WO2009075401A1 - Manufacturing method of functional drug nanoparticles using milling and functional drug nanoparticle formulation manufactured thereby - Google Patents

Manufacturing method of functional drug nanoparticles using milling and functional drug nanoparticle formulation manufactured thereby Download PDF

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Publication number
WO2009075401A1
WO2009075401A1 PCT/KR2007/006596 KR2007006596W WO2009075401A1 WO 2009075401 A1 WO2009075401 A1 WO 2009075401A1 KR 2007006596 W KR2007006596 W KR 2007006596W WO 2009075401 A1 WO2009075401 A1 WO 2009075401A1
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Prior art keywords
drug
water soluble
nanoparticles
soluble polymer
substance
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PCT/KR2007/006596
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French (fr)
Inventor
Jonghwi Lee
Sujung Kim
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Chung-Ang University Industry-Academy Cooperation Foundation
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Publication of WO2009075401A1 publication Critical patent/WO2009075401A1/en

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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
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/52—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
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    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6939—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
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    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to a method for producing functional drug nanoparticles using milling and a surface-modified drug nanoparticle formulation produced thereby.
  • the present invention relates to a method for producing drug nanoparticles, which comprises introducing selectively a pharmaceutically functional group on a surface of a drug during producing drug nanoparticles by means of wet grinding of a drug particle by milling, and a surface-modified drug nanoparticle formulation produced thereby.
  • Prior solid oral formulations have been produced by means of a process including granulation, mixing, tabletting and the like of drug crystalline particles having a size of several microns to several hundred microns.
  • the size of the crystalline particles has been regarded as significant limitative factors in the field of a drug formulation.
  • Nanoparticles of a drug can provide a various advantages including improvement of a drug absorbance, decrease of a drug content, accelerate of a drug absorption speed, and avoid of use of a various organic solvents or extreme pH and the like. Also, nanoparticles can be used as a basic technology for producing a target-oriented functional delivering agent by binding to various drug delivering vectors. Therefore, it is possible to produce a drug has a drug taste masking property or an extended release property, and to reduce fed/fasted variability.
  • Korean Patent Laid-Open Publication No. 1999-51527 describes a method for producing itraconazole of sparingly soluble drug having improved the dissolution of drug by reducing a particle diameter and modifying a crystalline by using saccharides.
  • U.S. Patent No. 6,407,079 describes a method for producing a pharmaceutical composition comprising inclusion compounds of itraconazole with beta-cyclodextrin to improve solubility and stability of a drug.
  • 6,599,535 describes a pharmaceutical composition in the form of a solid dispersion comprising a sparingly soluble drug, i.e., rapamycin or ascomycin, and a carrier medium, wherein a water soluble polymer is used as a solid dispersant carrier to increase an elution rate of a drug.
  • Korean Patent Laid-Open Publication No. 1997-14759 describes that a biodegradable block copolymer micelle having a hydrophilic portion and a hydrophobic portion, can be used as a drug delivering vector.
  • Korean Patent Laid-Open Publication No.2006-62734 describes a method for producing a stable oral micro-emulsion composition of a sparingly soluble drug. Further, U.S.
  • Patent No. 5,145,684 describes a method for producing drug nanoparticles by dispersing a sparingly soluble drug in an aqueous solution and carrying out wet milling and the like in the presence of a surface modifier.
  • the producing methods above mentioned should use in combination with surfactant, cosolvent and the like, and thus these substances may cause a side effect.
  • these substances may be diluted in the body and be affected by a temperature, a phenomenon of drug precipitation may occur.
  • these methods are uneconomic, since these methods should use complicated processes and faculties and expensive excipients.
  • the milling process uses a surface modifier to reduce a particle size
  • the milling process has an advantage that is simple.
  • a pharmaceutical functional group such as a target-oriented group or an extended release functional group is introduced during the milling process.
  • a method for producing nanoparticles as a drug delivering agent to introduce a pharmaceutical functional group includes a method for producing polymeric nanoparticles using self-emulsion diffusion, a method for producing polymer nanoparticles using a complex reaction of ionic polymer, a method for producing nanoparticles through a micelle formation using a block copolymer having a hydrophilic and a hydrophobic group.
  • Korean Patent Laid-Open Publication No. 2001-0086811 describes a method for producing biodegradable microparticles using an emulsion-diffusion method, wherein the microparticles exhibits improved release velocity and affinity to a biologic tissue.
  • U.S. patent No. 7,229,973 describes a method for producing nanoparticles having a release control property and a target-oriented property by producing a micelle by means of block copolymer which a ligand is bonded.
  • the particles produced by complicated process using the surfactant and the like are unstable and have disadvantages reduced a drug loading capacity.
  • the present inventors have studied to solve the above-mentioned problems of the prior art. As a result, the present inventors found out that surface-modified drug nanoparticles produced by simply grinding drug particles into nanoparticles and introducing a pharmaceutically functional group on a surface of the nanoparticles to form drug nanoparticles simultaneously, exhibit an extended release property, or a target-oriented property or a drug taste masking property dependent on a pharmaceutically functional substance, thereby completing the present invention.
  • Another object of the present invention is to provide a surface- modified drug nanoparticle formulation produced by the method of the present invention.
  • the present invention provides a method for producing functional drug nanoparticles, comprising; 1) wet- grinding a water soluble dispersion containing a drug and a surface stabilizing agent mainly comprising of a water soluble polymer by milling to produce a slurry mixture! and 2) adding an aqueous solution containing a pharmaceutically functional substance to the above- mentioned step, which produces the slurry mixture to react the water soluble polymer which is the surface stabilizing agent with the pharmaceutically functional substance, thereby introducing selectively the pharmaceutically functional group on a surface of the drug.
  • the wet grinded drug in the step (1) has a particle size of 50 to 800 nm and the drug nanoparticles in the step (2) also has a particle size of 50 to 800 nm, thus the size of drug nanoparticles produced in the grinding step are maintained without an aggregation among particles even after crosslinking reaction.
  • a water soluble polymer is mainly used.
  • the water soluble polymer include lecithin, polyoxyethylene, poloxamer, polypropylene glycol, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, benzethonium chloride, benzalconium chloride, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propyl paraben, methyl paraben, polyvinyl alcohol, polyvinyl pyrrolidone, carrageenan, alginic acid, sodium alginate, water soluble chitosan, protein comprising gluconic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate, sodium dodecyl sulfate (SDS or SLS), sodium dioctyl
  • the water soluble polymers can be used alone or in the form of a mixture of at least one polymer.
  • the drug used as an active ingredient in the present invention is contained in a saturated aqueous solution of a soluble polymer in the amount of 0.1 to 60% by weight.
  • an ionic crosslinking agent which is an organic or an inorganic substance can be further mixed in the amount of 0.1 to 20% by weight based on the weight of a polymer component in the step (1), wherein the ionic agent is any one selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compound.
  • the pharmaceutically functional substance is any one from target- oriented substance to a cancer cell or a drug taste masking substance, and is reactive with a water soluble polymer substance physically or chemically.
  • the present invention provides a drug nanoparticle formulation having a target-oriented property, wherein the drug nanoparticles and a water soluble polymer are dispersed uniformly; a pharmaceutically functional substance layer is formed selectively on a surface of the drug nanoparticles by reaction of the water soluble polymer with a target- oriented substance; and the drug nanoparticles are loaded in an inner portion of the pharmaceutical functional substance layer and a pharmaceutical functional group having a target-oriented property is introduced on a surface of a drug.
  • the present invention provides a drug nanoparticle formulation having a drug taste masking property, wherein the drug nanoparticles and a water soluble polymer are dispersed uniformly; a pharmaceutically functional substance layer is formed selectively on a surface of the drug nanoparticles by reaction of the water soluble polymer with a drug taste masking substance! and the drug nanoparticles are loaded in an inner portion of the pharmaceutical functional substance layer and a pharmaceutical functional group controlling taste of a drug is introduced on a surface of a drug.
  • the drug nanoparticles and a water soluble polymer are dispersed uniformly in wet grinding process by milling.
  • the drug nanoparticles have a volume average particle size of 50 to 800 nm.
  • a surface stabilizing agent is a water soluble polymer as described in the method of production above mentioned.
  • the drug nanoparticle formulation of the present invention is in the form of a liquid or a powder produced by freeze drying, vacuum drying or evaporation drying of the liquid formulation.
  • the present invention can provide a method for producing a functional drug nanoparticle which may introduce a pharmaceutically functional group as one step process in a grinding step, thereby providing a drug nanoparticle formulation that a surface of a drug is modified, which is produced by means of the method.
  • the drug nanoparticles are maintained in a nanoparticle size without an aggregation among particles through whole production process.
  • FIG. 1 is a scheme illustrating a surface-modified drug nanoparticle formulation produced by the producing method of the present invention.
  • FIG. 2 exhibits comparison results of a particle size in respective steps of the production process of a formulation containing sparingly soluble drug nanoparticles, wherein (a) is a particle size of a drug in the grinding step, and (b) is a particle size of a drug which is crosslinked with chitosan after addition of an ion crosslinking agent.
  • FIG. 3(a) is a photograph indicating a shape of polymer before removal of a drug and
  • FIG. 3(b) is a shape of crosslinked polymer in the production process of a formulation depicted in FIG. 2.
