Nothing Special   »   [go: up one dir, main page]

KR100961880B1 - 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

Info

Publication number
KR100961880B1
KR100961880B1 KR1020070128949A KR20070128949A KR100961880B1 KR 100961880 B1 KR100961880 B1 KR 100961880B1 KR 1020070128949 A KR1020070128949 A KR 1020070128949A KR 20070128949 A KR20070128949 A KR 20070128949A KR 100961880 B1 KR100961880 B1 KR 100961880B1
Authority
KR
South Korea
Prior art keywords
drug
water
nanoparticles
soluble
soluble polymer
Prior art date
Application number
KR1020070128949A
Other languages
Korean (ko)
Other versions
KR20090061933A (en
Inventor
이종휘
김수정
Original Assignee
중앙대학교 산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 중앙대학교 산학협력단 filed Critical 중앙대학교 산학협력단
Priority to KR1020070128949A priority Critical patent/KR100961880B1/en
Priority to PCT/KR2007/006596 priority patent/WO2009075401A1/en
Publication of KR20090061933A publication Critical patent/KR20090061933A/en
Application granted granted Critical
Publication of KR100961880B1 publication Critical patent/KR100961880B1/en

Links

Images

Classifications

    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • 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
    • A61K47/54—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
    • 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
    • A61K47/54—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
    • 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
    • A61K47/62—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
    • 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
    • A61K47/69—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
    • 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
    • A61K47/69—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
    • 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
    • A61K47/69—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
    • 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
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nanotechnology (AREA)
  • Immunology (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

본 발명은 밀링에 의한 기능성 약물나노입자의 제조방법 및 상기 제조방법에 의해 입자 표면이 개질된 약물나노입자 제제에 관한 것이다. The present invention relates to a method for producing functional drug nanoparticles by milling, and to a drug nanoparticle formulation in which particle surfaces are modified by the method.

본 발명의 제조방법은 약물과 수용성 고분자를 함유하는 수용성 분산액을 밀링을 통해 습식분쇄하여 나노입자로 제조하면서, 약학적 기능물질을 함유하는 수용액을 혼합하여상기 수용성 고분자와 약학적 기능물질을 반응시켜, 선택적으로 약물표면상에 약학적 기능성 작용기를 도입하는 것으로, 상기 제조방법에 의해 입자 표면이 개질된 약물나노입자 제제는 서방용출성, 표적지향성 또는 약물 맛을 제어가능하고, 약물나노입자가 전 제조공정에서 입자간의 응집 없이 나노입자크기로 유지된다. In the manufacturing method of the present invention, the aqueous dispersion containing the drug and the water-soluble polymer is wet-milled through milling to produce nanoparticles, and the aqueous solution containing the pharmaceutical functional material is mixed to react the water-soluble polymer with the pharmaceutical functional material. In addition, by selectively introducing a pharmaceutical functional group on the surface of the drug, the drug nanoparticle formulations with the particle surface modified by the manufacturing method is capable of controlling slow-release, target-oriented or drug taste, and drug nanoparticles The nanoparticle size is maintained without agglomeration between particles in the manufacturing process.

약물, 나노입자, 표적지향성, 방출조절, 고분자, 생체이용률 Drug, Nanoparticle, Target Orientation, Release Control, Polymer, Bioavailability

Description

밀링에 의한 기능성 약물나노입자의 제조방법 및 상기 제조방법에 의해 입자 표면이 개질된 약물나노입자 제제{MANUFACTURING METHOD OF FUNCTIONAL DRUG NANOPARTICLES USING MILLING AND FUNCTIONAL DRUG NANOPARTICLE FORMULATION MANUFACTURED THEREBY}Method of manufacturing functional drug nanoparticles by milling and drug nanoparticle formulations whose particle surface is modified by the above manufacturing method TECHNICAL FIELD USING MILLING AND FUNCTIONAL DRUG NANOPARTICLE FORMULATION MANUFACTURED THEREBY}

본 발명은 밀링에 의한 약학적 기능성 약물나노입자의 제조방법 및 상기 제조방법에 의해 입자 표면이 개질된 약물나노입자 제제에 관한 것으로서, 더욱 상세하게는 약물 입자를 밀링에 의해 습식분쇄하여 나노입자로 제조하면서 선택적으로 약물표면상에 약학적 기능성 작용기를 도입하는 약물나노입자의 제조방법 및 상기 제조방법에 의해 입자 표면이 개질된 약물나노입자 제제에 관한 것이다.The present invention relates to a method for producing a pharmaceutical functional drug nanoparticles by milling, and to a drug nanoparticle formulation in which the particle surface is modified by the preparation method, and more particularly, to wet-milling drug particles by milling to nanoparticles. The present invention relates to a method for preparing drug nanoparticles which selectively introduce pharmaceutically functional functional groups on the drug surface during preparation, and to a drug nanoparticle preparation in which the particle surface is modified by the method.

종래의 고형 경구 제제는 수 마이크론에서 수백 마이크론 크기의 약물 결정입자를 과립화(granulation), 혼합(mixing), 정제화(tabletting) 등의 공정을 통해 생산되어 왔다. 그러나, 상기 제한적인 약물 결정입자의 크기는 제제 분야에 상당히 제한적인 요소로 작용한다.Conventional solid oral formulations have been produced through processes such as granulation, mixing, tabletting, and the like, for several microns to several hundred microns in size. However, the limited size of the drug crystal grains is a very limited factor in the formulation field.

따라서 약물 결정입자 크기를 나노미터 수준으로 가공할 수 있는 방법들이 개발됨으로써, 약물의 용해속도 범위가 획기적으로 늘어나고, 이에 따라 난용성 약물의 생체이용률을 크게 향상시킨 결과가 보고되고 있다. Therefore, by developing methods that can process the drug crystal grain size to the nanometer level, the dissolution rate range of the drug is significantly increased, and thus the results of greatly improving the bioavailability of poorly soluble drugs have been reported.

약물의 나노입자는 약물의 흡수도 향상 외에도 약물의 함량 감소가 용이하고, 흡수속도를 빠르게 하며, 여러 유기용매의 사용 또는 극단적인 pH 사용을 피할 수 있다. 또한, 향후 다양한 약물전달체와 결합되어 표적지향성, 기능성 전달체를 제조하는 기초기술로도 이용될 수 있다. 나아가, 약물의 맛을 감추거나 긴 약효 지속 효과를 기대할 수도 있고, 식사시와 공복시 약물의 흡수도 차이(fed/fasted variability)를 감소시킬 수 있다.In addition to improving the absorbency of drugs, nanoparticles of drugs are easy to reduce the content of drugs, speed up the absorption rate, and avoid the use of various organic solvents or the use of extreme pH. In addition, it can be used in the future as a basic technology for producing a target-oriented, functional transporter combined with various drug delivery systems. Furthermore, it may be possible to hide the taste of the drug or to expect a long lasting effect, and to reduce the fed / fasted variability of the drug at the time of meal and fasting.

종래 난용성 약물의 용해도를 증가시키기 위한 다양한 방법이 제시되어 왔다. 그 일례로, 대한민국 특허공개 제1999-51527호에서는 당류를 이용하여 난용성 약물인 이트라코나졸의 입자경을 감소시키고 결정성을 변화시켜 용해도를 증가시킨 방법을 제시하고 있으며, 미합중국특허 제6,407,079호는 베타-사이클로덱스트린을 사용하여 이트라코나졸의 포접 화합물을 제조하여 약물의 용해도와 안정성을 개선시키는 방법이 개시되어 있다. Various methods have been proposed to increase the solubility of conventionally poorly soluble drugs. For example, Korean Patent Laid-Open Publication No. 1999-51527 discloses a method of increasing the solubility by reducing the particle size and changing the crystallinity of the poorly soluble drug itraconazole using sugars, and US Patent No. 6,407,079 discloses beta- Methods of preparing clathrate compounds of itraconazole using cyclodextrins to improve the solubility and stability of the drug are disclosed.

또한, 미합중국특허 제6,599,535호는 난용성 약물인 라파마이신 또는 아스코마이신의 고체 분산체 담체로서 수용성 고분자를 사용하여 약물의 용출률을 개선시킨 방법을 제시하고 있고, 대한민국 특허공개 제1997-14759호는 친수성 부분과 소수성 부분을 갖는 생분해성 블럭 공중합체가 미셀 구조의 약물 전달체로서 이용될 수 있는 방법을 공지하고 있고, 대한민국 특허공개 제2006-62734호는 난용성 약물의 안정한 경구용 마이크로에멀젼 조성물의 제조방법을 개시하고 있다. 이외에도, 미합중국특허 제5,145,684호에서는 난용성 약물을 수용액에 분산시킨 후 표면 변형제의 존재 하에 밀링 등의 방법으로 습식분쇄하여 나노약물입자를 제조하는 방법을 제시하고 있다. In addition, U.S. Patent No. 6,599,535 discloses a method of improving the dissolution rate of a drug by using a water-soluble polymer as a solid dispersion carrier of a poorly soluble drug, rapamycin or ascomycin, and Korean Patent Publication No. 1997-14759 discloses hydrophilicity. A biodegradable block copolymer having a moiety and a hydrophobic moiety can be used as a drug carrier having a micellar structure, and Korean Patent Publication No. 2006-62734 discloses a method for preparing a stable oral microemulsion composition of a poorly soluble drug. Is starting. In addition, US Pat. No. 5,145,684 proposes a method for preparing nanodrug particles by dispersing a poorly soluble drug in an aqueous solution and then wet milling by milling or the like in the presence of a surface modifier.

그러나 상기 제조방법에는 계면활성제, 보조용매 등이 병용되는데, 이들에 의한 부작용이 유발될 수 있으며, 이러한 물질들이 체액에서 희석되거나 온도에 영향을 받아 약물이 침전되는 현상이 발생할 수 있다. 또한 복잡한 제조공정 및 설비 사용의 문제 및 고가의 부형제 사용으로 인하여 경제성이 저하된다. However, the preparation method is used in combination with a surfactant, a co-solvent, and the like, may cause side effects caused by these, and the phenomenon that these substances are diluted in body fluids or affected by temperature may cause the drug to precipitate. In addition, the economical efficiency is reduced due to the complicated manufacturing process and the use of equipment and the use of expensive excipients.

밀링 공정의 경우 공정이 단순하고, 입자 크기 감소를 위한 표면 변형제를 사용하고 있으나, 밀링 공정 중에 표적지향성, 서방성기능기 등의 약학적 작용기의 도입은 아직까지 보고된 바 없다. In the milling process, the process is simple and surface modifiers are used to reduce the particle size, but the introduction of pharmaceutical functional groups such as target-oriented and sustained release functional groups has not been reported.

약학적 기능성을 도입하기 위한 약물전달용 나노입자의 제조방법에는 자가유화 확산법을 이용한 고분자성 나노입자, 이온성 고분자의 배위화합물(complex) 반응을 이용한 고분자 나노입자, 친수/친유성 그룹을 갖는 블록 공중합체(block copolymer) 등을 이용한 마이셀 형성을 통한 나노입자 등이 있다. Methods for preparing drug delivery nanoparticles for introducing pharmaceutical functionality include polymeric nanoparticles using a self-emulsifying diffusion method, polymeric nanoparticles using a complex reaction of ionic polymers, and blocks having hydrophilic / lipophilic groups. Nanoparticles through micelle formation using a block copolymer and the like.

