CN114668857B - 一种氨基功能化手性介孔二氧化硅的制备方法及其应用 - Google Patents
一种氨基功能化手性介孔二氧化硅的制备方法及其应用 Download PDFInfo
- Publication number
- CN114668857B CN114668857B CN202210370292.2A CN202210370292A CN114668857B CN 114668857 B CN114668857 B CN 114668857B CN 202210370292 A CN202210370292 A CN 202210370292A CN 114668857 B CN114668857 B CN 114668857B
- Authority
- CN
- China
- Prior art keywords
- mesoporous silica
- amino
- chiral mesoporous
- stirring
- alanine
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active
Links
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 title claims abstract description 138
- 239000000377 silicon dioxide Substances 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 47
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 21
- 229960003767 alanine Drugs 0.000 claims abstract description 20
- 229960000905 indomethacin Drugs 0.000 claims abstract description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 26
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 16
- 239000008367 deionised water Substances 0.000 claims description 13
- 229910021641 deionized water Inorganic materials 0.000 claims description 13
- IYUKFAFDFHZKPI-DFWYDOINSA-N methyl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](C)N IYUKFAFDFHZKPI-DFWYDOINSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 235000021314 Palmitic acid Nutrition 0.000 claims description 11
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 claims description 10
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 27
- 125000000524 functional group Chemical group 0.000 abstract description 9
- 230000008901 benefit Effects 0.000 abstract description 7
- 239000003937 drug carrier Substances 0.000 abstract description 7
- 239000011664 nicotinic acid Substances 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000004090 dissolution Methods 0.000 abstract description 4
- 230000004048 modification Effects 0.000 abstract description 2
- 238000012986 modification Methods 0.000 abstract description 2