  • FIG. 4 exhibits comparison results of a particle size in respective steps of production process of a formulation containing drug nanoparticles having a target-oriented property to a cancer cell, wherein (a) is a particle size of a drug in the grinding step, and (b) is a particle size of a drug which is crosslinked with chitosan after addition of an ion crosslinking agent, and (c) is a particle size of a drug after crosslinking reaction with a cancer cell target-oriented substance.
  • FIG. 5(a) is a shape of a polymer in the step (1) and FIG. 5(b) is a shape of crosslinked polymer in the step (3) in the production process of a formulation depicted in FIG.4.
  • FIG. 6 exhibits elution experiment results of in respective steps in the production process of a formulation having a target-oriented property to a cancer cell, wherein (a) is elution experiment results after dispersion of a drug and a chitosan in the step (1), and (b) is elution experiment results after crosslinking reaction of a cancer cell target- oriented substance to the drug in the step (3).
  • FIG. 7 exhibits results in relative to crosslinking a pharmaceutical functional group and a water soluble polymer in the production process of a formulation containing sparingly soluble drug nanoparticles.
  • FIG. 8 exhibits ultraviolet spectrometric results in relative to crosslinking of a water soluble chitosan dependent on a concentration of folic acid which is a pharmaceutical functional group in the production process of a formulation containing sparingly soluble drug nanoparticles.
  • the present invention provides a method for producing functional drug nanoparticles, comprising
  • the wet grinding process is to grind a drug into nanoparticles having a volume average particle size of 50 to 800 nm and to allow a drug and a water soluble polymer to disperse uniformly.
  • the particle size of a drug when the particle size of a drug is less than 50 nm, an aggregation among particles can occur, and when the particle size of a drug is more than 800 nm, an effect of nanoparticles and a dispersing effect of a drug particle and a water soluble polymer are reduced.
  • a water soluble polymer used as a surface stabilizing agent is adsorbed physically on a surface of a drug and to play a role as a surface stabilizing agent to prevent an aggregation of drug particles caused by a particle size reduction of a drug in the dispersion.
  • a water soluble polymer in the present invention a harmless organic substance can be used.
  • Preferable water soluble polymer includes lecithin, polyoxyethylene, poloxamer, polypropylene glycol, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, benzethonium chloride, benzalconium chloride, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propyl paraben, methyl paraben, polyvinyl alcohol, polyvinyl pyrrolidone, carrageenan, alginic acid, sodium alginate, water soluble chitosan, protein comprising gluconic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate, sodium dodecyl sulfate (SDS or SLS), sodium dioctyl sulfosuccinate, phospholipid, sorbitan, fatty acid ester(
  • the water soluble polymers can be used alone or in the form of a mixture of at least one polymer. More preferably, the water soluble polymer is water soluble chitosan, polyoxyethylene, poloxamer, polypropylene glycol and the like.
  • an ionic crosslinking agent for stabilizing a surface can be further mixed in the amount of 0.1 to 20% by weight based on the weight of a polymer component.
  • preferable ion crosslinking agent is any one selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compound.
  • a water soluble formulation containing a water soluble polymer used in the present invention can be obtained by an inexpensive and simple grinding method such as ball milling or media milling and the like.
  • a process temperature can be controlled appropriately dependent on characteristics and mechanical properties of a drug, and the grinding is carried out generally at a room temperature.
  • a grinding time can be determined broadly dependent on mechanical means and process conditions, and when ball milling which uses low shear energy is used, the grinding is carried out for 3 days or more, and when high shear energy is used, desired drug dispersion can be obtained within several minutes to several hours.
  • a solvent of the water soluble dispersion containing the water soluble polymer may be pure water or an aqueous solution or a buffer solution.
  • the step 2 of the present invention is to add an aqueous solution containing a pharmaceutically functional substance to the step 1, which produces the slurry mixture to react the water soluble polymer which is the surface stabilizing agent with the pharmaceutically functional drug, thereby introducing selectively the pharmaceutically functional group on a surface of the drug.
  • the target-oriented substance reacts with a water soluble polymer which is used as a surface stabilizing agent, as such the resulting reaction product has a target-oriented property to tissues, organs, cells and the like which a pharmacological effect was expressed.
  • a water soluble polymer which is used as a surface stabilizing agent
  • An example of the pharmaceutically functional substance may be any one selected from a cancer cell target- oriented substance or a drug taste masking substance although a target- oriented property may be varied dependent on characteristics of a drug.
  • the target-oriented substance to a cancer cell may be any one selected from the group consisting of folic acid, glycolic acid and a peptide constituted of specific amino acid such as RGD peptide (Arg- Gly-Asp).
  • the drug taste masking effect can be obtained by using any one selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compound.
  • the resulting drug nanoparticles produced in the step 2 satisfies a particle size of 50 to 800 nm, which is a particle size of wet grinded drug in the step 1, the drug nanoparticles produced according to the method of the present invention are maintained as nanoparticles without an aggregation among particles even after crosslinking reaction. Therefore, in the producing method of the present invention, nanoparticles are stabilized through whole production process.
  • the producing method of the present invention introduces a pharmaceutically functional group and then induces a crosslinking reaction to form a pharmaceutically functional layer on a surface of drug nanoparticles in a grinding process of a drug by milling, thereby forming stabilized polymer layer, which drug nanoparticles are stabilized after crosslinking reaction, and adsorption and desorption do not occur.
  • grinded particles are aggregated or, adsorbed or desorbed.
  • the producing method of the present invention is accomplished with a milling process and a chemical reaction simultaneously, therefore it is possible to provide a producing method which a pharmaceutically functional group can be introduced on a surface of a drug in one step.
  • FIG. 1 is a scheme illustrating a surface-modified drug nanoparticle formulation (1) produced by the producing method of the present invention, wherein a surface stabilizing agent (20) and a pharmaceutically functional group (30) are introduced selectively on a surface of drug nanoparticles (10).
  • a preferable first embodiment provides a drug nanoparticle formulation having a target- oriented property, wherein the drug nanoparticles and a water soluble polymer are dispersed uniformly! a pharmaceutically functional substance layer is formed selectively on a surface of the drug nanoparticles by reaction of the water soluble polymer with a target-oriented substance; and the drug nanoparticles are loaded in an inner portion of the pharmaceutically functional substance layer and a pharmaceutical functional group having a target-oriented property is introduced on a surface of a drug.
  • a preferable second embodiment provides a drug nanoparticle formulation having a drug taste masking property, wherein the drug nanoparticles and a water soluble polymer are dispersed uniformly; a pharmaceutically functional substance layer is formed selectively on a surface of the drug nanoparticles by reaction of the water soluble polymer with a drug taste masking substance; and the drug nanoparticles are loaded in an inner portion of the pharmaceutically functional substance layer and a pharmaceutical functional group controlling taste of a drug is introduced on a surface of a drug.
  • the sparingly soluble drug is an organic substance which exhibits sparing solubility in a liquid dispersion solvent such as water and an aqueous solution, wherein the liquid dispersion solvent may comprise alcohol and oil.
  • the term Sparingly soluble defines solubility of less than 10 mg/ml, preferably less than 1 mg/ml in a liquid dispersion solvent at a process temperature, for example room temperature.
  • the sparingly soluble drug may be used in the present invention are as follow: a non-steroid anti inflammatory agent including acetaminophen, acetyl salicylic acid, ibuprophen, phenbuprophen, phenoprophen, flubiprophen, indometacin, naproxen, etodolac, ketoprophen, dexibuprophen, piroxicam, aceclofenac and the like; an immunosuppressor or an atopic dermatitis treating agent including cyclosphorin, tacrolimus, rapamycin, mycophenylate, pimecrolimus and the like; a calcium channel blocker including nipedipin, nimodipin, nitrendipin, nilbodipin, pelodipin, amlodipin, isradipin and the like!
  • a non-steroid anti inflammatory agent including acetaminophen, acetyl salicylic acid, ibupro
  • an angiotensin II antagonist including valsartan, eprosartan, irbesartan, candersartan, telmisartan, olmesartan, rosartan and the like; a cholesterol synthesis controlling type hyperlipidemia treating agent including atorvastatin, lovastatin, simvastatin, fluvastatin, rosuvastatin, pravastatin and the like; a cholesterol secretion stimulating type hyperlipidemia treating agent including gemfibrozil, fenofibrate, etofibrate, bezafibrate and the like; a diabetes treating agent including pioglitazone, rosiglitazone, metformin and the like; a lipase inhibitor including orlistat and the like!
  • an anti fungal agent including itraconazol, amphotericin B, terbinafine, naistatin, griseofulvin, fluconazol, ketoconazol and the like; a liver protecting agent including biphenyl dimethyl dicarboxylate, silimarin, urusodeoxycholinic acid and the like; a digestive system disorder treating agent including sofalcone, omeprazole, pantoprazole, pamotidine, itopride, mesalazine and the like; a platelet aggregation inhibitor including cilostazole, clopidogrel and the like; an osteoporosis treating agent including raloxifene and the like; an anti viral agent including acyclovir, famcyclovir, lamivudine, oseltamivir and the like; antibiotics including clarithromycin, ciprofloxacin, cefuroxime and the like; an asthma treating agent or an anti histamine agent including pranr
  • the sparingly soluble drug used as an active ingredient in the present invention may be comprised in a saturated aqueous solution containing 0.1 to 60% by weight, preferably 2 to 40% by weight of a water soluble polymer.