예를 들면 대한민국 특허공개 2001-0086811는 유화-확산법을 이용한 생분해성 미세 입자를 제조하여 방출속도를 조절하고 생체조직에 친화력을 강화시킨 방법을 제시하고 있고, 미국특허 제7,229,973호는 리간드를 결합시킨 블록 공중합체를 이용하여 마이셀을 제조하여 방출제어, 표적지향성 기능을 가지는 나노입자 제조방법을 제시하고 있다. 그러나 상기 계면활성제 등을 사용하는 복잡한 공정을 통해 제조된 입자는 불안정하거나 약물의 담지능력이 떨어지는 문제점을 가지고 있다.For example, Korean Patent Publication No. 2001-0086811 discloses a method of controlling biodegradation by producing biodegradable microparticles using emulsion-diffusion method and enhancing affinity to biological tissues. US Pat. A method for preparing nanoparticles having a release control and target-oriented functions by preparing micelles using a block copolymer has been proposed. However, the particles produced through the complex process using the surfactant and the like has a problem that the support ability of the drug is unstable or poor.

이에, 본 발명자들은 종래의 문제점을 해소하고자 노력한 결과, 밀링에 의한 간단 한 분쇄방법으로 약물 입자를 나노입자로 제조하면서, 선택적으로 약물표면상에 약학적 기능성 작용기가 도입된 약물나노입자를 제조하고, 상기 방법에 의해 입자 표면이 개질된 약물나노입자 제제가 서방용출을 보이거나, 약학적 기능물질에 의해 표적지향 또는 약물 맛 제어 활성을 확인함으로써, 본 발명을 완성하였다.Accordingly, the present inventors have tried to solve the conventional problems, and as a result, while preparing the drug particles as nanoparticles by a simple milling method by milling, to produce a drug nanoparticles selectively introduced pharmaceutical functional functional groups on the drug surface and The present invention has been completed by the drug nanoparticle formulations whose particle surface is modified by the above method, showing sustained release, or confirming targeting or drug taste control activity by a pharmaceutical functional substance.

본 발명의 목적은 약물 입자를 밀링을 통해 습식분쇄하여 나노입자로 제조하면서 선택적으로 약물표면상에 약학적 기능성 작용기를 도입하는 약물나노입자의 제조방법을 제공하는 것이다.It is an object of the present invention to provide a method for preparing drug nanoparticles, wherein the drug particles are wet-milled through milling to produce nanoparticles and optionally introduce pharmaceutically functional functional groups on the drug surface.

본 발명의 다른 목적은 상기 제조방법에 의해 입자 표면이 개질된 약물나노입자 제제를 제공하는 것이다.It is another object of the present invention to provide a drug nanoparticle formulation in which the particle surface is modified by the preparation method.

상기 목적을 달성하기 위하여, 본 발명은 1) 약물과 표면안정화제(주로 수용성 고분자)를 함유하는 수용성 분산액을 밀링(milling)에 의해 습식분쇄하여 슬러리 혼합물을 제조하고, 2) 상기 슬러리 혼합물 제조공정에 약학적 기능물질을 함유하는 용액을 혼합하여 상기 수용성 고분자와 약학적 기능물질을 반응시켜, 선택적으로 약물표면상에 약학적 기능성 작용기를 도입하는 약물나노입자의 제조방법을 제공한다.In order to achieve the above object, the present invention provides a slurry mixture by wet grinding a water-soluble dispersion containing a drug and a surface stabilizer (mainly a water-soluble polymer) by milling, and 2) the slurry mixture manufacturing process. The present invention provides a method for preparing drug nanoparticles, in which a solution containing a pharmaceutical functional material is mixed with the water-soluble polymer to react the pharmaceutical functional material, and selectively introduce a pharmaceutical functional group onto the drug surface.

상기 단계 1의 습식분쇄된 약물은 부피평균 입자크기가 50 내지 800 nm 입자크기이며, 단계 2의 약물나노입자가 50 내지 800 nm 크기이므로, 분쇄단계에 제조된 약물 나노입자가 가교반응 이후에도 입자간 응집되지 않고 나노입자로 유지된다.The wet milled drug of step 1 has a volume average particle size of 50 to 800 nm particle size, and the drug nanoparticles of step 2 have a size of 50 to 800 nm, so that the drug nanoparticles prepared in the grinding step are separated between the particles even after the crosslinking reaction. It does not aggregate and remains as a nanoparticle.

본 발명에서 사용되는 표면안정화제로는 주로 수용성 고분자를 사용하며, 대표적인 예로는, 레시틴, 폴리옥시에틸렌, 폴록사머, 폴리프로필렌 글리콜, 메틸 셀룰로오스, 에틸 셀룰로오즈, 히드록시메틸 셀룰로오스, 히드록시에틸 셀룰로오스, 히드록시프로필 셀룰로오스, 히드록시프로필 메틸셀룰로오스, 카복시메틸 셀룰로오스, 염화벤제토늄, 염화벤잘코늄, 솔빈산, 솔빈산칼륨, 벤조산, 벤조산나트륨, 프로필파라벤, 메틸파라벤, 폴리비닐알코올, 폴리비닐피롤리돈, 카라긴산, 알긴산, 알긴산나트륨, 수용성 키토산, 글루코산 또는 페닐알라닌을 포함하는 단백질, 폴리아닐린, 폴리피롤, 셀룰로오스 아세테이트, 소듐 도데실 설페이트(SDS or SLS), 소듐 다이옥틸 설포숙시네이트, 포스포리피드, 소르비탄, 지방산 에스테르(예: 트윈(Tween)), 솔빈산칼륨 등이 있으며, 이들 중 1종 이상을 혼합하여 사용할 수 있다. As the surface stabilizer used in the present invention, a water-soluble polymer is mainly used. Representative examples thereof include lecithin, polyoxyethylene, poloxamer, polypropylene glycol, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxy. Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, benzogenium chloride, benzalkonium chloride, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propyl paraben, methyl paraben, polyvinyl alcohol, polyvinylpyrrolidone, Proteins, including carrageic acid, alginic acid, sodium alginate, water soluble chitosan, gluconic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate, sodium dodecyl sulfate (SDS or SLS), sodium dioctyl sulfosuccinate, phospholipid, sorbate Non-fatty, fatty acid esters (e.g. Tween), potassium sorbate, etc. , And it may be used by mixing one or more of these.

본 발명에서 활성성분으로 사용되는 약물은 수용성 고분자가 포화된 수용액에 0.1 내지 60중량%로 포함된다.The drug used as an active ingredient in the present invention is contained in 0.1 to 60% by weight in an aqueous solution of a water-soluble polymer.

또한, 상기 단계 1에 유기, 무기 이온물질인 트리폴리포스페이트, 염화칼슘, 수산화칼슘, 표면처리 또는 미처리된 사이클로덱스트린 및 카보다이이미드(carbodiimide) 화합물로 이루어진 군에서 선택되는 어느 하나의 이온 가교제를 고분자성분 중량 대비 0.1 내지 20 중량%를 더 혼합할 수 있다.In addition, in step 1, any one ion crosslinker selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface treated or untreated cyclodextrin, and carbodiimide compound, which are organic and inorganic ionic materials, is compared with the weight of the polymer component. 0.1 to 20 The weight percentages may be further mixed.

본 발명에서 사용되는 약학적 기능물질이 암세포 표적지향성 물질 또는 약물 맛 제어용 물질(taste masking)에서 선택되는 어느 하나이며, 수용해성 고분자 물질과 화학적 또는 물리적 반응을 일으키는 물질을 사용한다.The pharmaceutical functional substance used in the present invention is any one selected from cancer cell target-oriented substances or drug taste control substances (taste masking), and a substance that causes a chemical or physical reaction with a water-soluble polymer substance.

본 발명은 약물나노입자와 수용성 고분자가 균일 분산되고, 상기 수용성 고분자와 표적지향성 물질과의 반응에 의해 선택적으로 약물나노입자 표면상에 약학적 기능성물질층이 형성된 구조로서, 상기 기능성물질층 내부에 약물나노입자를 담지하고 약물표면상에 표적지향성이 도입되도록 한 약물나노입자 제제를 제공한다.The present invention is a structure in which the drug nanoparticles and the water-soluble polymer are uniformly dispersed, and a pharmaceutical functional material layer is selectively formed on the surface of the drug nanoparticles by reaction of the water-soluble polymer and the target-oriented material, and the inside of the functional material layer Provided is a drug nanoparticle formulation that supports drug nanoparticles and allows target orientation to be introduced on the drug surface.

또한 본 발명은 약물나노입자와 수용성 고분자가 균일 분산되고, 상기 수용성 고분자와 서방용출성 물질과의 가교결합에 의해 약물나노입자 표면상에 약학적 기능성물질층이 형성된 구조로서, 상기 기능성물질층 내부에 약물나노입자를 담지하고 약물표면상에 서방용출성이 도입되도록 한 약물나노입자 제제를 제공한다. In addition, the present invention is a structure in which the drug nanoparticles and the water-soluble polymer is uniformly dispersed, the pharmaceutical functional material layer is formed on the surface of the drug nanoparticles by crosslinking of the water-soluble polymer and the sustained-release material, the inside of the functional material layer The present invention provides a drug nanoparticle formulation in which drug nanoparticles are supported on the drug surface and sustained-release properties are introduced on the drug surface.

본 발명의 약물나노입자 제제에서, 상기 약물나노입자와 수용성 고분자가 밀링에 의한 습식분쇄 과정에서 균일 분산되는 것이다.In the drug nanoparticle formulation of the present invention, the drug nanoparticles and the water-soluble polymer are uniformly dispersed during the wet grinding process by milling.

본 발명의 약물나노입자 제제에서, 약물나노입자는 부피평균 입자크기가 50 내지 800 nm 입자크기를 충족한다.In the drug nanoparticle formulation of the present invention, the drug nanoparticles satisfy a volume average particle size of 50 to 800 nm particle size.

본 발명의 약물나노입자 제제에서, 표면안정화제는 수용성 고분자를 사용하며, 상기 제조방법에서 서술한 바와 같다.In the drug nanoparticle formulation of the present invention, the surface stabilizer uses a water-soluble polymer, and is as described in the preparation method.

또한, 본 발명의 약물나노입자 제제는 액상 제제 또는 상기 액상을 동결건조, 진공건조 또는 증발건조하여 제조된 분말 제제이다.In addition, the drug nanoparticle formulation of the present invention is a liquid formulation or a powder formulation prepared by freeze drying, vacuum drying or evaporating the liquid.

본 발명은 분쇄단계에서 약물표면상에 약학적 기능성 작용기를 일공정으로 도입할 수 있는 기능성 약물나노입자의 제조방법을 제공함으로써, 상기 제조방법에 의해 약물 표면이 개질된 약물나노입자 제제를 제공할 수 있다. The present invention provides a method for producing a functional drug nanoparticles that can introduce a pharmaceutically functional functional group on the drug surface in one step in the grinding step, thereby providing a drug nanoparticle formulation in which the drug surface is modified by the manufacturing method. Can be.

본 발명의 제조방법은 분쇄단계에서 제조된 약물나노입자가 전 제조공정 상에서 입자간의 응집 없이, 나노입자크기를 유지할 수 있다. In the manufacturing method of the present invention, the drug nanoparticles prepared in the grinding step can maintain the nanoparticle size without aggregation between the particles in the entire manufacturing process.

이하, 본 발명을 상세히 설명하고자 한다.Hereinafter, the present invention will be described in detail.

본 발명은 The present invention

1) 약물과 수용성 고분자로 이루어진 표면안정화제를 함유하는 수용성 분산액을 밀링에 의해 습식분쇄하여 슬러리 혼합물을 제조하고, 1) Wet milling an aqueous dispersion containing a surface stabilizer consisting of a drug and a water-soluble polymer by milling to prepare a slurry mixture,

2) 상기 슬러리 혼합물 제조공정에 약학적 기능물질을 함유하는 수용액을 혼합하고 상기 표면안정제인 수용성 고분자와 약학적 기능물질을 반응시켜, 선택적으로 약물표면상에 약학적 기능성 작용기가 도입되도록 한 기능성 약물나노입자의 제조방법을 제공한다. 2) A functional drug which mixes an aqueous solution containing a pharmaceutical functional material in the slurry mixture manufacturing process and reacts the surface stabilizer with a water-soluble polymer and a pharmaceutical functional material to selectively introduce a pharmaceutically functional functional group onto the drug surface. It provides a method for producing nanoparticles.