- 239000002086 nanomaterial Substances 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000003945 anionic surfactant Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- 239000011148 porous material Substances 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000000463 material Substances 0.000 description 8
- 238000010586 diagram Methods 0.000 description 7
- 238000011068 loading method Methods 0.000 description 7
- 241000700159 Rattus Species 0.000 description 6
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 6
- 238000012377 drug delivery Methods 0.000 description 6
- 238000007306 functionalization reaction Methods 0.000 description 6
- 229910052710 silicon Inorganic materials 0.000 description 6
- 239000010703 silicon Substances 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000003917 TEM image Methods 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 238000005452 bending Methods 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 229940117538 indomethacin 40 mg Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910003849 O-Si Inorganic materials 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 229910003872 O—Si Inorganic materials 0.000 description 1
- 206010035148 Plague Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000006087 Silane Coupling Agent Substances 0.000 description 1
- 229910002808 Si–O–Si Inorganic materials 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- -1 amino, carboxyl Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960004195 carvedilol Drugs 0.000 description 1
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000013335 mesoporous material Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 238000005475 siliconizing Methods 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- 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
- A61K47/6923—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 an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
- B01J20/10—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising silica or silicate
- B01J20/103—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising silica or silicate comprising silica
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
- B01J20/28016—Particle form
- B01J20/28019—Spherical, ellipsoidal or cylindrical
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
- C01B33/18—Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
- C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
- C01P2002/82—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by IR- or Raman-data
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/12—Surface area
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/14—Pore volume
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Analytical Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Ceramic Engineering (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于纳米材料和药物制剂技术领域,公开一种氨基功能化手性介孔二氧化硅的制备方法与递送药物的应用。以仿生模板阴离子表面活性剂C16‑L‑丙氨酸于介观结构稳定的合成条件下制备手性介孔二氧化硅,继而以共缩聚法嫁接氨基功能团。制备的氨基功能化手性介孔二氧化硅的载药量为38.5%,高于手性介孔二氧化硅的药物负载量,突显了氨基功能化的优势。将氨基功能化手性介孔二氧化硅载入吲哚美辛后,吲哚美辛的药物溶出度增大,药物生物利用度提高到195.3%。本发明氨基功能化手性介孔二氧化硅可堪称性能优越的药物载体,为手性介孔二氧化硅性能稳定和简易功能化修饰研究及提高药物生物利用度研究提供了重要的基础。
Description
技术领域
本发明属于纳米材料制备和药物制剂技术领域,涉及一种氨基功能化手性介孔二氧化硅的制备及其在制备药物递送系统中的应用。
背景技术
近年来,根据材料孔径大小分为微孔(Micropore,孔径<2nm),介孔(Mesopore,孔径2~50nm)和大孔(Macropore,孔径50nm~100nm)的无机纳米孔二氧化硅材料凭借其高比表面积和孔容、坚实的骨架、无毒及可生物降解和内外表面嫁接功能性基团的性质而分别具备优异的载荷药物能力、良好的物理稳定性和生物相容性以及灵活的功能化特性,由此跻身于药物载体研究的前沿。其中介孔二氧化硅作为药物载体的研究最为广泛,主要涉猎于速释,缓控释及智能型触发(pH,酶,光等)释放,以解决难溶性药物生物利用度低,药物临床应用效果差等制剂学瓶颈问题。
作为介孔二氧化硅家族中的一员,手性介孔二氧化硅已被予以很高的关注并致力于探寻其合成机制,手性化学及功能性。虽然对于手性介孔二氧化硅的合成有或深或浅的报道,其手性性能的均一和稳定一直未能很好实现,困扰着科学工作者。鉴于仿生技术无需高温,高压和极端的pH,是一种绿色的合成路线,且仿生硅化具有潜在的形态和结构调控能力,故引入仿生技术可以获得手性性能较为均一和稳定的手性介孔二氧化硅。
鉴于介孔二氧化硅的内外表面可接枝氨基,羧基,烷基,聚乙二醇和壳聚糖等基团。一般的,接枝手段主要为共价键嫁接法,共缩聚法和孔壁有机杂化法。共价键嫁接法是将模板去除,再将含有有机基团的硅源与介孔二氧化硅一起加入到适宜溶剂中。共缩聚法也称为一步法,指的是在合成介孔二氧化硅的初始溶液中,直接加入含有机官能团的硅源(有的可通过硅烷偶联剂实现),它可以与正硅酸酯同时发生水解并且交联形成有机无机杂化的介孔二氧化硅材料。孔壁有机杂化法是使用一种有机官能团R位于有机硅氧烷中间作为硅源,合成出来的介孔材料孔壁里面是含有有机硅源R基团的材料。三种方法中,共缩聚法以其功能基团均匀分布的优势脱颖而出。
由此可见,采用仿生技术合成手性介孔二氧化硅并以共缩聚法实现氨基功能化引领了新型介孔二氧化硅的研究,且在药物递送系统中可发挥不可估量的潜能。
发明内容
本发明所解决的技术问题是为了克服现有技术的缺陷,采用仿生方法合成手性介孔二氧化硅并以共缩聚法嫁接氨基功能基团,进而构建药物递送体系。本发明涉及的技术不仅确保了载体手性性能的均一和稳定,更赋予其均匀分布的氨基功能基团,使其构建的药物递送体系呈现独特优势和巨大的应用前景。