  • the drug has a particle size of 50 to 800 nm, which is processed into nanoparticles in wet grinding process by milling and are dispersed uniformly with a water soluble polymer.
  • the drug nanoparticles are produced by the producing method of the present invention.
  • FIG. 2 exhibits comparison results of a particle size in respective steps of the production process of a formulation containing sparingly soluble drug nanoparticles. As shown in FIG. 2, there is no significant change between the drug particle size of a grinding step and the drug particle size after binding with chitosan. Rather, it is possible to find that a particle size was increased by crosslinking reaction. Also, FIG.
  • FIG. 3 exhibits a shape of polymer before removal of a drug and a shape of crosslinked polymer in the production process of the present invention. As shown in FIG. 3, a polymer was not resolved and was maintained as a state of water soluble gel even after removal of a sparingly soluble drug. Therefore, it is possible to find that rigid crosslinking layers were introduced successfully. These layers can prevent a release of a drug and control a taste of a drug.
  • FIG. 4 and FIG. 5 exhibit respectively comparison results of a particle size and a shape in respective steps of production process of a formulation containing drug nanoparticles having target-oriented property to cancer cell. As shown in these results, a particle size of a drug was maintained through whole production process of the present invention. Therefore, it is possible to find that in the producing method of the present invention, although a drug is nanoparticlized in a grinding step, the nanoparticles are maintained without an aggregation among particles even when further subsequent chemical processes are carried out.
  • the water soluble polymer is same as described in the producing method above mentioned, preferably any one selected from the group consisting of water soluble chitosan, surface-treated or untreated cyclodextrin, protein comprising glycolic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate and polyethylene glycol.
  • water soluble chitosan, cyclodextrin, pluronic F127 and protein comprising glucoic [glutamic] acid or phenylalanine was used as a preferable water soluble polymer.
  • a aqueous solution comprising the water soluble polymer and a pharmaceutically functional substance is mixed and reacted with stirring at ambient temperature for several minutes to 3 days to form a pharmaceutically functional layer, thereby providing drug nanoparticles which a pharmaceutically functional group was introduced on a surface of particles.
  • the drug nanoparticle formulation of the present invention can exhibit an extended release property of a drug, since the drug nanoparticles was crosslinked on a surface of a drug to form a pharmaceutically functional layer. See FIG. 6.
  • examples of the present invention used folic acid which is known as a substance having anti cancer cell target-oriented property, but glycolic acid, a peptide constituted of specific amino acid such as RGD peptide and the like can be used.
  • a drug taste masking substance may be any one selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compound.
  • Step (1) 0.05 g of a water soluble chitosan and 6.85 g of distilled water were added to 0.6 g of naproxen which is a sparingly soluble drug, and the resulting mixture was wet grinded by ball milling at a room temperature for 5 days to produce a slurry mixture containing naproxen.
  • Step (2) 100 g of tripolyphosphate (hereinafter, it refers to TPP) solution of 0.2% by weight with stirring was added dropwise to the slurry mixture produced as described above, and was reacted at a room temperature for 1 hour with stirring to produce a liquid formulation.
  • TPP tripolyphosphate
  • Step (1) 0.05 g of water soluble chitosan and 7.15 g of distilled water were added to 0.3 g of paclitaxel which is an anti cancer drug, and the resulting mixture was wet grinded by high-speed milling at a room temperature for 2 hours to produce a slurry mixture containing 0.6% by weight of chitosan.
  • Step (2) to crosslink the chitosan, 50 g of TPP solution which is an ionic crosslinking agent of 0.02% by weight with stirring was added dropwise to the slurry mixture produced in the step (1), and reacted at a room temperature for 1 hour with stirring to produce a liquid formulation.
  • Step (3) a folic acid which is known substance having a target- oriented property to a liver cancer cell and N-3-dimethylaminopropyl- N'-ethylcarbodiimide hydrochloride (hereinafter, it refers to EDC) were mixed at a molar ratio of 1:1, and dissolved in a buffer solution of pH 9. In this case, a concentration of the folic acid was 0.25% by weight.
  • the slurry mixture produced in the step (2) was added dropwise to a buffer solution containing a folic acid and was reacted with stirring at a room temperature for 20 hours to produce a liquid formulation. After completion of the reaction, a presence of a folic acid was identified by means of NMR (the result was not shown).
  • Example 3 Production of formulation containing drug nanoparticles having a target-oriented property to a cancer cell This example was carried out in same manner as described in the example 2, except that, when the folic acid and EDC were mixed in a molar ratio of 1:1 and dissolved in a buffer solution having pH 9 of the step (3) of the example 2, 7.5 g of 1.33% by weight chitosan solution was added to a buffer solution containing a folic acid (wherein the concentration of the folic acid was changed to 0.125% by weight, 0.25% by weight and 0.5% by weight respectively), and was reacted with stirring at a room temperature for 20 hours.
  • Example 4 Production of formulation containing drug nanoparticles having a target-oriented property to a cancer cell This example was carried out in same manner as described in the example 2, except that, in place of the composition of the step (1) of the example 2, a slurry mixture containing 0.03% by weight of chitosan, which was produced by adding 0.025 g of chitosan and 7.175 g of distilled water to 0.3 g of paclitaxel and a slurry mixture containing 0.16% by weight of chitosan, which was produced by adding 0.0125 g of chitosan and 7.1875 g of distilled water to 0.3 g of paclitaxel were used.
  • Example 5 Production of formulation containing drug nanoparticles having a target-oriented property to a cancer cell This example was carried out in same manner as described in the example 2, except that, in place of a water soluble polymer which is adsorbed on a drug, i.e., chitosan, a slurry mixture was produced by adding 0.025 g of protein comprising glucoic acid (G-protein), 0.025 g of protein containing phenylalanine (F-protein) and 7.15 g of distilled water to 0.3 g of paclitaxel, and was wet grinded at a room temperature for 5 days to form a slurry mixture.
  • G-protein glucoic acid
  • F-protein protein containing phenylalanine
  • Example 6 Production of formulation containing drug nanoparticles This example was carried out in same manner as described in the example 2, except that, in place of a folic acid which is known substance having a target-oriented property to a liver cancer cell, alpha-lipoic acid K salt (ALA-K salt) having a mucoadhesive property was used as a functional target substance.
  • alpha-lipoic acid K salt ALA-K salt
  • Example 7 Production of formulation containing drug nanoparticles Step (1): To 0.3 g of paclitaxel was added 0.05 g of pluronic F127 as a water soluble polymer for stabilizing a surface and 7.15 g of a distilled water, and was wet grinded at a room temperature for 5 days to produce a slurry mixture.
  • Step (2) 0.01 g of a modified cyclodextrin which a folic acid was attached on a surface of cyclodextrin (folic acid-PEG-cyclodextrin) was dissolved in 1 g of distilled water, and then the resulting solution was added dropwise into the slurry mixture. During a milling process, a stirring reaction was carried out at a room temperature for 20 hours. A particle size of sufficiently grinded paclitaxel particles and a volume average particle size of paclitaxel after a crosslinking reaction with cyclodextrin were 440 nm and 450 nm respectively, and no change of a particle size was identified by means of light diffraction method.
  • a particle size of the slurry mixture produced in the each step of the example 1 was determined with laser diffraction particle size analyzer (Model LA 910, Horiba Co., Ltd., Japan) which a relative refraction index was set 1 in an aqueous condition during the production process.
  • a resolution power of the supersonic homogenizer is 40 W (39 KHz)
  • its stirring speed and circulation speed was 340 ml/min.
  • the determination of a particle size was carried out after a supersonic homogenization for 1 minute, and the results were shown in FIG. 2.
  • the particle size of naproxen in the step (1) was 0.25 ⁇ m and the particle size after a crosslinking reaction was 0.45 ⁇ m. Therefore, in the production of a formulation containing drug nanoparticles of the present invention, a drug was observed as nanoparticles in the wet grinding process by means of milling and the like, and the particle size of the nanoparticles was maintained without significant change even after crosslinking reaction process. 2. Determination of a particle surface in a production process
  • Naproxen particles were dissolved and then removed from the formulation containing naproxen nanoparticles prepared in the step (2) of the example 1.
  • Polymer shapes before and after a removal of a drug were observed by means of TEM (transmission electron microscopy, Rigaku D/Max-2500/PC X-ray diffractometer. Cu-Ka 0.154 nm, 40 kV, 40 mA) image.
  • FIG. 3 (a) exhibits a polymer shape in the liquid formulation of the step (2) of the example 1 before a removal of naproxen particles, and (b) exhibits a crosslinked polymer shape after a removal of naproxen particles.
  • a water soluble chitosan and TPP which was used as an ionic crosslinking agent formed stable crosslinking bond, and the crosslinking bond was maintained independent on a removal of naproxen particles.
  • the pharmaceutically functional substance layer was maintained as a water soluble gel state even in TEM determination after several purification steps when naproxen particles were dissolved and removed.
  • the method of. producing a formulation containing drug nanoparticles of the present invention could maintain a drug to nanoparticles and achieve a stabilization of nanoparticles. Further, it was possible to observe that a crosslinking bond between a water soluble chitosan and an ionic crosslinking agent was formed stably, even when ethanol, methanol or propanol was used as a solvent in addition to the solvent used in the example l(the result was not shown).