본 발명의 단계 1에서, 밀링에 의한 습식분쇄 공정은 약물을 부피평균 입자크기가 50 내지 800 nm의 나노입자크기로 분쇄하는 동시에, 약물과 수용성 고분자가 균일하게 분산되도록 한다. In step 1 of the present invention, the wet grinding process by milling the drug is pulverized to a nanoparticle size of 50 to 800 nm in volume average particle size, while allowing the drug and the water-soluble polymer to be uniformly dispersed.

이때, 약물의 입자크기가 50 nm 미만이면, 반응 후 입자간 응집이 될 수 있고, 800 nm를 초과하면, 나노입자로서의 효과 감소와 약물입자와 수용성 고분자와의 분산효과가 저하된다.At this time, if the particle size of the drug is less than 50 nm, it may be agglomerated between the particles after the reaction, if it exceeds 800 nm, the effect of reducing the nanoparticles and the dispersion effect of the drug particles and the water-soluble polymer is reduced.

상기 표면안정화제로 사용되는 수용성 고분자는 약물표면에 물리적으로 흡착하여 분산액 내에서 약물의 입자크기가 감소하면서 약물입자가 응집되지 않고 안정되게 분산시키는 표면 안정화제 역할을 수행한다. The water-soluble polymer used as the surface stabilizer acts as a surface stabilizer to physically adsorb onto the surface of the drug to reduce the particle size of the drug in the dispersion and to stably disperse the drug particles.

본 발명의 수용성 고분자는 물에 잘 녹으며, 인체에 무해한 유기물질을 사용할 수 있다. 바람직하게는 레시틴, 폴리옥시에틸렌, 폴록사머, 폴리프로필렌 글리콜, 메틸 셀룰로오스, 에틸 셀룰로오즈, 히드록시메틸 셀룰로오스, 히드록시에틸 셀룰로오스, 히드록시프로필 셀룰로오스, 히드록시프로필 메틸셀룰로오스, 카복시메틸 셀룰로오스, 염화벤제토늄, 염화벤잘코늄, 솔빈산, 솔빈산칼륨, 벤조산, 벤조산나트륨, 프로필파라벤, 메틸파라벤, 폴리비닐알코올, 폴리비닐피롤리돈, 카라긴산, 알긴산, 알긴산나트륨, 수용성 키토산, 표면처리 또는 미처리된 사이클로덱스트린, 글루코산 또는 페닐알라닌을 포함하는 단백질, 폴리아닐린, 폴리피롤, 셀룰로오스 아세테이트, 소듐 도데실 설페이트(SDS or SLS), 소듐 다이옥틸 설포숙시네이트, 포스포리피드, 소르비탄, 지방산 에스테르(트윈(Tween)) 및 솔빈산칼륨으로 이루어진 군에서 선택되는 단독 또는 1종 이상의 혼합형태를 사용할 수 있다. 더욱 바람직하게는 수용성 키토산, 폴리옥시에틸렌, 폴록사머, 폴리프로필렌 글리콜 등을 사용하는 것이다.The water-soluble polymer of the present invention is soluble in water, it is possible to use an organic material harmless to the human body. Preferably lecithin, polyoxyethylene, poloxamer, polypropylene glycol, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, benzethonium chloride , Benzalkonium chloride, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propylparaben, methylparaben, polyvinyl alcohol, polyvinylpyrrolidone, carrageic acid, alginic acid, sodium alginate, water soluble chitosan, surface treated or untreated cyclo Proteins containing dextrins, gluconic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate, sodium dodecyl sulfate (SDS or SLS), sodium dioctyl sulfosuccinate, phospholipid, sorbitan, fatty acid esters (Tween) ) And potassium sorbate alone You may use a mixture of one or more kinds. More preferably, water-soluble chitosan, polyoxyethylene, poloxamer, polypropylene glycol, or the like is used.

또한, 표면 안정화 목적으로, 고분자성분 중량 대비 이온 가교제 0.1 내지 20 중량%를 더 혼합할 수 있다. 이때, 바람직한 이온 가교제로는 유기, 무기 이온물질인 트리폴리포스페이트, 염화칼슘, 수산화칼슘, 표면처리 또는 미처리된 사이클로덱스트린 및 카보다이이미드(carbodiimide) 화합물로 이루어진 군에서 선택되는 어느 하나를 사용할 수 있다.In addition, for the purpose of surface stabilization, the ion crosslinking agent 0.1 to the weight of the polymer component To 20% by weight may be further mixed. At this time, the preferred ion crosslinking agent may be any one selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface treated or untreated cyclodextrin and carbodiimide compound, which are organic and inorganic ionic materials.

본 발명에서 사용되는 수용성 고분자를 함유하는 수용성 분산액은 볼 밀링 또는 미디어 밀링 등의 저렴하고 간단한 분쇄방법을 사용하여 얻을 수 있으며, 가공온도는 약물 특성과 기계적인 물성에 따라 적절하게 조절될 수 있고, 일반적으로 상온에서 분쇄한다. 분쇄시간은 기계적 수단 및 처리조건에 따라 광범위하게 적용될 수 있는데, 낮은 전단에너지를 이용하는 볼 밀링으로 수행할 경우는 3일 이상이 소요되고, 높은 전단에너지를 이용할 경우는 수 분 내지 수 시간 동안에 원하는 약물 분산액을 얻을 수 있다. 이때, 상기 수용성 고분자를 함유하는 수용성 분산액의 용매는 순수 또는 수용액 또는 완충액을 사용한다.The water-soluble dispersion containing the water-soluble polymer used in the present invention can be obtained using an inexpensive and simple grinding method such as ball milling or media milling, the processing temperature can be appropriately adjusted according to the drug properties and mechanical properties, Generally it is ground at room temperature. Grinding time can be widely applied depending on the mechanical means and processing conditions. It takes more than 3 days to perform ball milling with low shear energy, and the desired drug for several minutes to several hours with high shear energy. A dispersion can be obtained. At this time, the solvent of the aqueous dispersion containing the water-soluble polymer is pure water or an aqueous solution or a buffer solution.

본 발명의 단계 2는 상기 단계 1에서 슬러리 혼합물 제조공정 상에 약학적 기능물질을 함유하는 수용액을 혼합하여 상기 수용성 고분자와 약학적 기능물질을 반응시켜, 약물표면상에 약학적 기능성 작용기가 도입되도록 하는 공정이다.Step 2 of the present invention by mixing the aqueous solution containing the pharmaceutical functional material on the slurry mixture manufacturing process in step 1 to react the water-soluble polymer and the pharmaceutical functional material, so that the pharmaceutical functional functional groups are introduced on the drug surface It is a process to do it.

상기 약학적 기능물질이 표적지향성 물질인 경우 표면 안정화제로 사용되는 수용성 고분자와 반응하여 약효가 발현된 조직, 기관, 세포 등에 표적지향성 기능을 가진다. 상기 약학적 기능물질의 일례는 약물 특성에 따라 표적지향성이 달라질 수 있으나, 바람직하게는 암세포 표적지향성 물질 또는 약물 맛 제어용 물질(taste masking)을 선택 사용할 수 있다. When the pharmaceutical functional material is a target-oriented material, it has a target-oriented function in tissues, organs, cells, etc., in which the drug is expressed by reacting with a water-soluble polymer used as a surface stabilizer. An example of the pharmaceutical functional substance may be targeted depending on drug properties, but preferably, cancer cell target-oriented substances or drug taste control substances may be selected and used.

상기에서 암세포 표적지향성 물질은 엽산, 글리콜산, RGD 펩타이드(Arg-Gly-Asp)와 같은 특정 아미노산으로 구성된 펩타이드에서 선택 사용될 수 있으며, 약물 맛 제어효과는 유기, 무기 이온물질인 트리폴리포스페이트, 염화칼슘, 수산화칼슘 및 카 보다이이미드(carbodiimide) 화합물로 이루어진 군에서 선택 사용하여 그 효과를 얻을 수 있다.The cancer cell target-oriented substance may be selected from peptides composed of specific amino acids such as folic acid, glycolic acid, and RGD peptide (Arg-Gly-Asp), and the drug taste control effect is tripolyphosphate, calcium chloride, The effect can be obtained by selecting from the group consisting of calcium hydroxide and carbodiimide compounds.

본 발명의 단계 2에서 제조된 최종 약물나노입자는 단계 1에서 습식 분쇄된 입자크기50 내지 800 nm를 충족하므로, 본 발명의 제조방법은 습식분쇄된 약물나노입자가 가교반응 이후에도 입자간 응집 없이 입자크기가 유지된다. 따라서, 본 발명의 제조방법은 전 제조공정 상, 약물나노입자가 안정화된다.Since the final drug nanoparticles prepared in step 2 of the present invention satisfies the wet-pulverized particle size of 50 to 800 nm in step 1, the method of the present invention provides that the wet-pulverized drug nanoparticles do not have agglomerated particles even after crosslinking. The size is maintained. Therefore, in the manufacturing method of the present invention, the drug nanoparticles are stabilized in the entire manufacturing process.

따라서, 본 발명의 제조방법은 밀링에 의해 분쇄되는 과정에 약물학적 기능성기를 도입하여, 가교반응을 유도하여 약물나노입자 표면상에 약학적 기능성물질층을 형성함으로써, 가교반응 이후에도 약물나노입자가 안정화되고, 흡탈착이 일어나지 않는 안정된 고분자층을 형성한다. 반면에 종래 밀링에 의해 분쇄과정을 통해 제조된 단순 약물입자는 이후 공정 중에 분쇄된 입자가 응집되거나 흡탈착된다. 이에, 본 발명은 밀링 공정과 화학 반응을 동시에 일어나게 하여 약물표면상에 약학적 기능성 작용기를 일공정으로 도입할 수 있는 제조방법을 제공할 수 있다.Therefore, the manufacturing method of the present invention introduces a pharmacological functional group in the milling process by milling, induces a crosslinking reaction to form a pharmaceutical functional material layer on the surface of the drug nanoparticles, thereby stabilizing the drug nanoparticles even after the crosslinking reaction. This forms a stable polymer layer in which adsorption and desorption does not occur. On the other hand, the simple drug particles prepared by the conventional milling process are milled or adsorbed or desorbed during the subsequent process. Accordingly, the present invention can provide a manufacturing method that can introduce a pharmaceutically functional functional group on the surface of the drug in one step by causing the milling process and the chemical reaction at the same time.

또한, 본 발명은 상기 제조방법에 의해 입자 표면이 개질된 약물나노입자 제제를 제공한다.In another aspect, the present invention provides a drug nanoparticle formulation of the particle surface is modified by the production method.

도 1은 본 발명의 제조방법에 의해 제조된 약물나노입자 제제(1)의 모식도로서, 약물나노입자(10)의 표면상에 표면 안정화제(20)와 약학적 기능성 작용기(30)가 선택적으로 도입된 구조이다. 1 is a schematic view of a drug nanoparticle formulation (1) prepared by the manufacturing method of the present invention, the surface stabilizer 20 and the pharmaceutical functional group 30 selectively on the surface of the drug nanoparticles (10) It is a structure introduced.

본 발명의 약물나노입자 제제로서, 바람직한 제1실시형태로는 약물나노입자와 수용 성 고분자가 균일 분산되고, 상기 수용성 고분자와 표적지향성 물질과의 반응에 의해 약물나노입자 표면상에 약학적 기능성물질층이 형성된 구조이며, 상기 기능성물질층 내부에 약물나노입자를 담지하고 선택적으로 약물표면상에 표적지향성이 도입되도록 한 약물나노입자 제제를 제공한다. As the drug nanoparticle preparation of the present invention, in a first preferred embodiment, the drug nanoparticle and the water-soluble polymer are uniformly dispersed, and the pharmaceutical functional material is formed on the surface of the drug nanoparticle by the reaction of the water-soluble polymer with the target-oriented substance. It is a layered structure, and provides a drug nano-particles preparation to support the drug nanoparticles in the functional material layer and to selectively introduce the target orientation on the drug surface.