本发明是通过如下技术方案实现的:
本发明提供一种氨基功能化手性介孔二氧化硅,所述的氨基功能化手性介孔二氧化硅具有成型的介观结构,为多孔椭球状纳米粒子,螺旋孔道较密实。比表面积可达190.74m2/g以上,孔容0.3923cm3/g以上。
所述氨基功能化手性介孔二氧化硅采用如下方法制备得到:
(1)C16-L-丙氨酸仿生模板的制备;
(2)手性介孔二氧化硅的制备;
(3)氨基功能化手性介孔二氧化硅的制备。
所述步骤(1)中,C16-L-丙氨酸仿生模板的具体合成步骤为:
步骤1:十六酸溶液的配制:
十六酸和4-二甲氨基吡啶,在二氯甲烷中于-5-0℃冰浴下搅拌反应;
其中,十六酸与4-二甲氨基吡啶的摩尔比为:10~11:1;
十六酸与二氯甲烷的摩尔体积比(mmol/mL)为:1:2-4;
搅拌时间为1-2小时;
步骤2:L-丙氨酸甲酯盐酸盐溶液的配制:
L-丙氨酸甲酯盐酸盐与三乙胺在二氯甲烷中于室温下混合搅拌;
L-丙氨酸甲酯盐酸盐与二氯甲烷的摩尔体积比(mmol/mL)为:1:(1-2);
L-丙氨酸甲酯盐酸盐与三乙胺的摩尔体积比(mmol/mL)为8-9:1
搅拌时间为30min-60min;
步骤3:N,N'-二环己基碳酰亚胺溶液的配制:
将N,N'-二环己基碳酰亚胺溶解于二氯甲烷中;
N,N'-二环己基碳酰亚胺与二氯甲烷的摩尔体积比(mmol/mL)为:1:(1-2);
步骤4:体系反应与提纯:
将步骤1的十六酸溶液与步骤2的L-丙氨酸甲酯盐酸盐溶液在-5~0℃冰浴下混合并搅拌,滴加步骤3的N,N'-二环己基碳酰亚胺溶液,滴加完毕后继续搅拌3~5h,之后室温搅拌过夜。将体系过滤,加入适量二氯甲烷,依次用水,饱和NaCl,饱和NaHCO3,1M HCl,水萃取,加入无水硫酸镁,干燥过夜。继而过滤得到滤液,挥干溶剂后得粗品C16-L-丙氨酸甲酯。将粗品分别用乙酸乙酯和正己烷进行重结晶,滤液过滤得到C16-L-丙氨酸甲酯精品。
步骤5:水解C16-L-丙氨酸甲酯:
C16-L-丙氨酸甲酯在-5~0℃冰水浴下加入适量甲醇搅拌至完全溶解,随后加入NaOH溶液至反应液澄清,减压蒸馏除去甲醇得固液混合物。用HCl调节pH至2-3,得到白色析出沉淀,抽滤,水洗,干燥以获得C16-L-丙氨酸;
其中,所述NaOH溶液的浓度为0.05-0.1mol/L,HCl的浓度为0.5-1mol/L。
所述步骤(2)中,
C16-L-丙氨酸于70-80℃水浴条件下溶于去离子水中,加入0.1-0.2mol/L NaOH溶液搅拌,降温至室温后以0.01-0.02mol/L HCl调节体系pH至12-13,搅拌1-2小时。
所述步骤(3)中,
搅拌下,滴加3-氨丙基三乙氧基硅烷和正硅酸乙酯的混合物,滴加完毕后持续搅拌,静置,过滤,去离子水洗涤,干燥,将产物用乙醇胺的无水乙醇溶液在沸点下回流,通过回流法去除模板,保留了氨基基团在载体内外表面的嫁接。
其中,3-氨丙基三乙氧基硅烷和正硅酸乙酯的质量比为:1:6-8;
3-氨丙基三乙氧基硅烷和正硅酸乙酯的混合物与C16-L-丙氨酸与的质量比为4-5:1。
搅拌的速度为800-1000rpm。
本发明制备的氨基功能化手性介孔二氧化硅可以包载不同的药物,载药量高,且可以提高药物的生物利用度。
所述的药物可以为吲哚美辛、塞来昔布、吡罗昔康、卡维地洛等。
进一步地,本发明以吲哚美辛为模型药物,采用氨基功能化手性介孔二氧化硅制备药物递送体系。
吲哚美辛又称消炎痛,为难溶性非甾体抗炎药。该药通过抑制体内前列腺素合成而产生解热镇痛及消炎作用,临床上用于风湿性及类风湿性关节炎的治疗,常用剂量下对胃肠道和中枢神经系统常产生毒副作用,严重情况下引起胃肠道溃疡。将吲哚美辛载入介孔二氧化硅的孔道中可避免药物与胃肠道的直接接触而降低对胃肠道的刺激。此外,介孔二氧化硅能够提高难溶性药物生物利用度,且载体的氨基功能化对于含有羧基的药物有更强的作用力,故构建氨基功能化手性介孔二氧化硅载吲哚美辛体系具有十分重要的研究意义。
进一步地,本发明采用溶剂挥发法载药,即药物于溶剂挥发过程中载入载体的孔道中。具体载药步骤为:
称取质量比为2:1-4:1的氨基功能化手性介孔二氧化硅和吲哚美辛,加入丙酮,体系密闭搅拌后敞开,真空干燥直至溶剂挥干。
本发明采用傅里叶红外变换光谱(FTIR)表征氨基功能化的手性介孔二氧化硅,高分辨率透射电子显微镜(TEM)表征孔道形貌,比表面(BET)测试表征比表面积和孔径分布。载体对药物的功能主要通过X-射线衍射、溶出仪测定和大鼠药物动力学进行考察。
结果发现:通过共缩聚法可实现氨基功能基团的成功嫁接,此氨基功能化的手性介孔二氧化硅呈现手性螺旋孔道。氨基功能化后,材料的比表面积和孔容均降低。但氨基功能化手性介孔二氧化硅在提高载药量、释药和生物利用度的能力显著。综上所述,本发明氨基功能化手性介孔二氧化硅可堪称性能优越的药物载体,为手性介孔二氧化硅性能稳定和简易功能化修饰研究及提高药物生物利用度等应用问题带来巨大红利。
