヴィクター ジェイ． ドハーティ， 携帯型眼用イルミネーター
JP2007518804A (ja) * 2004-01-20 2007-07-12 アラーガン、インコーポレイテッド トリアムシノロンアセトニドおよびヒアルロン酸を好ましく含有する眼局所治療用組成物
JP2005238342A (ja) * 2004-02-24 2005-09-08 Japan Science & Technology Agency 有機化合物の超微粒子の製造方法
JP2008526352A (ja) * 2005-01-06 2008-07-24 ジーイー・ヘルスケア・アクスイェ・セルスカプ 光学イメージング
JP2007119456A (ja) * 2005-09-30 2007-05-17 Toyama Chem Co Ltd 難溶性薬物のナノ微粒子を含有する水性懸濁液剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KASSEM, M.A. ET AL.: "Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 340, no. 1-2, 12 March 2007 (2007-03-12), pages 126 - 133 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011155501A1 (fr) * 2010-06-11 2011-12-15 独立行政法人科学技術振興機構 Particules multimères pharmaceutiques et leur procédé de fabrication
JP5113958B2 (ja) * 2010-06-11 2013-01-09 独立行政法人科学技術振興機構 薬剤多量体微粒子及びその製造方法
WO2013161778A1 (fr) 2012-04-24 2013-10-31 国立大学法人大阪大学 Procédé de production d'une dispersion aqueuse de nanoparticules de médicament et son utilisation
EP2842545A4 (fr) * 2012-04-24 2015-12-16 Univ Osaka Procédé de production d'une dispersion aqueuse de nanoparticules de médicament et son utilisation
JP2016132616A (ja) * 2015-01-15 2016-07-25 大内新興化学工業株式会社 眼疾患治療用ナノ粒子製剤
CN110461311A (zh) * 2016-08-26 2019-11-15 奥野哲治 微细纳米化药剂及其应用
EP3505165A4 (fr) * 2016-08-26 2020-05-20 Tetsuji Okuno Agent médicinal fin de taille nanométrique et son utilisation
US11406684B2 (en) 2016-08-26 2022-08-09 Tetsuji Okuno Fine nano-sized medicinal agent and use thereof

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