또한, 바람직한 제2실시형태로서, 약물나노입자와 수용성 고분자가 균일 분산되고, 상기 수용성 고분자와 약물 맛 제어용으로 가교도가 높은 기능성물질층이 약물나노입자 표면상에 형성된 구조이며, 상기 기능성물질 내부에 약물나노입자를 담지하고 약물표면상 밖으로 약물 맛이 방출제어되도록 한 약물나노입자 제제를 제공한다.In addition, as a second preferred embodiment, the drug nanoparticles and the water-soluble polymer are uniformly dispersed, and the water-soluble polymer and the functional material layer having a high degree of crosslinking for controlling the drug taste are formed on the surface of the drug nanoparticles. Provided are drug nanoparticle formulations that support drug nanoparticles and allow drug taste to be controlled out of the drug surface.

본 발명에서 사용되는 약물로서, 실시예에서는 난용성 약물인 나프록센 또는 항암제인 파클리탁셀을 사용하여 상세히 설명하고 있으나, 본 발명에 활성성분으로 사용되는 난용성 약물은 특별히 제한되지는 않는다. 구체적으로는 상기 난용성 약물이 물 또는 수용액과 같은 액체 분산 용매에 대해 난용성을 나타내는 유기물로서, 상기 액체 분산 용매는 알콜 또는 오일을 포함할 수 있다. 이때, 상기 난용성이라 함은 공정상의 온도, 예를 들면 상온에서 액체 분산 용매에 대해 10 mg/㎖ 미만, 바람직하게는 1 mg/㎖ 미만의 용해도를 나타냄을 의미한다.As the drug used in the present invention, the embodiment is described in detail using a poorly soluble naproxen or an anticancer agent paclitaxel, but the poorly soluble drug used as an active ingredient in the present invention is not particularly limited. Specifically, the poorly soluble drug is an organic substance that shows poor solubility with respect to a liquid dispersion solvent such as water or an aqueous solution, and the liquid dispersion solvent may include an alcohol or an oil. In this case, the poorly soluble means that it exhibits a solubility of less than 10 mg / ml, preferably less than 1 mg / ml with respect to the liquid dispersion solvent at a process temperature, for example, room temperature.

본 발명에서 사용할 수 있는 난용성 약물의 구체적인 일례로는 아세트아미노펜, 아세틸살리실산, 이부프로펜, 펜부프로펜, 페노프로펜, 플루비프로펜, 인도메타신, 나프록센, 에토로락, 케토프로펜, 덱시부프로펜, 피록시캄, 아세클로페낙 등의 비스테로이드성 항염증제; 사이클로스포린, 타크로리무스, 라파마이신, 미코페닐레이 트, 피메크롤리무스 등의 면역억제제 또는 아토피성 피부염치료제; 니페디핀, 니모디핀, 니트렌디핀, 닐바디핀, 펠로디핀, 암로디핀, 이스라디핀 등의 칼슘 통로 차단제; 발사르탄, 에프로사르탄, 이르베사르탄, 칸데르사르탄, 텔미사르탄, 올메사르탄, 로사르탄 등의 안지오텐신 II 길항제; 아토르바스타틴, 로바스타틴, 심바스타틴, 플루바스타틴, 로수바스타틴, 프라바스타틴 등의 콜레스테롤 합성 억제형 고지혈증 치료제; 겜피브로질, 페노피브레이트, 에토피브레이트, 베자피브레이트 등의 콜레스테롤 대사 및 분비 촉진형 고지혈증 치료제; 피오글리타존, 로지글리타존, 메트포민 등의 당뇨병치료제; 오를리스타트 등의 리파아제 억제제; 이트라코나졸, 암포테리신 비, 테르비나핀, 나이스타틴, 글리세오풀빈, 플루코나졸, 케토코나졸 등의 항진균제; 비페닐 디메틸 디카복실레이트, 실리마린, 우루소데옥시콜린산 등의 간보호제; 소팔콘, 오메프라졸, 판토프라졸, 파모티딘, 이토프라이드, 메살라진 등의 소화기계 질환 치료제; 실로스타졸 클로피도그렐 등의 혈소판응집 억제제; 랄록시펜 등의 골다공증치료제; 아시클로버, 팜시클로버, 라미부딘, 오셀타미비르 등의 항바이러스제; 클라리스로마이신, 씨플로플록사신, 세푸록심 등의 항생제; 프란루카스트, 부데소나이드, 펙소페나딘 등의 천식치료제 또는 항히스타민제; 테스토스테론, 프레드니솔론, 에스트로겐, 코티손, 하이드로코티손, 덱사메타손 등의 호르몬제; 파클리탁셀, 도세탁셀, 파클리탁셀 유도체, 독소루비신, 아드리아미이신, 다우노마이신, 켐포테신, 에토포시드, 테니포사이드, 부설판 등의 항종양제; 치료학적으로 동등한 이들의 염; 이들의 약제학적 유도체; 및 이들의 혼합물 등이 있으며, 바람직하게는 나프록센, 타크로리무스, 발사르탄, 심바스타틴, 페노피브레 이트, 이트라코나졸, 비페닐 디메틸 디카복실레이트, 실리마린, 소팔콘, 판토프라졸, 실로스타졸, 이들의 염, 이들의 약제학적 유도체, 및 이들의 혼합물 등이 있다.Specific examples of poorly soluble drugs that can be used in the present invention include acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, phenopropene, flubiprofen, indomethacin, naproxen, etorolact, ketoprofen, Nonsteroidal anti-inflammatory agents such as dexibuprofen, pyroxhamm, and aceclofenac; Immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenylate, pimecrolimus, or atopic dermatitis; Calcium channel blockers such as nifedipine, nimodipine, nirenedipine, nilvadipine, felodipine, amlodipine, and isradipine; Angiotensin II antagonists such as valsartan, eprosartan, irbesartan, candersartan, telmisartan, olmesartan and losartan; Cholesterol synthesis inhibitor type hyperlipidemia therapeutic agents, such as atorvastatin, lovastatin, simvastatin, fluvastatin, rosuvastatin, pravastatin; Cholesterol metabolism and secretion promoting hyperlipidemia treatment agents such as gemfibrozil, fenofibrate, etofibrate, and bezafibrate; Antidiabetic agents such as pioglitazone, rosiglitazone, metformin; Lipase inhibitors such as orlistat; Antifungal agents such as itraconazole, amphotericin ratio, terbinafine, nystatin, glycerofulbin, fluconazole, ketoconazole; Hepatoprotective agents, such as biphenyl dimethyl dicarboxylate, silymarin, urusodeoxycholic acid; Agents for treating digestive diseases such as sofalcon, omeprazole, pantoprazole, pamotididine, itopride, and mesalazine; Platelet aggregation inhibitors such as cilostazol clopidogrel; Osteoporosis therapeutics such as raloxifene; Antiviral agents such as acyclovir, famcyclovir, lamivudine and oseltamivir; Antibiotics such as clarithromycin, ciflofloxacin and cefuroxime; Asthma treatment agents or antihistamines such as franlukast, budesonide, fexofenadine; Hormones such as testosterone, prednisolone, estrogen, cortisone, hydrocortisone, and dexamethasone; Anti-tumor agents such as paclitaxel, docetaxel, paclitaxel derivatives, doxorubicin, adriamycin, daunomycin, cempotesin, etoposide, teniposide, and busulfan; Therapeutically equivalent salts thereof; Pharmaceutical derivatives thereof; And mixtures thereof, preferably naproxen, tacrolimus, valsartan, simvastatin, fenofibrate, itraconazole, biphenyl dimethyl dicarboxylate, silymarin, sofalcone, pantoprazole, cilostazol, salts thereof, Pharmaceutical derivatives thereof, and mixtures thereof.

본 발명에서 활성성분으로 사용되는 난용성 약물은 수용성 고분자가 포화된 수용액에 0.1 내지 60중량%, 바람직하게는 2 내지 40중량% 범위로 포함될 수 있다.The poorly water-soluble drug used as an active ingredient in the present invention may be included in the range of 0.1 to 60% by weight, preferably 2 to 40% by weight in an aqueous solution in which the water-soluble polymer is saturated.

상기 약물은 50 내지 800 nm의 약물나노입자이며, 밀링에 의한 분쇄과정에서 나노입자화되고 수용성 고분자와 균일 분산되는 것으로서 본 발명의 제조방법에 의한다.The drug is 50 to 800 nm drug nanoparticles, which are nano-particles in the milling process by milling and uniformly dispersed with the water-soluble polymer according to the production method of the present invention.

도 2는 본 발명의 난용성 약물나노입자 함유 제제의 제조공정 상, 단계별 입자크기를 비교한 결과로서, 분쇄단계의 약물입자크기와 키토산과의 결합이후 약물입자크기가 큰 변화 없이 보존되었으며, 오히려, 가교반응으로 인해 보다 입자크기가 증가한 결과를 확인할 수 있다. Figure 2 is a result of comparing the particle size step by step in the manufacturing process of the poorly soluble drug nanoparticle-containing preparation of the present invention, the drug particle size after the bonding of the drug phase and chitosan in the grinding step was preserved without a large change, rather As a result, the particle size increased due to the crosslinking reaction.

또한, 도 3은 상기 난용성 약물나노입자 함유 제제의 제조공정 상, 상기 난용성 약물이 제거되기 전과 후의 고분자 형상을 관찰한 결과로서, 공정과정에서 난용성 약물이 제거된 후에도 고분자가 용해되지 않고 수용성 젤 상태로 유지된다. 따라서 단단한 가교층이 성공적으로 도입된 것을 확인할 수 있다. 이들 층은 약물의 방출을 방해하며 약물 맛의 제어가 가능하다. 3 is a result of observing the polymer shape before and after the poorly soluble drug is removed in the manufacturing process of the poorly soluble drug nanoparticle-containing preparation, the polymer is not dissolved even after the poorly soluble drug is removed in the process. It is kept in a water-soluble gel state. Therefore, it can be confirmed that the rigid crosslinked layer was successfully introduced. These layers interfere with the release of the drug and allow control of the drug taste.

도 4 및 도 5는 본 발명의 암세포 표적지향성을 갖는 약물나노입자 함유 제제의 제조공정 상, 단계별 입자크기를 비교한 결과로서, 전 제조공정 상에 거쳐 약물입자크기는 유지되는 것을 확인할 수 있다. 따라서 본 발명의 제조방법은 약물이 분쇄 단계에서 나노입자화된 후, 추가 화학적 공정에도 불구하고, 입자간의 응집 현상 없이, 나노입자가 유지됨을 확인할 수 있다. 4 and 5 is a result of comparing the particle size of the drug nanoparticle-containing preparation having a cancer cell target orientation of the present invention, step by step, it can be seen that the drug particle size is maintained throughout the entire manufacturing process. Therefore, the manufacturing method of the present invention can be confirmed that after the drug is nanoparticles in the milling step, despite the additional chemical process, the nanoparticles are maintained without aggregation phenomenon between the particles.