附图说明
图1为实施例1中C16-L-丙氨酸的FTIR图;
图2为实施例1中C16-L-丙氨酸的核磁共振图;
图3为实施例2-4手性介孔二氧化硅的小角X射线图;
图4为实施例5氨基功能化手性介孔二氧化硅的FTIR图;
图5为实施例5氨基功能化手性介孔二氧化硅的TEM图;
图6为BET测定结果图;
A:为实施例3手性介孔二氧化硅-2;
B:为实施例5氨基功能化手性介孔二氧化硅;
图7为实施例5和实施例7的X射线衍射图;
图8为实施例6和实施例7的体外溶出曲线图;
图9为实施例6和实施例7的大鼠血药浓度曲线图。
具体实施方式
实施例1
C16-L-丙氨酸的合成:
制备工艺:
步骤1:十六酸溶液的配制
十六酸26mmol和4-二甲氨基吡啶2.58mmol,加入100mL二氯甲烷于0℃冰浴下搅拌1h;
步骤2:L-丙氨酸甲酯盐酸盐溶液的配制
L-丙氨酸甲酯盐酸盐26mmol、3mL三乙胺与50mL二氯甲烷混合,于室温下搅拌40min,得到L-丙氨酸甲酯盐酸盐溶液。
步骤3:N,N'-二环己基碳酰亚胺(DCC)溶液的配制
将N,N'-二环己基碳酰亚胺28.4mmol溶解于50mL二氯甲烷制备N,N'-二环己基碳酰亚胺溶液。
步骤4:体系反应与提纯
将十六酸溶液与L-丙氨酸甲酯盐酸盐溶液在0℃冰浴下混合并搅拌,滴加DCC溶液,滴加完毕后体系继续搅拌3h,之后室温搅拌过夜。将体系过滤,加入适量二氯甲烷,依次用水,饱和NaCl,饱和NaHCO3,1M HCl,水萃取,加入10g无水硫酸镁,干燥过夜。继而过滤得到滤液,挥干溶剂后得粗品C16-L-丙氨酸甲酯。将粗品用乙酸乙酯和正己烷进行重结晶,滤液过滤得到C16-L-丙氨酸甲酯精品。
步骤5:水解C16-L-丙氨酸甲酯
称取3mmol C16-L-丙氨酸甲酯于圆底烧瓶中,冰水浴下加入适量甲醇搅拌至完全溶解,随后加入0.05M NaOH至反应液澄清,减压蒸馏除去甲醇得固液混合物。用1mol/L HCl调节pH至2-3,得到白色析出沉淀,抽滤,水洗,干燥以获得C16-L-丙氨酸。
图1中,C16-L-丙氨酸的FTIR谱图中出现了酰胺反应所获得的仲酰胺和长碳链的特征峰,初步确证了所得产物为目标化合物。用氘代氯仿分别溶解C16-L-丙氨酸,进行1H-NMR分析,见图2。结果表明各位置的氢原子数目与结构式完全吻合,说明产物结构与目标化合物一致。
实施例2
手性介孔二氧化硅-1的制备
处方:
制备工艺:
称取0.36g C16-L-丙氨酸于70℃水浴条件下溶于10mL去离子水中,加入10g0.1mol/L NaOH溶液搅拌,降温至室温后加入10g 0.01mol/LHCl搅拌1h,此时体系的pH为11。
800rpm的搅拌速度下滴加0.23g 3-氨丙基三乙氧基硅烷(APTES)和1.46g正硅酸乙酯(TEOS)的混合物,滴加完毕后持续搅拌30min,静置24h,过滤,去离子水洗涤,干燥,最后将产物焙烧(550℃,6h)去除模板后检测手性介孔二氧化硅-1的性质。
图3小角X射线表明含有模板的手性介孔二氧化硅在2.1-2.3°2θ角有一个衍射峰,说明硅源沉积完成可得到具有介观结构的材料。然而,去除模板后的手性介孔二氧化硅-1没有任何衍射峰,揭示手性介孔二氧化硅-1的胶束聚集体堆积能量弱使得二氧化硅骨架沉积不坚实,故在焙烧过程中有所塌陷致使介观结构未能检测。
实施例3
手性介孔二氧化硅-2的制备
处方:
制备工艺:
称取0.36g C16-L-丙氨酸于70℃水浴条件下溶于10mL去离子水中,加入10g0.1mol/L NaOH溶液搅拌,降温至室温搅拌1h,此时体系的pH为13。
800rpm的搅拌速度下滴加0.23g APTES和1.46g TEOS的混合物,滴加完毕后持续搅拌30min,静置24h,过滤,去离子水洗涤,干燥,最后将产物焙烧(550℃,6h)去除模板后检测手性介孔二氧化硅-2的性质。
图3小角X射线表征显示手性介孔二氧化硅-2由于胶束聚集体的堆积能量较强且粒子较为有序,在1-1.5°2θ角处呈现弱衍射峰,表明手性介孔二氧化硅-2骨架构成的介观结构较为坚实。进而对手性介孔二氧化硅-2进行BET测定,图6A显示手性介孔二氧化硅-2的比表面积为525.36m2/g,孔容为0.45cm3/g。
改变转速为1000rpm时,制备的手性介孔二氧化硅的性质无明显变化。
实施例4
手性介孔二氧化硅-3的制备
处方:
制备工艺:
称取0.36g C16-L-丙氨酸于70℃水浴条件下溶于10mL去离子水中,加入10g0.1mol/L NaOH溶液搅拌,降温至室温搅拌1h,此时体系的pH为13。
200rpm的搅拌速度下滴加0.23g APTES和1.46g TEOS的混合物,滴加完毕后持续搅拌30min,静置24h,过滤,去离子水洗涤,干燥,最后将产物焙烧(550℃,6h)去除模板后检测手性介孔二氧化硅-3的性质。