  • FIG. 4 exhibits comparison results of a particle size in respective steps of production process of a formulation containing drug nanoparticles having target-oriented property to a cancer cell, wherein the particle size of paclitaxel in the step (1) was 0.40 ⁇ m and the particle sizes in the step (2) and the step (3) were 0.37 ⁇ m and 0.44 ⁇ m respectively. As shown in the results of FIG.
  • the particle size of nanoparticles was maintained without a significant change even when a water soluble chitosan was crosslinked with an ionic crosslinking agent and was further reacted with a folic acid having a target-oriented property to a liver cancer cell. Therefore, in the production of a formulation containing drug nanoparticles of the present invention, a drug was nanoparticlized, and the particle size of the nanoparticles was maintained without an aggregation phenomenon even after further a subsequent process. 2. Determination of a particle surface in a production process
  • a particle shape of paclitaxel was observed by means of TEM image in the step (1) and (3) of the example 2.
  • the present inventors compared the elution velocity of a slurry mixture of drug nanoparticles produced in the step (1) of the example 2 with the elution velocity of a slurry mixture of drug nanoparticles in the step (3) of the example 2.
  • a dialysis membrane containing a slurry mixture containing 10 mg of paclitaxel was introduced into 500 ml of PBS solution of pH 7.4 and was stirred at 37.5 ° C and 100 rpm. 5 ml of PBS solution was removed and 5 ml of fresh PBS solution was introduced at a predetermined time.
  • a concentration of paclitaxel was determined by means of HPLC, and the results were shown in FIG. 6.
  • the paclitaxel drug of the step (3) which a chitosan was adsorbed was eluted more slowly than the non- crosslinked paclitaxel drug in the step (1). Accordingly, it was possible to obtain a drug taste masking effect and a stabilizing effect via such crosslinking.
  • Step (2) 0.43 ( ⁇ 0. 13) 0.46 ( ⁇ 0 .16)
  • Step (3) 0.45 ( ⁇ 0. 11) 0.41 ( ⁇ 0 .12)
  • a particle size of paclitaxel produced after a reaction with a folic acid was maintained with a significant change independent on an amount of a chitosan.
  • a particle size of drug nanoparticles of the present invention was maintained constantly during the whole production process independent on a process which a water soluble chitosan was adsorbed on a surface of a drug and a process which the water soluble chitosan was crosslinked with a folic acid of a functional substance. Namely, if a drug is nanoparticlized by means of a simple milling, a nanoparticle size of the drug was maintained during subsequent processes.
  • the present invention could implement stabilization of nanoparticles.
  • the present invention can provide a economical method of production, since, in the method of the present invention, a pharmaceutical functional group is introduced on a surface of a drug by providing a method of production which a pharmaceutical functional group can be introduced on a surface of a drug with a simple and an inexpensive milling technique in a grinding step.
  • the present invention can provide a method of stabilizing nanoparticles, since, in the present invention, a particle size of the nanoparticles produced in a grinding step was maintained constantly without an aggregation among particles during the whole production process. As a result, the range of utilization of drug nanoparticles can be expanded.
  • the invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.

Abstract

The present invention relates to a method for producing functional drug nanoparticles and a surface -modified drug nanoparticle formulation produced thereby. The producing method of the present invention comprises wet-grinding a water soluble dispersion containing a drug and surface stabilizing agent comprising of a water soluble polymer by milling to produce a slurry mixture; and adding an aqueous solution containing a pharmaceutically functional substance in the above-mentioned step, which produces to react the water soluble polymer and the pharmaceutically functional substance, thereby introducing selectively the pharmaceutically functional group on a surface of the drug. The particle surface-modified drug nanoparticle formulation produced by the method has an extended releasing property and a target-oriented property, and may control a taste of a drug. Also, the drug nanoparticles are maintained in a nanoparticle size without an aggregation among particles through whole production process.

Description

[DESCRIPTION] [Invention Title]
MANUFACTURING METHOD OF FUNCTIONAL DRUG NANOPARTICLES USING MILLING AND FUNCTIONAL DRUG NANOPARTICLE FORMULATION MANUFACTURED THEREBY
[Technical Field]
The present invention relates to a method for producing functional drug nanoparticles using milling and a surface-modified drug nanoparticle formulation produced thereby. Specifically, the present invention relates to a method for producing drug nanoparticles, which comprises introducing selectively a pharmaceutically functional group on a surface of a drug during producing drug nanoparticles by means of wet grinding of a drug particle by milling, and a surface-modified drug nanoparticle formulation produced thereby. [Background Art]
Prior solid oral formulations have been produced by means of a process including granulation, mixing, tabletting and the like of drug crystalline particles having a size of several microns to several hundred microns. However, the size of the crystalline particles has been regarded as significant limitative factors in the field of a drug formulation.
Therefore, the study results have been reported that a resolution velocity of a drug has been increased significantly and thus a bioavailability of a sparingly soluble drug has been also increased significantly by developing methods which can process a size of drug particles to the nanometer level.
Nanoparticles of a drug can provide a various advantages including improvement of a drug absorbance, decrease of a drug content, accelerate of a drug absorption speed, and avoid of use of a various organic solvents or extreme pH and the like. Also, nanoparticles can be used as a basic technology for producing a target-oriented functional delivering agent by binding to various drug delivering vectors. Therefore, it is possible to produce a drug has a drug taste masking property or an extended release property, and to reduce fed/fasted variability.
Various methods have been suggested for increasing solubility of a sparingly soluble drug. For example, Korean Patent Laid-Open Publication No. 1999-51527 describes a method for producing itraconazole of sparingly soluble drug having improved the dissolution of drug by reducing a particle diameter and modifying a crystalline by using saccharides. U.S. Patent No. 6,407,079 describes a method for producing a pharmaceutical composition comprising inclusion compounds of itraconazole with beta-cyclodextrin to improve solubility and stability of a drug. Also, U.S. patent No. 6,599,535 describes a pharmaceutical composition in the form of a solid dispersion comprising a sparingly soluble drug, i.e., rapamycin or ascomycin, and a carrier medium, wherein a water soluble polymer is used as a solid dispersant carrier to increase an elution rate of a drug. Korean Patent Laid-Open Publication No. 1997-14759 describes that a biodegradable block copolymer micelle having a hydrophilic portion and a hydrophobic portion, can be used as a drug delivering vector. And, Korean Patent Laid-Open Publication No.2006-62734 describes a method for producing a stable oral micro-emulsion composition of a sparingly soluble drug. Further, U.S. Patent No. 5,145,684 describes a method for producing drug nanoparticles by dispersing a sparingly soluble drug in an aqueous solution and carrying out wet milling and the like in the presence of a surface modifier. However, the producing methods above mentioned should use in combination with surfactant, cosolvent and the like, and thus these substances may cause a side effect. Also, since these substances may be diluted in the body and be affected by a temperature, a phenomenon of drug precipitation may occur. Finally, these methods are uneconomic, since these methods should use complicated processes and faculties and expensive excipients.
Although the milling process uses a surface modifier to reduce a particle size, the milling process has an advantage that is simple. However, it has not been reported yet that a pharmaceutical functional group such as a target-oriented group or an extended release functional group is introduced during the milling process.
A method for producing nanoparticles as a drug delivering agent to introduce a pharmaceutical functional group includes a method for producing polymeric nanoparticles using self-emulsion diffusion, a method for producing polymer nanoparticles using a complex reaction of ionic polymer, a method for producing nanoparticles through a micelle formation using a block copolymer having a hydrophilic and a hydrophobic group.
For example, Korean Patent Laid-Open Publication No. 2001-0086811 describes a method for producing biodegradable microparticles using an emulsion-diffusion method, wherein the microparticles exhibits improved release velocity and affinity to a biologic tissue. Also, U.S. patent No. 7,229,973 describes a method for producing nanoparticles having a release control property and a target-oriented property by producing a micelle by means of block copolymer which a ligand is bonded. However, the particles produced by complicated process using the surfactant and the like are unstable and have disadvantages reduced a drug loading capacity.
The present inventors have studied to solve the above-mentioned problems of the prior art. As a result, the present inventors found out that surface-modified drug nanoparticles produced by simply grinding drug particles into nanoparticles and introducing a pharmaceutically functional group on a surface of the nanoparticles to form drug nanoparticles simultaneously, exhibit an extended release property, or a target-oriented property or a drug taste masking property dependent on a pharmaceutically functional substance, thereby completing the present invention. [Disclosure] [Technical Problem] Accordingly, it is an object of the present invention to provide a method for producing drug nanoparticles, which comprises introducing selectively a pharmaceutically functional group on a surface of a drug during producing drug nanoparticles by means of wet grinding of a drug particle by milling.
Another object of the present invention is to provide a surface- modified drug nanoparticle formulation produced by the method of the present invention.
[Technical Solution]
To achieve the above objects, the present invention provides a method for producing functional drug nanoparticles, comprising; 1) wet- grinding a water soluble dispersion containing a drug and a surface stabilizing agent mainly comprising of a water soluble polymer by milling to produce a slurry mixture! and 2) adding an aqueous solution containing a pharmaceutically functional substance to the above- mentioned step, which produces the slurry mixture to react the water soluble polymer which is the surface stabilizing agent with the pharmaceutically functional substance, thereby introducing selectively the pharmaceutically functional group on a surface of the drug. Since the wet grinded drug in the step (1) has a particle size of 50 to 800 nm and the drug nanoparticles in the step (2) also has a particle size of 50 to 800 nm, thus the size of drug nanoparticles produced in the grinding step are maintained without an aggregation among particles even after crosslinking reaction.
As surface stabilizing agent used in the present invention, a water soluble polymer is mainly used. Representative examples of the water soluble polymer include lecithin, polyoxyethylene, poloxamer, polypropylene glycol, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, benzethonium chloride, benzalconium chloride, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propyl paraben, methyl paraben, polyvinyl alcohol, polyvinyl pyrrolidone, carrageenan, alginic acid, sodium alginate, water soluble chitosan, protein comprising gluconic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate, sodium dodecyl sulfate (SDS or SLS), sodium dioctyl sulfosuccinate, phospholipid, sorbitan, fatty acid ester(for example, Tween), potassium sorbate and a combination thereof. The water soluble polymers can be used alone or in the form of a mixture of at least one polymer. The drug used as an active ingredient in the present invention is contained in a saturated aqueous solution of a soluble polymer in the amount of 0.1 to 60% by weight.
Also, an ionic crosslinking agent which is an organic or an inorganic substance can be further mixed in the amount of 0.1 to 20% by weight based on the weight of a polymer component in the step (1), wherein the ionic agent is any one selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compound. The pharmaceutically functional substance is any one from target- oriented substance to a cancer cell or a drug taste masking substance, and is reactive with a water soluble polymer substance physically or chemically.
The present invention provides a drug nanoparticle formulation having a target-oriented property, wherein the drug nanoparticles and a water soluble polymer are dispersed uniformly; a pharmaceutically functional substance layer is formed selectively on a surface of the drug nanoparticles by reaction of the water soluble polymer with a target- oriented substance; and the drug nanoparticles are loaded in an inner portion of the pharmaceutical functional substance layer and a pharmaceutical functional group having a target-oriented property is introduced on a surface of a drug.
Also, the present invention provides a drug nanoparticle formulation having a drug taste masking property, wherein the drug nanoparticles and a water soluble polymer are dispersed uniformly; a pharmaceutically functional substance layer is formed selectively on a surface of the drug nanoparticles by reaction of the water soluble polymer with a drug taste masking substance! and the drug nanoparticles are loaded in an inner portion of the pharmaceutical functional substance layer and a pharmaceutical functional group controlling taste of a drug is introduced on a surface of a drug. In the drug nanoparticle formulation of the present invention, the drug nanoparticles and a water soluble polymer are dispersed uniformly in wet grinding process by milling.
In the drug nanoparticle formulation of the present invention, the drug nanoparticles have a volume average particle size of 50 to 800 nm. In the drug nanoparticle formulation of the present invention, a surface stabilizing agent is a water soluble polymer as described in the method of production above mentioned.
Also, the drug nanoparticle formulation of the present invention is in the form of a liquid or a powder produced by freeze drying, vacuum drying or evaporation drying of the liquid formulation.
[Advantageous Effects]
The present invention can provide a method for producing a functional drug nanoparticle which may introduce a pharmaceutically functional group as one step process in a grinding step, thereby providing a drug nanoparticle formulation that a surface of a drug is modified, which is produced by means of the method.
In the method of the present invention, the drug nanoparticles are maintained in a nanoparticle size without an aggregation among particles through whole production process. [Description of Drawings]
FIG. 1 is a scheme illustrating a surface-modified drug nanoparticle formulation produced by the producing method of the present invention. FIG. 2 exhibits comparison results of a particle size in respective steps of the production process of a formulation containing sparingly soluble drug nanoparticles, wherein (a) is a particle size of a drug in the grinding step, and (b) is a particle size of a drug which is crosslinked with chitosan after addition of an ion crosslinking agent. FIG. 3(a) is a photograph indicating a shape of polymer before removal of a drug and FIG. 3(b) is a shape of crosslinked polymer in the production process of a formulation depicted in FIG. 2.
FIG. 4 exhibits comparison results of a particle size in respective steps of production process of a formulation containing drug nanoparticles having a target-oriented property to a cancer cell, wherein (a) is a particle size of a drug in the grinding step, and (b) is a particle size of a drug which is crosslinked with chitosan after addition of an ion crosslinking agent, and (c) is a particle size of a drug after crosslinking reaction with a cancer cell target-oriented substance. FIG. 5(a) is a shape of a polymer in the step (1) and FIG. 5(b) is a shape of crosslinked polymer in the step (3) in the production process of a formulation depicted in FIG.4.
FIG. 6 exhibits elution experiment results of in respective steps in the production process of a formulation having a target-oriented property to a cancer cell, wherein (a) is elution experiment results after dispersion of a drug and a chitosan in the step (1), and (b) is elution experiment results after crosslinking reaction of a cancer cell target- oriented substance to the drug in the step (3).
FIG. 7 exhibits results in relative to crosslinking a pharmaceutical functional group and a water soluble polymer in the production process of a formulation containing sparingly soluble drug nanoparticles. FIG. 8 exhibits ultraviolet spectrometric results in relative to crosslinking of a water soluble chitosan dependent on a concentration of folic acid which is a pharmaceutical functional group in the production process of a formulation containing sparingly soluble drug nanoparticles. [Best Mode]
The present invention is described in detail.
The present invention provides a method for producing functional drug nanoparticles, comprising
1) wet-grinding a water soluble dispersion containing a drug and a surface stabilizing agent comprising of a water soluble polymer by milling to produce a slurry mixture; and
2) adding an aqueous solution containing a pharmaceutically functional substance to the above-mentioned step, which produces the slurry mixture to react the water soluble polymer which is the surface stabilizing agent with the pharmaceutically functional substance, thereby introducing selectively the pharmaceutically functional group on a surface of the drug.
In the step 1 of the present invention, the wet grinding process is to grind a drug into nanoparticles having a volume average particle size of 50 to 800 nm and to allow a drug and a water soluble polymer to disperse uniformly.
In this case, when the particle size of a drug is less than 50 nm, an aggregation among particles can occur, and when the particle size of a drug is more than 800 nm, an effect of nanoparticles and a dispersing effect of a drug particle and a water soluble polymer are reduced.
A water soluble polymer used as a surface stabilizing agent is adsorbed physically on a surface of a drug and to play a role as a surface stabilizing agent to prevent an aggregation of drug particles caused by a particle size reduction of a drug in the dispersion. As a water soluble polymer in the present invention, a harmless organic substance can be used. Preferable water soluble polymer includes lecithin, polyoxyethylene, poloxamer, polypropylene glycol, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, benzethonium chloride, benzalconium chloride, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propyl paraben, methyl paraben, polyvinyl alcohol, polyvinyl pyrrolidone, carrageenan, alginic acid, sodium alginate, water soluble chitosan, protein comprising gluconic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate, sodium dodecyl sulfate (SDS or SLS), sodium dioctyl sulfosuccinate, phospholipid, sorbitan, fatty acid ester(Tween), potassium sorbate and a combination thereof. The water soluble polymers can be used alone or in the form of a mixture of at least one polymer. More preferably, the water soluble polymer is water soluble chitosan, polyoxyethylene, poloxamer, polypropylene glycol and the like.
Also, an ionic crosslinking agent for stabilizing a surface can be further mixed in the amount of 0.1 to 20% by weight based on the weight of a polymer component. In this case, preferable ion crosslinking agent is any one selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compound.
A water soluble formulation containing a water soluble polymer used in the present invention can be obtained by an inexpensive and simple grinding method such as ball milling or media milling and the like. A process temperature can be controlled appropriately dependent on characteristics and mechanical properties of a drug, and the grinding is carried out generally at a room temperature. A grinding time can be determined broadly dependent on mechanical means and process conditions, and when ball milling which uses low shear energy is used, the grinding is carried out for 3 days or more, and when high shear energy is used, desired drug dispersion can be obtained within several minutes to several hours. In this case, a solvent of the water soluble dispersion containing the water soluble polymer may be pure water or an aqueous solution or a buffer solution.
The step 2 of the present invention is to add an aqueous solution containing a pharmaceutically functional substance to the step 1, which produces the slurry mixture to react the water soluble polymer which is the surface stabilizing agent with the pharmaceutically functional drug, thereby introducing selectively the pharmaceutically functional group on a surface of the drug.
When the pharmaceutically functional substance is a target-oriented substance, the target-oriented substance reacts with a water soluble polymer which is used as a surface stabilizing agent, as such the resulting reaction product has a target-oriented property to tissues, organs, cells and the like which a pharmacological effect was expressed. An example of the pharmaceutically functional substance may be any one selected from a cancer cell target- oriented substance or a drug taste masking substance although a target- oriented property may be varied dependent on characteristics of a drug.
The target-oriented substance to a cancer cell may be any one selected from the group consisting of folic acid, glycolic acid and a peptide constituted of specific amino acid such as RGD peptide (Arg- Gly-Asp). Also, the drug taste masking effect can be obtained by using any one selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compound.
Since the resulting drug nanoparticles produced in the step 2 satisfies a particle size of 50 to 800 nm, which is a particle size of wet grinded drug in the step 1, the drug nanoparticles produced according to the method of the present invention are maintained as nanoparticles without an aggregation among particles even after crosslinking reaction. Therefore, in the producing method of the present invention, nanoparticles are stabilized through whole production process. Therefore, the producing method of the present invention introduces a pharmaceutically functional group and then induces a crosslinking reaction to form a pharmaceutically functional layer on a surface of drug nanoparticles in a grinding process of a drug by milling, thereby forming stabilized polymer layer, which drug nanoparticles are stabilized after crosslinking reaction, and adsorption and desorption do not occur. Meanwhile, in case of prior drug particles produced according to grinding process by milling, grinded particles are aggregated or, adsorbed or desorbed. However, the producing method of the present invention is accomplished with a milling process and a chemical reaction simultaneously, therefore it is possible to provide a producing method which a pharmaceutically functional group can be introduced on a surface of a drug in one step. Also, the present invention provides surface-modified nanoparticles produced according to the producing method of the present invention. FIG. 1 is a scheme illustrating a surface-modified drug nanoparticle formulation (1) produced by the producing method of the present invention, wherein a surface stabilizing agent (20) and a pharmaceutically functional group (30) are introduced selectively on a surface of drug nanoparticles (10).
As a drug nanoparticle formulation of the present invention, a preferable first embodiment provides a drug nanoparticle formulation having a target- oriented property, wherein the drug nanoparticles and a water soluble polymer are dispersed uniformly! a pharmaceutically functional substance layer is formed selectively on a surface of the drug nanoparticles by reaction of the water soluble polymer with a target-oriented substance; and the drug nanoparticles are loaded in an inner portion of the pharmaceutically functional substance layer and a pharmaceutical functional group having a target-oriented property is introduced on a surface of a drug.
Also, a preferable second embodiment provides a drug nanoparticle formulation having a drug taste masking property, wherein the drug nanoparticles and a water soluble polymer are dispersed uniformly; a pharmaceutically functional substance layer is formed selectively on a surface of the drug nanoparticles by reaction of the water soluble polymer with a drug taste masking substance; and the drug nanoparticles are loaded in an inner portion of the pharmaceutically functional substance layer and a pharmaceutical functional group controlling taste of a drug is introduced on a surface of a drug. In example of the present invention, naproxen as a sparingly soluble drug and paclitaxel as an anti cancer agent are used as a drug used in the present invention, however there in no specific limitations on a sparingly soluble drug which is used as an active ingredient in the present invention. Specifically, the sparingly soluble drug is an organic substance which exhibits sparing solubility in a liquid dispersion solvent such as water and an aqueous solution, wherein the liquid dispersion solvent may comprise alcohol and oil. In this description, the term Sparingly soluble?defines solubility of less than 10 mg/ml, preferably less than 1 mg/ml in a liquid dispersion solvent at a process temperature, for example room temperature.
Specific examples of the sparingly soluble drug may be used in the present invention are as follow: a non-steroid anti inflammatory agent including acetaminophen, acetyl salicylic acid, ibuprophen, phenbuprophen, phenoprophen, flubiprophen, indometacin, naproxen, etodolac, ketoprophen, dexibuprophen, piroxicam, aceclofenac and the like; an immunosuppressor or an atopic dermatitis treating agent including cyclosphorin, tacrolimus, rapamycin, mycophenylate, pimecrolimus and the like; a calcium channel blocker including nipedipin, nimodipin, nitrendipin, nilbodipin, pelodipin, amlodipin, isradipin and the like! an angiotensin II antagonist including valsartan, eprosartan, irbesartan, candersartan, telmisartan, olmesartan, rosartan and the like; a cholesterol synthesis controlling type hyperlipidemia treating agent including atorvastatin, lovastatin, simvastatin, fluvastatin, rosuvastatin, pravastatin and the like; a cholesterol secretion stimulating type hyperlipidemia treating agent including gemfibrozil, fenofibrate, etofibrate, bezafibrate and the like; a diabetes treating agent including pioglitazone, rosiglitazone, metformin and the like; a lipase inhibitor including orlistat and the like! an anti fungal agent including itraconazol, amphotericin B, terbinafine, naistatin, griseofulvin, fluconazol, ketoconazol and the like; a liver protecting agent including biphenyl dimethyl dicarboxylate, silimarin, urusodeoxycholinic acid and the like; a digestive system disorder treating agent including sofalcone, omeprazole, pantoprazole, pamotidine, itopride, mesalazine and the like; a platelet aggregation inhibitor including cilostazole, clopidogrel and the like; an osteoporosis treating agent including raloxifene and the like; an anti viral agent including acyclovir, famcyclovir, lamivudine, oseltamivir and the like; antibiotics including clarithromycin, ciprofloxacin, cefuroxime and the like; an asthma treating agent or an anti histamine agent including pranrukast, budenoside, fexofenadine and the like; a hormone agent including testosterone, prednisolone, estrogen, cortisone, hydrocortisone, dexametasone and the like; an anti tumor agent including paclitaxel, docetaxel, paclitaxel derivatives, doxorubicin, adriamycin, daunomycin, camptothecin, etoposide, teniposide, busulfan and the like; therapeutically identical salts thereof; pharmaceutical derivatives thereof; and mixtures thereof and the like! and preferably naproxen, tacrolimus, valsartan, simvastatin, fenofibrate, itraconazole, biphenyl dimethyl dicarboxylate, silimarin, sofalcone, fantoprazole, silostazole, salts thereof, pharmaceutical derivatives thereof, and mixtures thereof and the like. The sparingly soluble drug used as an active ingredient in the present invention may be comprised in a saturated aqueous solution containing 0.1 to 60% by weight, preferably 2 to 40% by weight of a water soluble polymer.
The drug has a particle size of 50 to 800 nm, which is processed into nanoparticles in wet grinding process by milling and are dispersed uniformly with a water soluble polymer. The drug nanoparticles are produced by the producing method of the present invention. FIG. 2 exhibits comparison results of a particle size in respective steps of the production process of a formulation containing sparingly soluble drug nanoparticles. As shown in FIG. 2, there is no significant change between the drug particle size of a grinding step and the drug particle size after binding with chitosan. Rather, it is possible to find that a particle size was increased by crosslinking reaction. Also, FIG. 3 exhibits a shape of polymer before removal of a drug and a shape of crosslinked polymer in the production process of the present invention. As shown in FIG. 3, a polymer was not resolved and was maintained as a state of water soluble gel even after removal of a sparingly soluble drug. Therefore, it is possible to find that rigid crosslinking layers were introduced successfully. These layers can prevent a release of a drug and control a taste of a drug.
FIG. 4 and FIG. 5 exhibit respectively comparison results of a particle size and a shape in respective steps of production process of a formulation containing drug nanoparticles having target-oriented property to cancer cell. As shown in these results, a particle size of a drug was maintained through whole production process of the present invention. Therefore, it is possible to find that in the producing method of the present invention, although a drug is nanoparticlized in a grinding step, the nanoparticles are maintained without an aggregation among particles even when further subsequent chemical processes are carried out.
The water soluble polymer is same as described in the producing method above mentioned, preferably any one selected from the group consisting of water soluble chitosan, surface-treated or untreated cyclodextrin, protein comprising glycolic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate and polyethylene glycol. In examples of the present invention, water soluble chitosan, cyclodextrin, pluronic F127 and protein comprising glucoic [glutamic] acid or phenylalanine was used as a preferable water soluble polymer. A aqueous solution comprising the water soluble polymer and a pharmaceutically functional substance is mixed and reacted with stirring at ambient temperature for several minutes to 3 days to form a pharmaceutically functional layer, thereby providing drug nanoparticles which a pharmaceutically functional group was introduced on a surface of particles. The drug nanoparticle formulation of the present invention can exhibit an extended release property of a drug, since the drug nanoparticles was crosslinked on a surface of a drug to form a pharmaceutically functional layer. See FIG. 6. As a preferable example of a pharmaceutically functional substance, examples of the present invention used folic acid which is known as a substance having anti cancer cell target-oriented property, but glycolic acid, a peptide constituted of specific amino acid such as RGD peptide and the like can be used.
Also, a drug taste masking substance may be any one selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compound.
[Mode for Invention]
Hereinafter, the present invention will be described in detail with reference to the following examples. The following examples are set forth to assist in understanding the invention and should not, of course, be construed as specifically limiting the invention described and claimed herein.
<Example 1> Production of formulation containing drug nanoparticles
Step (1): 0.05 g of a water soluble chitosan and 6.85 g of distilled water were added to 0.6 g of naproxen which is a sparingly soluble drug, and the resulting mixture was wet grinded by ball milling at a room temperature for 5 days to produce a slurry mixture containing naproxen.
Step (2): 100 g of tripolyphosphate (hereinafter, it refers to TPP) solution of 0.2% by weight with stirring was added dropwise to the slurry mixture produced as described above, and was reacted at a room temperature for 1 hour with stirring to produce a liquid formulation. <Example 2> Production of formulation containing drug nanoparticles having a target-oriented property to a cancer cell
Step (1): 0.05 g of water soluble chitosan and 7.15 g of distilled water were added to 0.3 g of paclitaxel which is an anti cancer drug, and the resulting mixture was wet grinded by high-speed milling at a room temperature for 2 hours to produce a slurry mixture containing 0.6% by weight of chitosan.