상기 수용성 고분자는 전술한 제조방법에 기술한 바와 동일하며, 바람직하게는 수용성 키토산, 표면처리 또는 미처리된 사이클로덱스트린, 글루코산 또는 페닐알라닌을 포함하는 단백질, 폴리아닐린, 폴리피롤, 셀룰로오스 아세테이트 및 폴리에틸렌글리콜로 이루어진 군에서 선택되는 어느 하나를 사용하는 것이다. 본 발명의 실시예에서는 바람직한 일례로서 수용성 키토산, 사이클로덱스트린, 플루로닉(pluronic) F127 및 글루코산 또는 페닐알라닌을 포함하는 단백질을 사용한다.The water-soluble polymer is the same as described in the above-described preparation method, preferably a group consisting of a protein containing polysoluble, polyaniline, polypyrrole, cellulose acetate and polyethylene glycol containing water-soluble chitosan, surface-treated or untreated cyclodextrin, glucosan or phenylalanine. It is to use any one selected from. In a preferred embodiment of the present invention, as a preferred example, a protein containing water-soluble chitosan, cyclodextrin, pluronic F127, and gluconic acid or phenylalanine is used.

상기 수용성 고분자와 약학적 기능물질을 함유하는 수용액을 혼합하여 수 분 내지 3일 동안 상온에서 교반 반응하여 약물표면상에 약학적 기능성물질층을 형성함으로써, 입자 표면에 약학적 기능성 작용기가 도입된 약물나노입자 제제를 제공할 수 있다.By mixing the aqueous solution containing the water-soluble polymer and the pharmaceutical functional material and stirred at room temperature for several minutes to three days to form a layer of the pharmaceutical functional material on the surface of the drug, a drug with a functional functional group introduced to the particle surface Nanoparticle formulations may be provided.

본 발명의 약물나노입자 제제가 약물표면상에 가교되어 약학적 기능성물질층을 형성함으로써, 약물의 서방용출성을 구현할 수 있다[도 6]. Drug nanoparticle formulation of the present invention is cross-linked on the drug surface to form a pharmaceutical functional material layer, it is possible to implement the sustained-release properties of the drug [ Figure 6 ].

약학적 기능물질의 바람직한 일례로 표적지향성 물질로서, 본 발명의 실시예에서는 암세포 표적지향성을 갖는 물질로 공지된 엽산을 사용하고 있으나, 글리콜산, RGD 펩타이드와 같은 특정 아미노산으로 구성된 펩타이드 등에서 선택 사용될 수 있다.As a target-oriented substance as a preferred example of a pharmaceutical functional substance, folic acid known as a cancer cell target-oriented substance is used in embodiments of the present invention, but may be selected from peptides composed of specific amino acids such as glycolic acid and RGD peptide. have.

또한, 약물 맛 제어용 물질은 유기, 무기 이온물질인 트리폴리포스페이트, 염화칼슘, 수산화칼슘, 표면처리 또는 미처리된 사이클로덱스트린 및 카보다이이미드 화합물에서 선택 사용할 수 있다.In addition, the drug taste control material may be selected from organic and inorganic ionic tripolyphosphate, calcium chloride, calcium hydroxide, surface-treated or untreated cyclodextrin and carbodiimide compounds.

이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. Hereinafter, the present invention will be described in more detail with reference to Examples.

본 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것이며, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. This embodiment is intended to illustrate the present invention in more detail, and the scope of the present invention is not limited to these examples.

<실시예 1> 약물나노입자 함유 제제의 제조Example 1 Preparation of Drug Nanoparticle-Containing Formulation

단계 1: 난용성 약물인 나프록센 0.6g에 수용성 키토산 0.05g, 증류수 6.85g를 가하여 실온에서 5일 동안 볼 밀링 방법으로 습식분쇄하여 나프록센 함유 슬러리 혼합물을 제조하였다. Step 1: To 0.6 g of poorly soluble naproxen, 0.05 g of water-soluble chitosan and 6.85 g of distilled water were added and wet-pulverized by ball milling at room temperature for 5 days to prepare a naproxen-containing slurry mixture.

단계 2: 0.02 중량%의 트리폴리포스페이트(Tripolyphosphate, 이하 TPP라 한다) 용액 100g을 교반시키면서 상기 제조된 나프록센 함유 슬러리 혼합물에 한방울씩(dropwise) 떨어뜨리면서 혼합하고, 1시간동안 실온에서 교반을 유지하면서 반응시켜 액상 제제로 제조하였다.Step 2: Mix 100 g of 0.02 wt% Tripolyphosphate (hereinafter referred to as TPP) solution while dropwise dropping it into the naproxen-containing slurry mixture prepared above, and react while maintaining stirring at room temperature for 1 hour. To prepare a liquid formulation.

<실시예 2><Example 2> 암세포Cancer cell 표적지향성을 갖는 약물나노입자 함유 제제의 제조Preparation of Drug Nanoparticle-containing Formulations with Target Orientation

단계 1: 항암제인 파클리탁셀 0.3g에 수용성 키토산 0.05g 및 증류수 7.15g를 가하여 실온에서 2 시간 동안 고속 밀링 방법으로 습식 분쇄하여(0.6 중량% 키토산 함유) 슬러리 혼합물을 제조하였다. Step 1: A slurry mixture was prepared by adding 0.05 g of water-soluble chitosan and 7.15 g of distilled water to 0.3 g of paclitaxel, an anticancer agent, and wet grinding (containing 0.6 wt% chitosan) at room temperature for 2 hours.

단계 2: 키토산을 가교시키기 위해, 이온가교제인 0.02 중량%의 TPP 용액 50g을 교반시키면서, 단계 1에서 제조된 슬러리 혼합물에 한방울씩 떨어뜨렸다. 1시간동안 실온에서 교반하면서 액상 제제를 제조하였다. Step 2: In order to crosslink the chitosan, 50 g of a 0.02% by weight TPP solution, an ion crosslinker, was added dropwise to the slurry mixture prepared in Step 1 with stirring. Liquid formulations were prepared with stirring at room temperature for 1 hour.

단계 3: 간암세포 표적지향성을 가지는 공지물질인 엽산과 N-3-디메틸아미노프로필 -N'-에틸카르보디이미드 하이드로클로라이드 (dimethylaminopropyl-N'-ethylcarbo diimide hydrochloride, 이하 EDC라 한다)를 1:1 몰 비율로 혼합하고 pH 9의 완충용액에 녹여 제조하였다. 이때, 엽산의 농도는 0.25 중량%였다. 상기 단계 2의 슬러리 혼합물을 엽산이 함유된 완충용액에 한 방울씩 떨어뜨려 실온에서 20시간동안 교반 반응시켜, 액상 제제를 제조하였다. 반응종료 후, 엽산의 존재는 NMR 스펙트럼을 통하여 확인하였다[미도시]. Step 3: Folic acid and N-3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (known as EDC), which are known targets for targeting liver cancer cells, are called 1: 1. It was prepared by mixing in a molar ratio and dissolved in a buffer solution of pH 9. At this time, the concentration of folic acid was 0.25% by weight. The slurry mixture of step 2 was dropped dropwise into the buffer solution containing folic acid and stirred at room temperature for 20 hours to prepare a liquid formulation. After completion of the reaction, the presence of folic acid was confirmed by NMR spectrum [not shown].

<실시예 3> 암세포Example 3 Cancer Cells 표적지향성을 갖는 약물나노입자 함유 제제의 제조Preparation of Drug Nanoparticle-containing Formulations with Target Orientation

상기 실시예 2의 단계 3에서 엽산과 EDC를 1:1 몰 비율로 혼합하고 pH 9의 완충용액에 녹여 제조할 때, 엽산의 농도를 각각 0.125 중량%, 0.25 중량% 및 0.5 중량%로 변화시킨, 엽산이 함유된 완충용액에 1.33 중량% 키토산 용액 7.5 g을 한 방울씩 떨어뜨려 실온에서 20 시간동안 교반 반응하는 것을 제외하고는, 상기 실시예 2와 동일하게 실시하여 표적지향성을 갖는 약물나노입자 함유 제제를 제조하였다.When folic acid and EDC are mixed in a 1: 1 molar ratio in step 3 of Example 2 and dissolved in a buffer solution of pH 9, the concentration of folic acid is changed to 0.125 wt%, 0.25 wt%, and 0.5 wt%, respectively. In the same manner as in Example 2, except that 7.5 g of a 1.33 wt% chitosan solution was added dropwise to a buffer solution containing folic acid, and stirred at room temperature for 20 hours. Containing formulations were prepared.

<실시예 4> 암세포 표적지향성을 갖는 약물나노입자 함유 제제의 제조Example 4 Preparation of Drug Nanoparticle-Containing Formulation with Cancer Cell Target Orientation

상기 실시예 2의 단계 1의 조성 대신에, 파클리탁셀 0.3 g에 수용성 키토산 0.025 g 및 증류수 7.175g로 이루어진 (0.3 중량% 키토산 함유) 슬러리 혼합물과 파클리탁셀 0.3g에 수용성 키토산 0.0125g 및 7.1875g로 이루어진 (0.16 중량% 키토산 함유) 슬러리 혼합물을 사용하는 것을 제외하고는, 상기 실시예 2와 동일하게 수행하였다.Instead of the composition of step 1 of Example 2, a slurry mixture (containing 0.3 wt% chitosan) of 0.025 g of water-soluble chitosan and 7.175 g of distilled water in 0.3 g of paclitaxel and 0.0125 g and 7.1875 g of water-soluble chitosan in 0.3 g of paclitaxel ( The same procedure as in Example 2 was carried out except that a slurry mixture containing 0.16 wt% chitosan was used.

<실시예 5> 암세포 표적지향성을 갖는 약물나노입자 함유 제제의 제조Example 5 Preparation of Drug Nanoparticle-Containing Formulation with Cancer Cell Target Orientation

상기 실시예 2에서 약물에 흡착되는 수용성 고분자로서 수용성 키토산 대신에, 파 클리탁셀 0.3g에 글루코산을 포함하는 단백질(G-protein) 0.025g, 페닐알라닌을 포함하는 단백질(F-protein) 0.025g 및 증류수 7.15g를 가하여 실온에서 5일 동안 습식 분쇄하여 슬러리 혼합물을 제조하여 사용하는 것을 제외하고는, 상기 실시예 2와 동일하게 수행하였다.Instead of water-soluble chitosan as a water-soluble polymer adsorbed to the drug in Example 2, 0.025 g of G-protein containing glucoic acid in 0.3 g of paclitaxel, 0.025 g of F-protein containing phenylalanine, and 7.15 g of distilled water was added thereto, followed by wet grinding at room temperature for 5 days to prepare and use a slurry mixture.

상기 실시예 5에서 제조된 표적지향성을 갖는 약물나노입자 함유 제제는 약물에 흡착된 수용성 고분자의 변화에도 불구하고, 상기 단백질과 엽산과의 화학적 결합을 확인하였으며, 이때, 파클리탁셀의 약물입자의 크기가 가교 전후에 차이가 없음을 광산란법을 통하여 확인하였다.The drug nanoparticle-containing preparation having the target orientation prepared in Example 5, despite the change of the water-soluble polymer adsorbed to the drug, confirmed the chemical binding of the protein and folic acid, wherein the size of the drug particles of paclitaxel It was confirmed through the light scattering method that there is no difference before and after crosslinking.

<실시예 6> 약물나노입자 함유 제제의 제조Example 6 Preparation of Drug Nanoparticle-Containing Formulation

상기 실시예 2에서 사용된 기능성 표적물질로서, 간암세포 표적지향성 엽산 대신에 점액점성(mucoadhesive)을 지닌 ALA-K 염(alpha-lipoic acid K salt)을 사용하는 것을 제외하고는, 상기 실시예 2와 동일하게 수행하였다. As a functional target material used in Example 2, except for using an alpha-lipoic acid K salt having mucoadhesive mucoadhesive instead of liver cancer cell-targeted folic acid, Example 2 Was performed in the same manner.