图3手性介孔二氧化硅-3的小角X射线图表明材料的粒子纳米孔的有序度最低使得模板焙烧去除过程中部分二氧化硅骨架未能支撑其介观结构。
综合实施例2-4,根据小角X射线图,表明pH为13和滴加硅源时的搅拌速度800-1000rpm时的手性介孔二氧化硅-2有成型的衍射峰,具有明显的介孔结构,为合成介观结构稳定的介孔二氧化硅最佳条件。
实施例5
氨基功能化手性介孔二氧化硅的制备
处方:
制备工艺:
称取实施例1得到的C16-L-丙氨酸0.36g于70℃水浴条件下溶于10mL去离子水中,加入10g 0.1mol/L NaOH溶液搅拌,降温至室温搅拌1h,此时体系的pH为13。
800rpm的搅拌速度下滴加0.23g 3-氨丙基三乙氧基硅烷和1.46g正硅酸乙酯的混合物,滴加完毕后持续搅拌30min,静置24h,过滤,去离子水洗涤,干燥。将产物用乙醇胺(17%,v/v)的无水乙醇溶液在沸点下回流12h。
图4氨基功能化手性介孔二氧化硅的FTIR图可见461.7cm-1处Si-O-Si弯曲振动峰和1070.5cm-1处Si-O-Si不对称伸缩振动峰等二氧化硅典型峰位,及1490.1cm-1处–NH2弯曲振动峰、1571.3cm-1处–NH2不对称伸缩振动峰、3362.1cm-1处N-H伸缩振动峰,证实了氨基基团的成功嫁接。
图5氨基功能化手性介孔二氧化硅的TEM图,可见其为多孔椭球状纳米粒子,且由于功能基团嫁接,螺旋孔道较密实。
图6B可见,相比于母体手性介孔二氧化硅-2,氨基功能化后比表面积为190.74m2/g,孔容为0.3923cm3/g。
实施例6
实施例3的手性介孔二氧化硅-2载吲哚美辛体系
处方:
手性介孔二氧化硅-2 80mg
吲哚美辛 40mg
丙酮 2mL
制备方法:
称取80mg载体和40mg吲哚美辛使载体与药物的质量比为2:1,精密移入2mL丙酮,体系密闭搅拌24h后敞开,真空干燥直至溶剂挥干。
载药量的测定:
精密称取5mg的载药载体,加入20mL甲醇反复超声使药物溶出溶解,0.45μm油膜过滤,采用紫外分光光度法于318nm处测定吸光度值。经计算,手性介孔二氧化硅-2的载药量为34.8%。
实施例7
实施例5的氨基功能化手性介孔二氧化硅载吲哚美辛体系
处方:
氨基功能化手性介孔二氧化硅 80mg
吲哚美辛 40mg
丙酮 2mL
制备方法:
称取80mg载体和40mg吲哚美辛使载体与药物的质量比为2:1,精密移入2mL丙酮,体系密闭搅拌24h后敞开,真空干燥直至溶剂挥干。
载药量的测定:
精密称取5mg的载药载体,加入20mL甲醇反复超声使药物溶出溶解,0.45μm油膜过滤,采用紫外分光光度法于318nm处测定吸光度值。经计算,氨基功能化手性介孔二氧化硅的载药量为38.5%,稍高于手性介孔二氧化硅的药物负载量,表明氨基功能化手性介孔二氧化硅即便比表面积和孔容低于非氨基化手性介孔二氧化硅,但载体的氨基与吲哚美辛的羧基可以形成氢键,从而增强载体的吸附药物作用力,突显了氨基功能化的优势。
此外,氨基功能化手性介孔二氧化硅的其他功能分别由X射线衍射、药物溶出测试和大鼠药物动力学考察。
药物溶出测试方法:采用中国药典体外释放浆法(50rpm,37℃,250mL pH 6.8磷酸盐缓冲液),以实施例7的载药载体及与实施例7中吲哚美辛等量的原料药为测试样品,分别于设定的时间点取溶出介质5mL并立即补加等量等温的空白介质。溶出介质过0.45μm微孔滤膜,弃去初滤液,取续滤液,于320nm处测定紫外吸光度值,计算各个时间点的药物累积释放量以绘制药物体外释放图。
大鼠药物动力学方法:将9只体重为250±10g的雄性SD大鼠随机分为三组,分别为吲哚美辛组,手性介孔二氧化硅-2载药组和氨基功能化手性介孔二氧化硅载药组。实验前将大鼠禁食过夜,分别取吲哚美辛8mg、载荷8mg吲哚美辛的手性介孔二氧化硅-2和氨基功能化手性介孔二氧化硅,精密称定,于离心管中,加2ml去离子水,灌胃给药。分别于设定的时间点眼眶取血约0.5mL,10000rpm离心4min,收集上层血浆放置于冰箱冷冻室。取血浆0.2mL,加内标10μL,混匀,加入10%K2HPO4(pH 3.0)90μL和二氯甲烷1mL,涡旋3min,10000rpm离心4min。然后去除上层水相,涡旋1min,10000rpm离心2min,进样分析,测定各血浆样品中药物浓度,数据用DAS2.1.1药动学计算程序处理,求算药动学参数。
图7结果表明吲哚美辛为高度晶化结构,2θ角在19.88°,22.16°,26.6°等处有明显的衍射峰。氨基功能化手性介孔二氧化硅的XRD图谱中2θ在15°~30°呈现一个宽峰且无其他衍射峰,证实其为无定型材料。药物载入载体后,药物的衍射峰均不可见,只体现载体的宽峰,说明载体的螺旋孔道构成了对药物的空间限制以达到抑制药物晶型的作用。据此,无定型吲哚美辛具有更高的能量状态使得表观溶解度增大,使药物溶出度(见图8)和AUC(见图9)显著提高。经计算,载入氨基功能化手性介孔二氧化硅的吲哚美辛生物利用度提高到195.3%,而手性介孔二氧化硅负载吲哚美辛的生物利用度仅提高到163.2%,表明氨基功能化手性介孔二氧化硅递送药物体系具有突出的应用优势。