Step (2): to crosslink the chitosan, 50 g of TPP solution which is an ionic crosslinking agent of 0.02% by weight with stirring was added dropwise to the slurry mixture produced in the step (1), and reacted at a room temperature for 1 hour with stirring to produce a liquid formulation.
Step (3): a folic acid which is known substance having a target- oriented property to a liver cancer cell and N-3-dimethylaminopropyl- N'-ethylcarbodiimide hydrochloride (hereinafter, it refers to EDC) were mixed at a molar ratio of 1:1, and dissolved in a buffer solution of pH 9. In this case, a concentration of the folic acid was 0.25% by weight. The slurry mixture produced in the step (2) was added dropwise to a buffer solution containing a folic acid and was reacted with stirring at a room temperature for 20 hours to produce a liquid formulation. After completion of the reaction, a presence of a folic acid was identified by means of NMR (the result was not shown).
<Example 3> Production of formulation containing drug nanoparticles having a target-oriented property to a cancer cell This example was carried out in same manner as described in the example 2, except that, when the folic acid and EDC were mixed in a molar ratio of 1:1 and dissolved in a buffer solution having pH 9 of the step (3) of the example 2, 7.5 g of 1.33% by weight chitosan solution was added to a buffer solution containing a folic acid (wherein the concentration of the folic acid was changed to 0.125% by weight, 0.25% by weight and 0.5% by weight respectively), and was reacted with stirring at a room temperature for 20 hours.
<Example 4> Production of formulation containing drug nanoparticles having a target-oriented property to a cancer cell This example was carried out in same manner as described in the example 2, except that, in place of the composition of the step (1) of the example 2, a slurry mixture containing 0.03% by weight of chitosan, which was produced by adding 0.025 g of chitosan and 7.175 g of distilled water to 0.3 g of paclitaxel and a slurry mixture containing 0.16% by weight of chitosan, which was produced by adding 0.0125 g of chitosan and 7.1875 g of distilled water to 0.3 g of paclitaxel were used.
<Example 5> Production of formulation containing drug nanoparticles having a target-oriented property to a cancer cell This example was carried out in same manner as described in the example 2, except that, in place of a water soluble polymer which is adsorbed on a drug, i.e., chitosan, a slurry mixture was produced by adding 0.025 g of protein comprising glucoic acid (G-protein), 0.025 g of protein containing phenylalanine (F-protein) and 7.15 g of distilled water to 0.3 g of paclitaxel, and was wet grinded at a room temperature for 5 days to form a slurry mixture.
In the drug nanoparticles having a target-oriented property produced in the example 5, a chemical bond of the proteins and the folic acid was identified in spite of a change of a water soluble polymer which was adsorbed on a drug. In this case, a drug particle size of a paclitaxel was maintained without any significant change before and after the crosslinking as shown light scattering method.
<Example 6> Production of formulation containing drug nanoparticles This example was carried out in same manner as described in the example 2, except that, in place of a folic acid which is known substance having a target-oriented property to a liver cancer cell, alpha-lipoic acid K salt (ALA-K salt) having a mucoadhesive property was used as a functional target substance.
After completion of reaction, since absorption peaks at 1700 to 1750 cm~l were observed by means of ultraviolet spectrophotometry, it was possible to identify that ALA was in the drug nanoparticles (the result was not shown), and a reduction of a particle size and an effective crosslinking of a functional target substance on a surface of a particle can be obtained by means of milling. Also, since ALA-K is an antioxidant which is in human body and has sulfide group, ALA-K is readily adsorbed to a protein constituting a mucous via the sulfide group. Therefore, the nanoparticles with which ALA-K salt having a mucoadhesive property was crosslinked can be utilized as selective enteric coating agent. <Example 7> Production of formulation containing drug nanoparticles Step (1): To 0.3 g of paclitaxel was added 0.05 g of pluronic F127 as a water soluble polymer for stabilizing a surface and 7.15 g of a distilled water, and was wet grinded at a room temperature for 5 days to produce a slurry mixture.
Step (2): 0.01 g of a modified cyclodextrin which a folic acid was attached on a surface of cyclodextrin (folic acid-PEG-cyclodextrin) was dissolved in 1 g of distilled water, and then the resulting solution was added dropwise into the slurry mixture. During a milling process, a stirring reaction was carried out at a room temperature for 20 hours. A particle size of sufficiently grinded paclitaxel particles and a volume average particle size of paclitaxel after a crosslinking reaction with cyclodextrin were 440 nm and 450 nm respectively, and no change of a particle size was identified by means of light diffraction method. Also, a crosslinking bond between pluronic Fl 27 and folic acid-PEG- cyclodextrin was identified by means of X-ray diffraction method. See FIG.7. As shown in the results of FIG. 7, when a peak was observed while a ratio of cyclodextrin to a polymer was changed to 20:12 (a), 10:12 (b) and 5:12 (c) in relative to a spectrum of cyclodextrin itself, a peak was identified in a range of 18 to 20 degree, which means a state crosslinked by cyclodextrin. Experimental Example 1>
1. Determination of a particle size change in a production process A particle size of the slurry mixture produced in the each step of the example 1 was determined with laser diffraction particle size analyzer (Model LA 910, Horiba Co., Ltd., Japan) which a relative refraction index was set 1 in an aqueous condition during the production process. On determining the particle size, a resolution power of the supersonic homogenizer is 40 W (39 KHz), its stirring speed and circulation speed was 340 ml/min. In this case, the determination of a particle size was carried out after a supersonic homogenization for 1 minute, and the results were shown in FIG. 2.
As shown in the results of FIG. 2, the particle size of naproxen in the step (1) was 0.25 μm and the particle size after a crosslinking reaction was 0.45 μm. Therefore, in the production of a formulation containing drug nanoparticles of the present invention, a drug was observed as nanoparticles in the wet grinding process by means of milling and the like, and the particle size of the nanoparticles was maintained without significant change even after crosslinking reaction process. 2. Determination of a particle surface in a production process
Naproxen particles were dissolved and then removed from the formulation containing naproxen nanoparticles prepared in the step (2) of the example 1. Polymer shapes before and after a removal of a drug were observed by means of TEM (transmission electron microscopy, Rigaku D/Max-2500/PC X-ray diffractometer. Cu-Ka 0.154 nm, 40 kV, 40 mA) image.
In FIG. 3, (a) exhibits a polymer shape in the liquid formulation of the step (2) of the example 1 before a removal of naproxen particles, and (b) exhibits a crosslinked polymer shape after a removal of naproxen particles. As shown in the results, a water soluble chitosan and TPP which was used as an ionic crosslinking agent formed stable crosslinking bond, and the crosslinking bond was maintained independent on a removal of naproxen particles. The pharmaceutically functional substance layer was maintained as a water soluble gel state even in TEM determination after several purification steps when naproxen particles were dissolved and removed.
Accordingly, the method of. producing a formulation containing drug nanoparticles of the present invention could maintain a drug to nanoparticles and achieve a stabilization of nanoparticles. Further, it was possible to observe that a crosslinking bond between a water soluble chitosan and an ionic crosslinking agent was formed stably, even when ethanol, methanol or propanol was used as a solvent in addition to the solvent used in the example l(the result was not shown). Experimental Example 2>
1. Determination of a particle size change in a production process A particle size of the slurry mixture produced in the each step of the example 2 was determined with laser diffraction particle size analyzer (Model LA 910, Horiba Co., Ltd., Japan) which a relative refraction index was set 1 in an aqueous condition during the production process. FIG. 4 exhibits comparison results of a particle size in respective steps of production process of a formulation containing drug nanoparticles having target-oriented property to a cancer cell, wherein the particle size of paclitaxel in the step (1) was 0.40 μm and the particle sizes in the step (2) and the step (3) were 0.37 μm and 0.44 μm respectively. As shown in the results of FIG. 4, the particle size of nanoparticles was maintained without a significant change even when a water soluble chitosan was crosslinked with an ionic crosslinking agent and was further reacted with a folic acid having a target-oriented property to a liver cancer cell. Therefore, in the production of a formulation containing drug nanoparticles of the present invention, a drug was nanoparticlized, and the particle size of the nanoparticles was maintained without an aggregation phenomenon even after further a subsequent process. 2. Determination of a particle surface in a production process
A particle shape of paclitaxel was observed by means of TEM image in the step (1) and (3) of the example 2.
As shown in the results of FIG.5 (a) and FIG.5 (b), there was no significant change in terms of a surface shape of paclitaxel between the step (1) and the step (3).
Experimental Example 3> Experiment of elution velocity For a formulation containing drug nanoparticles produced in the example 2, an elution experiment was carried out as follow in order to identify an effect of a crosslinking of a chitosan on an elution velocity of a drug.
The present inventors compared the elution velocity of a slurry mixture of drug nanoparticles produced in the step (1) of the example 2 with the elution velocity of a slurry mixture of drug nanoparticles in the step (3) of the example 2. A dialysis membrane containing a slurry mixture containing 10 mg of paclitaxel was introduced into 500 ml of PBS solution of pH 7.4 and was stirred at 37.5 °C and 100 rpm. 5 ml of PBS solution was removed and 5 ml of fresh PBS solution was introduced at a predetermined time. A concentration of paclitaxel was determined by means of HPLC, and the results were shown in FIG. 6.
As shown in the result of FIG. 6, the paclitaxel drug of the step (3) which a chitosan was adsorbed was eluted more slowly than the non- crosslinked paclitaxel drug in the step (1). Accordingly, it was possible to obtain a drug taste masking effect and a stabilizing effect via such crosslinking.
EXPERIMENTAL EXAMPLE 4> Reaction with a chitosan dependent on a concentration of a folic acid.
For a formulation containing drug nanoparticles having a target- oriented property produced in the example 3, an experiment was carried out in order to observe an amount which was reacted with a water soluble chitosan dependent on a concentration of a folic acid. After completion of the reaction in the example 3, a drug treated group was dialyzed through a dialysis membrane (MWCO: 1000) for 3 days. The dialyzed mixture was divided by a centrifuger into an upper layer and a lower layer, and then the upper layer was freeze dried with liquid nitrogen. The dried powder was dissolved in water, and a concentration of a reacted folic acid was determined by means of ultraviolet spectrophotometer. FIG. 8 exhibits ultraviolet spectrometric results in relative to crosslinking bond of a water soluble chitosan dependent on a concentration of folic acid which is a pharmaceutical functional group, i.e., (a) 0.125% by weight, (b) 0.25% by weight and (c) 0.5% by weight. As shown in the results of FIG. 8, it was possible to identify a presence of a folic acid since it was observed that an absorption wavelength of a folic acid was 370 nm, and a concentration of a folic acid which was reacted with a functional drug layer was maintained constantly without a significant change. Accordingly, a concentration of a folic acid in relative to a total weight of a folic acid and a chitosan forming a functional drug layer was about 1 to 10% by weight. Experimental Example 5>
For the formulation containing drug nanoparticles having target- oriented property produced in the example 4, a change of a particle size was observed after an amount of chitosan which is mixed with a drug was changed and then reacted with folic acid. A particle size of a drug dependent on an amount of chitosan was shown in the Table 1.
[Table 1 ]
Particle size (fflQ) Amount of chitosan
0.025 g 0.0125 g
Step (D 0.42 (± 0. 12) 0.41 (± 0 .12)
Step (2) 0.43 (± 0. 13) 0.46 (± 0 .16)
Step (3) 0.45 (± 0. 11) 0.41 (± 0 .12)
As shown in the results of the table 1, a particle size of paclitaxel produced after a reaction with a folic acid was maintained with a significant change independent on an amount of a chitosan. As shown in the results, a particle size of drug nanoparticles of the present invention was maintained constantly during the whole production process independent on a process which a water soluble chitosan was adsorbed on a surface of a drug and a process which the water soluble chitosan was crosslinked with a folic acid of a functional substance. Namely, if a drug is nanoparticlized by means of a simple milling, a nanoparticle size of the drug was maintained during subsequent processes. As a result, the present invention could implement stabilization of nanoparticles. [Industrial Applicability] As described above, the present invention can provide a economical method of production, since, in the method of the present invention, a pharmaceutical functional group is introduced on a surface of a drug by providing a method of production which a pharmaceutical functional group can be introduced on a surface of a drug with a simple and an inexpensive milling technique in a grinding step.
The present invention can provide a method of stabilizing nanoparticles, since, in the present invention, a particle size of the nanoparticles produced in a grinding step was maintained constantly without an aggregation among particles during the whole production process. As a result, the range of utilization of drug nanoparticles can be expanded. The invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.

Claims

[CLAIMS] [Claim 1] A method for producing functional drug nanoparticles, comprising
1) wet-grinding a water soluble dispersion containing a drug and a surface stabilizing agent comprising of a water soluble polymer by milling to produce a slurry mixture! and
2) adding an aqueous solution containing a pharmaceutically functional substance in the above-mentioned step, which produces the slurry mixture to react the water soluble polymer which is the surface stabilizing agent with the pharmaceutically functional substance, thereby introducing selectively the pharmaceutically functional group on a surface of the drug.
[Claim 2]
The method of claim 1, characterized in that the wet grinded drug of the step (1) has a particle size of 50 to 800 nm.
[Claim 3]
The method of claim 1, characterized in that the drug nanoparticles of the step (2) have a particle size of 50 to 800 nm.
[Claim 4] The method of claim 1, characterized in that the drug is contained in the amount of 0.1 to 60% by weight in the water soluble dispersion containing the water soluble polymer.
[Claim 5]
The method of claim 1, characterized in that the water soluble polymer is any one selected from the group consisting of lecithin, polyoxyethylene, poloxamer, polypropylene glycol, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, benzethonium chloride, benzalconium chloride, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propyl paraben, methyl paraben, polyvinyl alcohol, polyvinyl pyrrolidone, carrageenan, alginic acid, sodium alginate, water soluble chitosan, protein comprising gluconic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, phospholipid, sorbitan, fatty acid ester, potassium sorbate and a combination thereof.
[Claim 6]
The method of claim 1, characterized in that an ion crosslinking agent selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compound is further mixed in the amount of 0.1 to 20% by weight based on the weight of the water soluble polymer.
[Claim 7] The method of claim 1, characterized in that the pharmaceutically functional substance is any one selected from a target-oriented substance to a cancer cell or a drug taste masking substance, and is water soluble substance.
[Claim 8] A drug nanoparticle formulation having a target-oriented property, characterized in that the drug nanoparticles and a water soluble polymer are dispersed uniformly; a pharmaceutically functional substance layer is formed selectively on a surface of the drug nanoparticles by reaction of the water soluble polymer with a target- oriented substance; and the drug nanoparticles are loaded in an inner portion of the pharmaceutically functional substance layer and a pharmaceutical functional group having a target-oriented property is introduced on a surface of a drug.
[Claim 9] A drug nanoparticle formulation having a drug taste masking property, characterized in that the drug nanoparticles and a water soluble polymer are dispersed uniformly; a pharmaceutically functional substance layer is formed selectively on a surface of the drug nanoparticles by reaction of the water soluble polymer with a drug taste masking substance; and the drug nanoparticles are loaded in an inner portion of the pharmaceutically functional substance layer and a pharmaceutical functional group controlling a taste of a drug is introduced on a surface of a drug.
[Claim 10] The drug nanoparticle formulation of claim 8 or 9, characterized in that the drug nanoparticles and the water soluble polymer are dispersed uniformly in the wet grinding process by milling.
[Claim 11]
The drug nanoparticle formulation of claim 8 or 9, characterized in that the drug nanoparticles have a particle size of 50 to 800 nm.
[Claim 12] The drug nanoparticle formulation of claim 8 or 9, characterized in that the water soluble polymer is any one selected from the group consisting of lecithin, polyoxyethylene, poloxamer, polypropylene glycol, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, benzethonium chloride, benzalconium chloride, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propyl paraben, methyl paraben, polyvinyl alcohol, polyvinyl pyrrolidone, carrageenan, alginic acid, sodium alginate, water soluble chitosan, protein comprising gluconic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, phospholipid, sorbitan, fatty acid ester, potassium sorbate and a combination thereof.
[Claim 13] The drug nanoparticle formulation of claim 8 or 9, characterized in that the drug nanoparticle formulation is in the form of a liquid or a powder.
[Claim 14]
The drug nanoparticle formulation of claim 8 or 9, characterized in that the drug nanoparticles are sparingly soluble drug. [Claim 15]
The drug nanoparticle formulation of claim 8, characterized in that the target-oriented substance is any one selected from the group consisting of folic acid, glycolic acid and RGD peptide. [Claim 16] The drug nanoparticle formulation of claim 9, characterized in that the drug taste masking substance is any one selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compound.
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Cited By (9)

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Publication number Priority date Publication date Assignee Title
WO2011154755A1 (en) 2010-06-08 2011-12-15 Nanoform Cardiovascular Therapeutics Ltd. Nanostructured atorvastatin, its pharmaceutically acceptable salts and compositions of them, process for the preparation thereof and pharmaceutical compositions containing them
WO2012116434A1 (en) * 2011-03-01 2012-09-07 4413261 Canada Inc. (Spencer Canada) Two speed monolithic system for controlled release of drugs
EP2978420A4 (en) * 2013-03-28 2016-12-21 Bbs Nanotechnology Ltd Stable nanocomposition comprising paclitaxel, process for the preparation thereof, its use and pharmaceutical compositions containing it
US10047072B2 (en) 2013-09-16 2018-08-14 Astrazeneca Ab Therapeutic polymeric nanoparticles and methods of making and using same
US10577351B2 (en) 2013-09-16 2020-03-03 Astrazeneca Ab Therapeutic polymeric nanoparticles and methods of making and using same
WO2015071841A1 (en) 2013-11-12 2015-05-21 Druggability Technologies Holdings Limited Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them
CN107596366A (en) * 2017-08-18 2018-01-19 中国科学院生物物理研究所 A kind of diagnoses and treatment preparation with multiple stimulation response type drug controlled-releasing function and its preparation method and application
CN107596366B (en) * 2017-08-18 2018-10-16 中国科学院生物物理研究所 A kind of diagnoses and treatment preparation and its preparation method and application with multiple stimulation response type drug controlled-releasing function
EP3505154B1 (en) * 2017-12-26 2022-04-06 Industrial Technology Research Institute Composition for improving the solubility of poorly soluble substances, use thereof and complex formulation containing thereof

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