반응 종료 후, 자외선 분광광도계를 이용하여 1700 내지 1750 cm-1에서 흡수가 관찰되므로, 약물나노입자에 ALA가 존재함을 확인하고[미도시], 밀링에 의해 입자크기를 감소시키는 동시에 입자표면에 기능성 표적물질이 원활히 가교됨을 확인하였다. 또한, ALA-K는 인체내에 존재하는 항산화제로서 설파이드기를 함유하고 있어 상기 설파이드기를 통해 점막을 구성하는 단백질에 쉽게 흡착된다. 따라서 상기 점막부착성(mucoadhesive)을 지닌 ALA-K 염이 가교된 약물나노입자는 선택적 장용제로 활용할 수 있다.After completion of the reaction, absorption was observed at 1700 to 1750 cm -1 using an ultraviolet spectrophotometer, thus confirming the presence of ALA in the drug nanoparticles [not shown], and reducing the particle size by milling, It was confirmed that the functional target material was smoothly crosslinked. In addition, ALA-K contains sulfide groups as antioxidants present in the human body and is easily adsorbed to proteins constituting mucosa through the sulfide groups. Therefore, the drug nanoparticles crosslinked with the ALA-K salt having mucoadhesive may be used as a selective enteric agent.

<실시예 7> 약물나노입자 함유 제제의 제조Example 7 Preparation of Drug Nanoparticle-Containing Formulation

단계 1: 파클리탁셀 0.3g에 표면안정화를 위한 수용성 고분자로서, 플루로닉(pluronic) F127 0.05g 및 증류수 7.15g를 가하여 실온에서 5일 동안 저속밀링 방법으로 습식 분쇄하여 슬러리 혼합물을 제조하였다. Step 1: As a water-soluble polymer for surface stabilization to 0.3 g of paclitaxel, 0.05 g of pluronic F127 and 7.15 g of distilled water were added, and the resultant slurry was prepared by wet milling at room temperature for 5 days by slow milling.

단계 2: 사이클로덱스트린 표면에 엽산이 부착된 변형된 사이클로덱스트린(엽산-PEG-사이클로덱스트린) 0.01g을 증류수 1g에 녹이고 상기 슬러리 혼합물에 한 방울씩 떨어뜨렸다. 밀링 공정 동안 실온에서 20시간동안 교반 반응시켰다. Step 2: 0.01 g of modified cyclodextrin (folic acid-PEG-cyclodextrin) with folic acid attached to the surface of the cyclodextrin was dissolved in 1 g of distilled water and dropped dropwise into the slurry mixture. The reaction was stirred for 20 hours at room temperature during the milling process.

충분히 분쇄된 입자크기와 사이클로덱스트린과의 가교반응 후 파클리탁셀의 부피평균 입자크기는 각각 440 nm 및 450 nm로서, 입자크기 변화가 없음을 광산란법을 이용하여 확인하였다. 또한, X-ray 산란(diffraction) 결과로부터, 플루로닉 F127과 엽산-PEG-사이클로덱스트린이 가교 결합된 것을 확인하였다[도 7]. 도 7에서 보는 바와 같이, 사이클로덱스트린 자체의 스펙트럼에 대비하여, 사이클로덱스트린과 고분자의 비를 20:12(a), 10:12(b) 및 5:12(c)로 달리하여 관찰한 결과, 18∼20도 범위에서 피크를 확인함으로써, 사이클로덱스트린에 의해 가교된 상태를 확인하였다.The volume average particle size of paclitaxel after crosslinking reaction with sufficiently pulverized particle size and cyclodextrin was 440 nm and 450 nm, respectively, and it was confirmed using the light scattering method. From the results of X-ray scattering, it was confirmed that Pluronic F127 and folic acid-PEG-cyclodextrin were crosslinked [ FIG. 7 ]. As shown in Figure 7, compared with the spectrum of the cyclodextrin itself, the ratio of the cyclodextrin and the polymer was observed by differently 20: 12 (a), 10: 12 (b) and 5: 12 (c), By confirming the peak in the range of 18 to 20 degrees, the state crosslinked by cyclodextrin was confirmed.

<실험예 1> Experimental Example 1

1. 공정 상 입자크기 변화측정1. Measurement of particle size change in process

상기 실시예 1의 각 단계에서 제조된 슬러리 혼합물의 입자 크기에 대하여, 레이저 회절 입도 분석기(일본, 호리바사, 모델명 LA 910)를 사용하고 상대굴절률(Relative Refraction Index)을 1로 설정하여 제조공정 상, 수성 조건에서 측정하였다. For the particle size of the slurry mixture prepared in each step of Example 1, using a laser diffraction particle size analyzer (Horiba, Japan, model name LA 910) and the relative refractive index (Relative Refraction Index) is set to 1 in the manufacturing process , Measured under aqueous conditions.

입자 크기 측정 시, 사용된 초음파 분산기의 분해 전력은 40W(39 kHz)이고, 교반 속도와 순환속도는 340 ㎖/분이다. 이때, 초음파 분산 1분을 수행한 후, 입자크기를 측정하여 그 결과를 도 2에 도시하였다. In the particle size measurement, the dissipation power of the ultrasonic disperser used was 40 W (39 kHz), and the stirring speed and circulation rate were 340 ml / min. At this time, after performing the ultrasonic dispersion for 1 minute, the particle size is measured and the result is shown in FIG.

도 2의 결과로부터, 단계 1에서 나프록센의 입자크기는 0.25 ㎛였고, 단계 2에서 가교반응 후의 입자크기는 0.45 ㎛로 관찰되었다. 따라서, 본 발명의 약물나노입자를 함유하는 제제의 제조방법은 볼 밀링 등의 습식분쇄 공정에서 약물의 나노입자크기로 관찰되며, 가교반응 공정 이후에도 약물의 입자크기의 변화 없이 보존되었다.From the results of FIG. 2, the particle size of naproxen in step 1 was 0.25 μm, and the particle size after crosslinking in step 2 was 0.45 μm. Therefore, the preparation method of the preparation containing the drug nanoparticles of the present invention was observed in the nanoparticle size of the drug in the wet grinding process, such as ball milling, and was preserved without changing the particle size of the drug even after the crosslinking reaction process.

2. 공정 상 입자표면 측정2. Measurement of particle surface in process

실시예 1의 단계 2에서 제조된 나프록센 약물의 나노입자를 함유하는 제제에서 나프록센 입자를 녹여 제거하고, 약물제거 전후의 가교된 고분자 형상을 TEM(transmission electron microscopy, Rigaku D/Max-2500/PC X-ray diffractometer. Cu-Kα 0.154 nm, 40 kV, 40 mA) 이미지를 이용하여 관찰하였다. In the formulation containing nanoparticles of naproxen drug prepared in step 2 of Example 1, naproxen particles are dissolved and removed, and crosslinked polymer shapes before and after drug removal are TEM (transmission electron microscopy, Rigaku D / Max-2500 / PC X). -ray diffractometer Cu-Kα 0.154 nm, 40 kV, 40 mA) was observed using the image.

도 3에서 (a)는 실시예 1의 단계 2를 액상 제제에서, 나프록센 입자를 제거하기 전이고 (b)는 나프록센 입자를 제거한 후의 가교된 고분자 형상결과이다. 상기 결과로부터, 수용성 키토산과 이온 가교제로 사용된 TPP는 안정된 가교결합 형태로 관찰되었으며, 나프록센 입자를 제거와 무관하게 가교 결합형태가 유지되었다. 본 약학적 기능성물질층은 나프록센 입자를 녹여 제거할 때, 수 차례 정제 후 TEM 실험을 측정하는 과정에서도, 용해되지 않는 수용성 젤 상태로 유지되었다.In Figure 3 (a) is a step 2 of Example 1 in the liquid formulation, before removing the naproxen particles and (b) is a cross-linked polymer shape after removing the naproxen particles. From the above results, the water-soluble chitosan and the TPP used as the ion crosslinking agent were observed in a stable crosslinked form, and the crosslinked form was maintained regardless of the removal of naproxen particles. The pharmaceutical functional layer was maintained in an insoluble water-soluble gel state even after measuring the TEM experiment after several times of purification when dissolving and removing naproxen particles.

따라서, 본 발명의 약물나노입자를 함유하는 제제의 제조방법은 나노입자크기를 유지하고 나노입자의 안정화를 구현하였다.Therefore, the preparation method of the preparation containing the drug nanoparticles of the present invention is to maintain the nanoparticle size and to stabilize the nanoparticles.

더 나아가, 실시예 1에서 사용된 용매 이외에도, 에탄올, 메탄올 또는 프로판올과의 혼합용매 조건에서도 수용성 키토산과 이온가교제간의 안정된 가교를 확인하였다[미도시]. Furthermore, in addition to the solvent used in Example 1, stable crosslinking between the water-soluble chitosan and the ion crosslinking agent was confirmed even under mixed solvent conditions with ethanol, methanol or propanol [not shown].

<실험예 2> Experimental Example 2

1. 공정 상 입자크기 변화측정1. Measurement of particle size change in process

상기 실시예 2의 각 단계에서 제조된 슬러리 혼합물의 입자 크기에 대하여, 레이저 회절 입도 분석기(일본, 호리바사, 모델명 LA 910)를 통해 파클리탁셀 입자의 평균입경을 측정하였다. For the particle size of the slurry mixture prepared in each step of Example 2, the average particle diameter of paclitaxel particles was measured through a laser diffraction particle size analyzer (Horiba, Japan, model name LA 910).

도 4는 본 발명의 표적지향성 항암제의 약물나노입자를 함유하는 액상 제제에 대하여 공정 상, 단계별 입자크기를 비교한 결과로서, 단계 1에서의 파클리탁셀의 입자크기는 0.40 ㎛, 단계 2 및 3에서의 입자크기는 각각 0.37 ㎛ 및 0.44 ㎛로 관찰되었다. 4 is a result of comparing the particle size of the liquid phase containing the drug nanoparticles of the target-oriented anticancer agent of the present invention in the process, step by step, the particle size of paclitaxel in step 1 is 0.40 ㎛, step 2 and 3 Particle sizes were observed to be 0.37 μm and 0.44 μm, respectively.

상기 결과로부터, 수용성 키토산이 이온가교제와 가교반응하고, 간암세포 표적지향성의 엽산과의 추가 반응 이후에도, 파클리탁셀의 나노입자크기는 거의 변화가 없었다. 따라서 본 발명의 제조방법은 약물이 나노입자화된 이후, 추가공정을 실시함에도 불구하고, 나노입자의 응집 현상 없이, 나노입자가 유지됨을 확인하였다.From the above results, the water-soluble chitosan crosslinked with the ion crosslinking agent, and even after further reaction with the liver cancer cell-oriented folate, the nanoparticle size of paclitaxel was almost unchanged. Therefore, the manufacturing method of the present invention was confirmed that the nanoparticles are maintained without agglomeration phenomenon of the nanoparticles, even though the drug is nanoparticles, after performing the additional process.

2. 공정 상 입자표면 측정2. Measurement of particle surface in process

실시예 2의 단계 1 및 단계 3의 공정 상, 파클리탁셀 입자형상을 TEM 이미지를 이 용하여 관찰하였다. In the process of Step 1 and Step 3 of Example 2, paclitaxel particle shape was observed using a TEM image.

도 5에서 보는 바와 같이, (a)는 단계 1 및 (b)는 단계 3의 파클리탁셀 입자를 관찰한 결과, 표면형상 역시 거의 변화가 없었다. As shown in Figure 5, (a) step 1 and (b) observed the paclitaxel particles of step 3, the surface shape also showed little change.

<실험예 3>Experimental Example 3 용출속도 실험 Dissolution Rate Experiment

상기 실시예 2에서 제조된 약물나노입자 함유 제제에 있어서, 키토산의 가교가 약물의 용출속도에 미치는 영향을 알아보기 위하여 하기와 같이 용출 실험하였다. In the drug nanoparticle-containing preparation prepared in Example 2, the dissolution experiment was carried out as follows to determine the effect of crosslinking chitosan on the dissolution rate of the drug.