Claims (2)
1.一种氨基功能化手性介孔二氧化硅在制备提高吲哚美辛生物利用度的药物中的应用,其特征在于,所述的氨基功能化手性介孔二氧化硅通过如下方法制备:
C16-L-丙氨酸 0.36 g
水 10 mL
0.1 mol/L NaOH 10 g
3-氨丙基三乙氧基硅烷 0.23 g
正硅酸乙酯 1.46 g
称取 0.36g C16-L-丙氨酸于70 ℃水浴条件下溶于10mL去离子水中,加入10g 0.1mol/L NaOH溶液搅拌,降温至室温搅拌1h,此时体系的pH为13;
800rpm的搅拌速度下滴加0.23g 3-氨丙基三乙氧基硅烷和1.46g 正硅酸乙酯的混合物,滴加完毕后持续搅拌30min,静置24h,过滤,去离子水洗涤,干燥,将产物用17% v/v 的乙醇胺的无水乙醇溶液在沸点下回流12h;
所述的C16-L-丙氨酸通过如下方法制备:
步骤1:十六酸溶液的配制
十六酸26mmol和4-二甲氨基吡啶2.58mmol,加入100mL二氯甲烷于0℃冰浴下搅拌1h;
步骤2:L-丙氨酸甲酯盐酸盐溶液的配制
L- 丙氨酸甲酯盐酸盐26mmol、3mL三乙胺与50mL二氯甲烷混合,于室温下搅拌40min,得到L-丙氨酸甲酯盐酸盐溶液;
步骤3:N,N'- 二环己基碳酰亚胺溶液的配制
将N,N'- 二环己基碳酰亚胺28.4mmol溶解于50mL二氯甲烷制备N,N'- 二环己基碳酰亚胺溶液;
步骤4:体系反应与提纯
将十六酸溶液与L-丙氨酸甲酯盐酸盐溶液在0℃冰浴下混合并搅拌,滴加N,N'- 二环己基碳酰亚胺溶液,滴加完毕后体系继续搅拌3h, 之后室温搅拌过夜;将体系过滤,加入适量二氯甲烷,依次用水,饱和NaCl,饱和NaHCO3,1M HCl,水萃取,加入10g无水硫酸镁,干燥过夜;继而过滤得到滤液,挥干溶剂后得粗品C16-L- 丙氨酸甲酯;将粗品用乙酸乙酯和正己烷进行重结晶,滤液过滤得到C16-L-丙氨酸甲酯精品;
步骤5:水解C16-L-丙氨酸甲酯
称取3mmolC16-L-丙氨酸甲酯于圆底烧瓶中,冰水浴下加入适量甲醇搅拌至完全溶解,随后加入0.05 M NaOH至反应液澄清,减压蒸馏除去甲醇得固液混合物,用1mol/L HCl 调节pH至2-3,得到白色析出沉淀,抽滤,水洗,干燥以获得C16-L-丙氨酸。
2.如权利要求1所述的应用,其特征在于,吲哚美辛与氨基功能化手性介孔二氧化硅的质量比为1:2-4。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210370292.2A CN114668857B (zh) | 2022-04-09 | 2022-04-09 | 一种氨基功能化手性介孔二氧化硅的制备方法及其应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210370292.2A CN114668857B (zh) | 2022-04-09 | 2022-04-09 | 一种氨基功能化手性介孔二氧化硅的制备方法及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114668857A CN114668857A (zh) | 2022-06-28 |
CN114668857B true CN114668857B (zh) | 2024-05-17 |
Family
ID=82078558
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210370292.2A Active CN114668857B (zh) | 2022-04-09 | 2022-04-09 | 一种氨基功能化手性介孔二氧化硅的制备方法及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114668857B (zh) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111217372A (zh) * | 2018-11-23 | 2020-06-02 | 沈阳药科大学 | 手性介孔核-壳结构二氧化硅纳米粒及其制备方法和应用 |
-
2022
- 2022-04-09 CN CN202210370292.2A patent/CN114668857B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111217372A (zh) * | 2018-11-23 | 2020-06-02 | 沈阳药科大学 | 手性介孔核-壳结构二氧化硅纳米粒及其制备方法和应用 |