실시예 2에서 제조된 약물 나노입자의 제조단계 1의 슬러리 혼합물과 제조단계 3에서 제조된 슬러리 혼합물의 용출속도를 비교하였다. The dissolution rate of the slurry mixture prepared in Preparation Step 1 and the slurry mixture prepared in Preparation Step 3 of the drug nanoparticles prepared in Example 2 was compared.

파클리탁셀 10 mg을 함유한 슬러리 혼합물이 들어 있는 투석막을 pH 7.4의 PBS 용액 500 ㎖에 넣고, 37.5℃에서 100rpm으로 교반하였다. 정해진 시간마다 PBS 용액을 5 ㎖씩 꺼내고 새로운 PBS 용액 5 ㎖을 넣어주었다. 파클리탁셀 농도는 HPLC를 사용하여 측정하여 그 결과를 도 6에 기재하였다.The dialysis membrane containing the slurry mixture containing 10 mg of paclitaxel was placed in 500 ml of a PBS solution of pH 7.4 and stirred at 100 rpm at 37.5 ° C. 5 ml of PBS solution was taken out every 5 hours and 5 ml of fresh PBS solution was added. Paclitaxel concentration was measured using HPLC and the results are shown in FIG. 6.

도 6에서 보는 바와 같이, 가교된 키토산이 흡착된 단계 3의 파클리탁셀 약물이 가교되지 않은 단계 1에 비해 더 천천히 용출됨을 확인하였다. 따라서, 이러한 가교를 통해 약물의 맛을 차단(taste masking)하는 효과와 안정화 효과를 얻을 수 있다. As shown in FIG. 6, it was confirmed that the paclitaxel drug of step 3 to which the crosslinked chitosan was adsorbed was more slowly eluted than that of step 1 which was not crosslinked. Therefore, through the crosslinking it is possible to obtain a taste masking effect and the stabilizing effect of the drug (taste masking).

<실험예 4> 엽산 농도에 따른 키토산과의 반응 Experimental Example 4 Reaction with Chitosan According to Folic Acid Concentration

상기 실시예 3에서 제조된 표적지향성을 갖는 약물나노입자 함유 제제에 대하여, 엽산의 농도에 따라 수용성 키토산과 반응하는 양을 관찰하기 위하여 하기와 같이 실험하였다. The drug nanoparticle-containing preparation having the target orientation prepared in Example 3 was tested as follows to observe the amount of reacting with the water-soluble chitosan according to the concentration of folic acid.

상기 실시예 3에서 반응 완료된 약물처리군을 투석막(MWCO: 1000)을 통하여 3일 동안 투석시켰다. 투석시킨 혼합물을 원심분리기를 사용하여 상층과 하층으로 분리시킨 후에 상층액은 액체질소에 얼려 동결 건조시켰다. 건조된 분말을 물에 녹여 반응한 엽산의 농도를 자외선 분광광도계를 이용하여 측정하였다. The drug treatment group in which the reaction was completed in Example 3 was dialyzed through a dialysis membrane (MWCO: 1000) for 3 days. After the dialysis mixture was separated into an upper layer and a lower layer using a centrifuge, the supernatant was lyophilized by freezing in liquid nitrogen. The concentration of folic acid reacted by dissolving the dried powder in water was measured using an ultraviolet spectrophotometer.

도 8은 본 발명의 난용성 약물나노입자 함유 제제의 제조공정 상, 약학적 기능기인 엽산의 농도 0.125 중량%(a), 0.25 중량%(b) 및 0.5 중량%(c)에 따른 수용성 키토산과의 가교결합에 대한 자외선 분광학적인 결과이다. 그 결과, 엽산의 흡수파장은 370 nm으로 관찰됨으로써 엽산의 존재를 확인하고, 사용한 농도에 큰 변화 없이 표면 기능성약물층에 반응한 엽산의 농도는 일정하였다. 따라서, 기능성약물층을 형성하는 키토산과 엽산의 전체 중량 대비 엽산의 농도는 약 1 내지 10 중량%이었다.8 is a water-soluble chitosan according to the concentration of 0.125% by weight (a), 0.25% by weight (b) and 0.5% by weight (c) of folic acid as a pharmaceutical functional group in the preparation process of the poorly soluble drug nanoparticle-containing preparation of the present invention Ultraviolet spectroscopic results for crosslinking of. As a result, the absorption wavelength of folic acid was observed at 370 nm to confirm the presence of folic acid, and the concentration of folic acid in response to the surface functional drug layer was constant without significant change in the concentration used. Therefore, the concentration of folic acid relative to the total weight of chitosan and folic acid forming the functional drug layer was about 1 to 10% by weight.

<실험예 5> Experimental Example 5

상기 실시예 4에서 제조된 표적지향성을 갖는 약물나노입자 함유 제제에 대하여, 약물과 혼합하는 키토산의 양을 변화시킨 후 엽산과 반응시켜 입자크기의 변화를 관찰하였다.For the drug nanoparticle-containing preparation prepared in Example 4, the amount of chitosan mixed with the drug was changed and then reacted with folic acid to observe a change in particle size.

상기 키토산 양에 따른 약물입자의 크기를 하기 표 1에 기재하였다.The size of the drug particles according to the amount of chitosan is shown in Table 1 below.

Figure 112007089305545-pat00001
Figure 112007089305545-pat00001

상기 표 1에서 보이는 바와 같이, 키토산의 양에 상관없이 엽산과 반응 후에 제조된 파클리탁셀의 입자크기는 거의 변화가 없었다. 상기의 결과로부터, 본 발명의 수용성 키토산이 약물 표면에 흡착되는 공정과 기능성 물질인 엽산과의 가교반응 공정에 무관하게 나노입자로 제조된 약물의 크기는 전 공정을 거쳐 일정하게 유지됨을 확인하였다. 즉, 밀링의 간단한 공정을 통하여 약물이 나노입자화되면, 이후 공정에도 나노입자크기가 유지되므로, 본 발명의 제조방법은 나노입자의 안정화를 구현한다. As shown in Table 1, regardless of the amount of chitosan, the particle size of paclitaxel prepared after the reaction with folic acid was almost unchanged. From the above results, regardless of the step of adsorbing the water-soluble chitosan of the present invention on the surface of the drug and the crosslinking reaction with folic acid as a functional material, it was confirmed that the size of the drug made of nanoparticles is kept constant throughout the entire process. That is, if the drug is nanoparticles through a simple process of milling, since the nanoparticle size is maintained in subsequent processes, the production method of the present invention implements stabilization of the nanoparticles.

상기에서 살펴본 바와 같이, 본 발명은 As described above, the present invention

첫째, 밀링에 의한 분쇄단계에서 약물표면상에 약학적 기능성 작용기를 일공정으로 도입할 수 있는 제조방법을 제공함으로써, 간단하고 저렴한 밀링 방법으로 수행하면서 약물표면상에 약학적 기능성 작용기가 도입하므로 경제적인 제조방법을 제공할 수 있다. First, by providing a manufacturing method that can introduce the pharmacological functional group on the drug surface in one step in the milling step by milling, it is economical because it introduces the pharmacological functional group on the drug surface while performing a simple and inexpensive milling method Phosphorus manufacturing method can be provided.

둘째, 분쇄단계에서 제조된 약물의 나노입자가 전 공정과정에서 입자간의 응집 없 이, 나노입자크기를 유지할 수 있으므로 나노입자의 안정화방법을 제공함으로써, 약물나노입자의 활용도를 높일 수 있다.Second, since the nanoparticles of the drug prepared in the grinding step can maintain the nanoparticle size without agglomeration between the particles in the whole process, by providing a method for stabilizing the nanoparticles, it is possible to increase the utilization of drug nanoparticles.

이상에서 본 발명은 기재된 구체 예에 대해서만 상세히 설명되었지만 본 발명의 기술사상 범위내에서 다양한 변형 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속함은 당연한 것이다. Although the present invention has been described in detail only with respect to the described embodiments, it will be apparent to those skilled in the art that various modifications and variations are possible within the technical spirit of the present invention, and such modifications and modifications belong to the appended claims.

도 1은 본 발명의 제조방법에 의해 제조된 표면이 개질된 약물나노입자 제제의 모식도이고, 1 is a schematic diagram of a drug nanoparticle formulation having a surface modified by the production method of the present invention,

도 2는 본 발명의 난용성 약물나노입자 함유 제제의 제조공정 상, 단계별 입자크기를 비교한 결과로서, (a)는 분쇄단계의 약물입자크기이고, (b)는 이온가교제 첨가로 키토산과 가교된 후의 약물입자크기이고, Figure 2 is a result of comparing the particle size of the poorly soluble drug nanoparticle-containing preparation of the present invention, step by step, (a) is the drug particle size of the grinding step, (b) is crosslinked with chitosan by the addition of an ion crosslinking agent Drug particle size after

도 3은 도 2의 제제의 제조공정 상, (a)는 약물이 제거되기 전의 가교된 고분자 형상이고, (b)는 약물이 제거된 후의 가교된 고분자 형상이고, 3 is in the preparation of the formulation of Figure 2, (a) is a cross-linked polymer shape before the drug is removed, (b) is a cross-linked polymer shape after the drug is removed,

도 4는 본 발명의 암세포 표적지향성을 갖는 약물나노입자 함유 제제의 공정 상, 단계별 입자크기를 비교한 결과로서, (a)는 분쇄단계의 약물입자크기이고, (b)는 이온가교제 첨가로 키토산과 가교된 후의 약물입자크기이고, (c)는 암세포 표적지향성물질과의 가교반응 후의 약물입자크기이고, 4 is a cancer cell of the present invention As a result of comparing the particle size for each step of the drug nanoparticle-containing preparation having a target orientation, (a) is the drug particle size of the grinding step, (b) is the drug particle size after crosslinking with chitosan by the addition of an ion crosslinking agent (C) is the drug particle size after crosslinking reaction with the cancer cell target-oriented substance,

도 5는 도 4의 제제의 제조공정 상, (a)는 단계 1의 고분자 형상이고, (b)는 단계 3의 가교된 고분자 형상이고, 5 is in the manufacturing process of the formulation of Figure 4, (a) is a polymer of step 1, (b) is a cross-linked polymer of step 3,

도 6은 본 발명의 암세포 표적지향성을 갖는 약물나노입자 함유 제제의 공정 상, 단계별 약물의 용출실험결과를 나타낸 것으로 (a)는 단계 1의 약물과 키토산이 분산된 후의 용출실험결과이고, (b)는 단계 3의 약물에 암세포 표적지향성물질과의 가교반응 후의 용출실험결과이고, 6 is a cancer cell of the present invention The results of the dissolution test of the drug step by step in the drug nanoparticle-containing preparation having a target orientation, (a) is the dissolution test result after the drug of step 1 and chitosan is dispersed, (b) is the drug of step 3 Results of elution after crosslinking reaction with cancer cell target-oriented substances,

도 7은 본 발명의 난용성 약물나노입자 함유 제제의 제조공정 상, 약학적 기능기와 수용성 고분자간의 가교결합에 대한 결과이고, 7 is a result of the crosslinking between the pharmaceutical functional group and the water-soluble polymer in the manufacturing process of the poorly water-soluble drug nanoparticle-containing preparation of the present invention,

도 8은 본 발명의 난용성 약물나노입자 함유 제제의 제조공정 상, 약학적 기능기인 엽산의 농도에 따른 수용성 키토산의 가교결합에 대한 자외선 분광학적인 결과이다. 8 is an ultraviolet spectroscopic result of crosslinking of water-soluble chitosan according to the concentration of folic acid as a pharmaceutical functional group in the preparation process of the poorly soluble drug nanoparticle-containing preparation of the present invention.

Claims (16)

1) 약물과 수용성 고분자로 이루어진 표면안정화제를 함유하는 수용성 분산액을 밀링에 의해 상기 약물의 입자크기를 50 내지 800 nm로 습식분쇄하여 슬러리 혼합물을 제조하고, 1) a slurry mixture is prepared by wet grinding an aqueous dispersion containing a surface stabilizer consisting of a drug and a water-soluble polymer by milling the particle size of the drug to 50 to 800 nm. 2) 상기 슬러리 혼합물 제조공정에, 암세포 표적지향성 물질을 포함하는 약학적 기능물질 함유 수용액을 혼합하여 상기 수용성 고분자와 약학적 기능물질을 화학가교반응시켜, 2) chemically crosslinking the water-soluble polymer and the pharmaceutical functional material by mixing an aqueous solution containing a pharmaceutical functional material containing a cancer cell target-oriented substance in the slurry mixture manufacturing process, 상기 밀링 공정과 화학가교반응동안 약물의 입자크기가 50 내지 800nm로 유지되면서 약물나노입자 표면상에 선택적으로 약학적 기능물질이 도입되도록 하는 약물나노입자의 제조방법.A method for producing drug nanoparticles to selectively introduce a pharmaceutical functional material on the surface of the drug nanoparticles while maintaining the particle size of the drug at 50 to 800 nm during the milling process and the chemical crosslinking reaction. 삭제delete 삭제delete 제1항에 있어서, 상기 약물이 수용성 고분자를 함유하는 수용성 분산액에 0.1 내지 60중량% 함유하는 것을 특징으로 하는 상기 제조방법.The method according to claim 1, wherein the drug is contained in an aqueous dispersion containing 0.1 to 60% by weight in an aqueous dispersion containing a water-soluble polymer. 제1항에 있어서, 상기 수용성 고분자가 레시틴, 폴리옥시에틸렌, 폴록사머, 폴리프로필렌 글리콜, 메틸 셀룰로오스, 에틸 셀룰로오즈, 히드록시메틸 셀룰로오스, 히드록시에틸 셀룰로오스, 히드록시프로필 셀룰로오스, 히드록시프로필 메틸셀룰로오스, 카복시메틸 셀룰로오스, 폴리비닐알코올, 폴리비닐피롤리돈, 카라긴산, 알긴산, 알긴산나트륨, 수용성 키토산, 글루코산 또는 페닐알라닌을 포함하는 단백질, 폴리아닐린, 폴리피롤, 셀룰로오스 아세테이트로 이루어진 군에서 선택되는 단독 또는 1종 이상의 혼합형태인 것을 특징으로 하는 상기 제조방법.The method of claim 1, wherein the water-soluble polymer is lecithin, polyoxyethylene, poloxamer, polypropylene glycol, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, carrageic acid, alginic acid, sodium alginate, water soluble chitosan, gluconic acid or phenylalanine protein, polyaniline, polypyrrole, cellulose acetate alone or one selected from the group consisting of Said manufacturing method characterized by the above-mentioned mixed form. 제1항에 있어서, 상기 단계 1에 트리폴리포스페이트, 염화칼슘, 수산화칼슘, 표면처리 또는 미처리된 사이클로덱스트린 및 카보다이이미드 화합물로 이루어진 군에서 선택되는 어느 하나의 이온 가교제를 수용성 고분자 성분 중량 대비 0.1 내지 20 중량%를 더 혼합하는 것을 특징으로 하는 상기 제조방법.The method according to claim 1, wherein in step 1, any one ion crosslinker selected from the group consisting of tripolyphosphate, calcium chloride, calcium hydroxide, surface treated or untreated cyclodextrin, and carbodiimide compound is 0.1 to 20% by weight based on the weight of the water-soluble polymer component. Said production method, characterized in that the mixture further. 제1항에 있어서, 상기 암세포 표적지향성 물질이 엽산, 글리콜산 및 RGD 펩타이드로 이루어진 군에서 선택되는 어느 하나이며, 수용해성 물질인 것을 특징으로 하는 상기 제조방법.The method of claim 1, wherein the cancer cell target-directing material is any one selected from the group consisting of folic acid, glycolic acid, and RGD peptide, and the water-soluble substance. 제1항의 제조방법으로부터 난용성 약물나노입자와 수용성 고분자가 밀링에 의한 습식분쇄로 난용성 약물의 입자크기가 50 내지 800nm로 균일 분산되고, 상기 수용성 고분자와 표적지향성 물질과의 화학가교반응에 의해, According to claim 1, the poorly soluble drug nanoparticles and the water-soluble polymer are uniformly dispersed to 50 to 800 nm in particle size of the poorly soluble drug by wet grinding by milling, and by the chemical crosslinking reaction between the water-soluble polymer and the target-oriented material. , 난용성 약물나노입자 표면상에 표적지향성 물질층이 형성된 구조이며, 상기 표적지향성 물질층 내부에 상기 난용성 약물나노입자를 담지하고 난용성 약물 표면상에서 표적지향성을 가지는 약물나노입자 제제. A drug nanoparticle formulation having a structure in which a target-oriented material layer is formed on a surface of a poorly soluble drug nanoparticle, carrying the poorly soluble drug nanoparticle in the target-oriented material layer, and having a target orientation on a poorly soluble drug surface. 삭제delete 삭제delete 삭제delete 제8항에 있어서, 상기 수용성 고분자가 수용성 키토산; 표면처리 또는 미처리된 사이클로덱스트린; 글루코산 또는 페닐알라닌을 포함하는 단백질; 폴리아닐린; 폴리피롤; 셀룰로오스 아세테이트; 및 폴리에틸렌글리콜;로 이루어진 군에서 선택되는 단독 또는 1종 이상의 혼합형태인 것을 특징으로 하는 상기 약물나노입자 제제. The method of claim 8, wherein the water-soluble polymer is water-soluble chitosan; Surface treated or untreated cyclodextrins; Proteins including glucoic acid or phenylalanine; Polyaniline; Polypyrrole; Cellulose acetate; And polyethylene glycol; wherein the drug nanoparticles preparation is selected from the group consisting of one or more. 삭제delete 삭제delete 제8항에 있어서, 상기 표적지향성 물질이 엽산, 글리콜산 및 RGD 펩타이드로 이루어진 군에서 선택되는 어느 하나인 것을 특징으로 하는 상기 약물나노입자 제제.The drug nanoparticle formulation of claim 8, wherein the target-oriented substance is any one selected from the group consisting of folic acid, glycolic acid, and RGD peptide. 삭제delete
KR1020070128949A 2007-12-12 2007-12-12 Manufacturing method of functional drug nanoparticles using milling and functional drug nanoparticle formulation manufactured thereby KR100961880B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1020070128949A KR100961880B1 (en) 2007-12-12 2007-12-12 Manufacturing method of functional drug nanoparticles using milling and functional drug nanoparticle formulation manufactured thereby
PCT/KR2007/006596 WO2009075401A1 (en) 2007-12-12 2007-12-17 Manufacturing method of functional drug nanoparticles using milling and functional drug nanoparticle formulation manufactured thereby

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020070128949A KR100961880B1 (en) 2007-12-12 2007-12-12 Manufacturing method of functional drug nanoparticles using milling and functional drug nanoparticle formulation manufactured thereby

Publications (2)

Publication Number Publication Date
KR20090061933A KR20090061933A (en) 2009-06-17
KR100961880B1 true KR100961880B1 (en) 2010-06-09

Family

ID=40755625

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020070128949A KR100961880B1 (en) 2007-12-12 2007-12-12 Manufacturing method of functional drug nanoparticles using milling and functional drug nanoparticle formulation manufactured thereby

Country Status (2)

Country Link
KR (1) KR100961880B1 (en)
WO (1) WO2009075401A1 (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUP1000299A2 (en) 2010-06-08 2012-02-28 Nanoform Cardiovascular Therapeutics Ltd Nanostructured atorvastatin, its pharmaceutically acceptable salts and pharmaceutical compositions containing them and process for their preparation
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
TN2016000077A1 (en) 2013-09-16 2017-07-05 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
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
ES2914305T3 (en) * 2017-12-26 2022-06-09 Ind Tech Res Inst Composition to improve the solubility of poorly soluble substances, use thereof and complex formulation containing the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2207961A1 (en) * 1995-01-05 1996-07-11 Robert J. Levy Surface-modified nanoparticles and method of making and using same
KR100345466B1 (en) * 1999-10-08 2002-07-26 한국과학기술연구원 Surface modified microspheres with cholera toxin B subunit

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles

Also Published As

Publication number Publication date
WO2009075401A1 (en) 2009-06-18
KR20090061933A (en) 2009-06-17

Similar Documents

Publication Publication Date Title
KR100961880B1 (en) Manufacturing method of functional drug nanoparticles using milling and functional drug nanoparticle formulation manufactured thereby
KR20100052262A (en) Process for preparing powder comprising nanoparticles of sparingly soluble drug, powder prepared by same process and pharmaceutical composition comprising same powder
Seljak et al. Mesoporous silica nanoparticles as delivery carriers: An overview of drug loading techniques
Yang et al. Improved pH-dependent drug release and oral exposure of telmisartan, a poorly soluble drug through the formation of drug-aminoclay complex
Fong et al. Solubility enhancement of BCS Class II drug by solid phospholipid dispersions: Spray drying versus freeze-drying
KR20090027734A (en) Process for preparing powder comprising nanoparticles of sparingly soluble drug
EP3466264B1 (en) Methods for drug delivery comprising unfolding and folding proteins and peptide nanoparticles
CN101237891B (en) Pharmaceutical formulation with high stability and dissolution and manufacturing process
Fang et al. Novel hydrophobin-coated docetaxel nanoparticles for intravenous delivery: in vitro characteristics and in vivo performance
Liu et al. A wet-milling method for the preparation of cilnidipine nanosuspension with enhanced dissolution and oral bioavailability
WO2014108076A1 (en) Gel composition of insoluble drug and preparation method therefor
KR20060123384A (en) Drug-containing nanoparticle, process for producing the same and parenterally administered preparation from the nanoparticle
JP2007238593A (en) Percutaneous administration composition containing piroxicam-inorganic substance complex and patch system using the same
CA2678455A1 (en) Enhanced delivery of immunosuppressive drug compositions for pulmonary delivery
Zhang et al. Development of novel mesoporous nanomatrix-supported lipid bilayers for oral sustained delivery of the water-insoluble drug, lovastatin
Kamble et al. Norfloxacin mixed solvency based solid dispersions: An in-vitro and in-vivo investigation
US20120148637A1 (en) Nanoparticulate olmesartan medoxomil compositions, process for the preparation thereof and pharmaceutical compositions containing them
WO2020043735A1 (en) Preparation of nanosuspension comprising nanocrystals of active pharmaceutical ingredients with little or no stabilizing agents
Sharma et al. Cubosome: a potential liquid crystalline carrier system
Gârea et al. Clay–polymer nanocomposites for controlled drug release
Chen et al. A facile nanoaggregation strategy for oral delivery of hydrophobic drugs by utilizing acid–base neutralization reactions
Das et al. An outlook towards nano-sponges: a unique drug delivery system and its application in drug delivery
Liu et al. Unlocking the potential of amorphous calcium carbonate: A star ascending in the realm of biomedical application
KR100834148B1 (en) Pharmaceutical formulations for itraconazole
Kanaujia et al. Preparation, characterization and prevention of auto-oxidation of amorphous sirolimus by encapsulation in polymeric films using hot melt extrusion

Legal Events

Date Code Title Description
A201 Request for examination
E902 Notification of reason for refusal
AMND Amendment
E601 Decision to refuse application
AMND Amendment
J121 Written withdrawal of request for trial
J201 Request for trial against refusal decision
B701 Decision to grant
GRNT Written decision to grant
FPAY Annual fee payment

Payment date: 20130429

Year of fee payment: 4

FPAY Annual fee payment

Payment date: 20140326

Year of fee payment: 5

FPAY Annual fee payment

Payment date: 20150417

Year of fee payment: 6

FPAY Annual fee payment

Payment date: 20160325

Year of fee payment: 7

LAPS Lapse due to unpaid annual fee