Non-Patent Citations (2)
Title |
---|
Amino functionalized chiral mesoporous silica nanoparticles for improved loading and release of poorly water-soluble drug;Xin Wang等;Asian Journal of Pharmaceutical Sciences;第14卷;第405-412页 * |
Biomimetic synthesized chiral mesoporous silica: Structures and controlled release functions as drug carrier;Jing Li等;Materials Science and Engineering C;第55卷;第367–372页 * |
Also Published As
Publication number | Publication date |
---|---|
CN114668857A (zh) | 2022-06-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2009242175B2 (en) | Ordered mesoporous silica material | |
CN102276827A (zh) | 改性的聚赖氨酸 | |
JP2012136538A (ja) | 臭化チオトロピウムの新規な形態およびそれを製造する方法 | |
CN201260790Y (zh) | 一种内循环旋转填充床超重力场装置 | |
Wang et al. | Amino functionalized chiral mesoporous silica nanoparticles for improved loading and release of poorly water-soluble drug | |
CN114668857B (zh) | 一种氨基功能化手性介孔二氧化硅的制备方法及其应用 | |
CN111298132B (zh) | 一种树状分子吉西他滨自组装纳米前药及其制备方法和应用 | |
CN108586753B (zh) | 多金属氧簇-笼型倍半硅氧烷杂化分子构筑的立方相囊泡纳米材料的制备方法 | |
CN114920739A (zh) | Mrtx849化合物的晶型及其制备方法和用途 | |
CN114605406A (zh) | Amg510化合物的晶型及其制备方法和用途 | |
WO2015081566A1 (zh) | 曲美替尼及其溶剂化物的晶型、其制备方法、含有它们的药物组合物及其用途 | |
CN101721312A (zh) | 一种纳微结构药物颗粒的制备方法及装置 | |
CN113562737A (zh) | 手性结构可调控的介孔二氧化硅纳米粒及其制备方法和应用 | |
US20020107275A1 (en) | Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation | |
CN108349903B (zh) | Ttp488加成盐及其晶型、制备方法及药物组合物 | |
CN112778290B (zh) | 一种s1p1受体激动剂的加成盐及其晶型和药物组合物 | |
CN105367492B (zh) | 他喹莫德的晶型及其制备方法、其药物组合物和用途 | |
TWI662031B (zh) | 1-{2-氟-4-[5-(4-異丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸的晶型 | |
CN103626993A (zh) | 聚乙二醇单甲醚大豆磷脂酰乙醇胺衍生物及其制备 | |
CN113563219B (zh) | L-酪氨酸衍生物和球状介孔二氧化硅纳米粒及其制备方法和应用 | |
Patil et al. | Inclusion of water insoluble drugs in amorphous silica nanoparticles | |
WO2019170092A1 (zh) | 含酮羰基的疏水性抗肿瘤药物及其缀合物、含有缀合物的纳米制剂及其制备方法及应用 | |
CN114349985B (zh) | 一种二氧化硅微球及其制备方法和应用 | |
WO2014169770A1 (zh) | 达拉菲尼的晶型及其制备方法和用途 | |
US20070232578A1 (en) | Crystalline forms of ciclesonide |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |