CN117255617A - 功能化仿生羟基磷灰石 - Google Patents
功能化仿生羟基磷灰石 Download PDFInfo
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- CN117255617A CN117255617A CN202280033052.1A CN202280033052A CN117255617A CN 117255617 A CN117255617 A CN 117255617A CN 202280033052 A CN202280033052 A CN 202280033052A CN 117255617 A CN117255617 A CN 117255617A
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- Prior art keywords
- functionalized
- hap
- hydroxyapatite
- carbonate
- cations
- Prior art date
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- Pending
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- 229910052588 hydroxylapatite Inorganic materials 0.000 title claims abstract description 49
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 title claims abstract description 49
- 239000011664 nicotinic acid Substances 0.000 title description 2
- -1 benzalkonium halides Chemical class 0.000 claims abstract description 61
- 239000000203 mixture Substances 0.000 claims abstract description 40
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 38
- 230000003115 biocidal effect Effects 0.000 claims abstract description 23
- 239000003139 biocide Substances 0.000 claims abstract description 22
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960004830 cetylpyridinium Drugs 0.000 claims abstract description 11
- 229960003260 chlorhexidine Drugs 0.000 claims abstract description 11
- 239000002537 cosmetic Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 229960001716 benzalkonium Drugs 0.000 claims abstract description 8
- 150000001768 cations Chemical class 0.000 claims description 25
- 229910052751 metal Inorganic materials 0.000 claims description 13
- 239000002184 metal Substances 0.000 claims description 13
- 229910052802 copper Inorganic materials 0.000 claims description 9
- 239000003899 bactericide agent Substances 0.000 claims description 6
- 230000002070 germicidal effect Effects 0.000 claims description 6
- 229910052719 titanium Inorganic materials 0.000 claims description 4
- 239000002245 particle Substances 0.000 description 29
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 26
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 23
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 18
- 239000011575 calcium Substances 0.000 description 18
- 239000000725 suspension Substances 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- 239000007900 aqueous suspension Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000010949 copper Substances 0.000 description 11
- 239000008367 deionised water Substances 0.000 description 11
- 229910021641 deionized water Inorganic materials 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 229910019142 PO4 Inorganic materials 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- 229910052791 calcium Inorganic materials 0.000 description 10
- 239000010452 phosphate Substances 0.000 description 10
- 230000000844 anti-bacterial effect Effects 0.000 description 9
- 239000001569 carbon dioxide Substances 0.000 description 9
- 229910002092 carbon dioxide Inorganic materials 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 239000007789 gas Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 210000000988 bone and bone Anatomy 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 235000011007 phosphoric acid Nutrition 0.000 description 5
- 229910052709 silver Inorganic materials 0.000 description 5
- 239000004332 silver Substances 0.000 description 5
- 239000000606 toothpaste Substances 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 210000003298 dental enamel Anatomy 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 229940091250 magnesium supplement Drugs 0.000 description 4
- 239000010936 titanium Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 3
- 239000000920 calcium hydroxide Substances 0.000 description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 229940034610 toothpaste Drugs 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- FMRLDPWIRHBCCC-UHFFFAOYSA-L Zinc carbonate Chemical compound [Zn+2].[O-]C([O-])=O FMRLDPWIRHBCCC-UHFFFAOYSA-L 0.000 description 2
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 229940043430 calcium compound Drugs 0.000 description 2
- 150000001674 calcium compounds Chemical class 0.000 description 2
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000015218 chewing gum Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 229910000365 copper sulfate Inorganic materials 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 239000002781 deodorant agent Substances 0.000 description 2
- 229940032049 enterococcus faecalis Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 2
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 2
- 239000011572 manganese Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000002324 mouth wash Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 238000004626 scanning electron microscopy Methods 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000011667 zinc carbonate Substances 0.000 description 2
- 235000004416 zinc carbonate Nutrition 0.000 description 2
- 229910000010 zinc carbonate Inorganic materials 0.000 description 2
- 229940006486 zinc cation Drugs 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- BHHYHSUAOQUXJK-UHFFFAOYSA-L zinc fluoride Chemical compound F[Zn]F BHHYHSUAOQUXJK-UHFFFAOYSA-L 0.000 description 2
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 2
- BNGXYYYYKUGPPF-UHFFFAOYSA-M (3-methylphenyl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].CC1=CC=CC(C[P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 BNGXYYYYKUGPPF-UHFFFAOYSA-M 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910014497 Ca10(PO4)6(OH)2 Inorganic materials 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 description 1
- 239000005750 Copper hydroxide Substances 0.000 description 1
- 208000002064 Dental Plaque Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 description 1
- NNCOOIBIVIODKO-UHFFFAOYSA-N aluminum;hypochlorous acid Chemical compound [Al].ClO NNCOOIBIVIODKO-UHFFFAOYSA-N 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229910052586 apatite Inorganic materials 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 1
- 229910001634 calcium fluoride Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000011246 composite particle Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229940116318 copper carbonate Drugs 0.000 description 1
- 229910001956 copper hydroxide Inorganic materials 0.000 description 1
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000000551 dentifrice Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 1
- 235000019838 diammonium phosphate Nutrition 0.000 description 1
- FWBOFUGDKHMVPI-UHFFFAOYSA-K dicopper;2-oxidopropane-1,2,3-tricarboxylate Chemical compound [Cu+2].[Cu+2].[O-]C(=O)CC([O-])(C([O-])=O)CC([O-])=O FWBOFUGDKHMVPI-UHFFFAOYSA-K 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- MHJAJDCZWVHCPF-UHFFFAOYSA-L dimagnesium phosphate Chemical compound [Mg+2].OP([O-])([O-])=O MHJAJDCZWVHCPF-UHFFFAOYSA-L 0.000 description 1
- 229910000395 dimagnesium phosphate Inorganic materials 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000004337 magnesium citrate Substances 0.000 description 1
- 235000002538 magnesium citrate Nutrition 0.000 description 1
- 229960005336 magnesium citrate Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000011742 magnesium glycerophosphate Substances 0.000 description 1
- 235000001130 magnesium glycerophosphate Nutrition 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000012254 magnesium hydroxide Nutrition 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 229910000400 magnesium phosphate tribasic Inorganic materials 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- BHJKUVVFSKEBEX-UHFFFAOYSA-L magnesium;2,3-dihydroxypropyl phosphate Chemical compound [Mg+2].OCC(O)COP([O-])([O-])=O BHJKUVVFSKEBEX-UHFFFAOYSA-L 0.000 description 1
- QQFLQYOOQVLGTQ-UHFFFAOYSA-L magnesium;dihydrogen phosphate Chemical compound [Mg+2].OP(O)([O-])=O.OP(O)([O-])=O QQFLQYOOQVLGTQ-UHFFFAOYSA-L 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229910000401 monomagnesium phosphate Inorganic materials 0.000 description 1
- 235000019785 monomagnesium phosphate Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000395 remineralizing effect Effects 0.000 description 1
- 230000035440 response to pH Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- NBYLLBXLDOPANK-UHFFFAOYSA-M silver 2-carboxyphenolate hydrate Chemical compound C1=CC=C(C(=C1)C(=O)O)[O-].O.[Ag+] NBYLLBXLDOPANK-UHFFFAOYSA-M 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229940071575 silver citrate Drugs 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- FJOLTQXXWSRAIX-UHFFFAOYSA-K silver phosphate Chemical compound [Ag+].[Ag+].[Ag+].[O-]P([O-])([O-])=O FJOLTQXXWSRAIX-UHFFFAOYSA-K 0.000 description 1
- 229940019931 silver phosphate Drugs 0.000 description 1
- 229910000161 silver phosphate Inorganic materials 0.000 description 1
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000002336 sorption--desorption measurement Methods 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical compound [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- QUTYHQJYVDNJJA-UHFFFAOYSA-K trisilver;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Ag+].[Ag+].[Ag+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QUTYHQJYVDNJJA-UHFFFAOYSA-K 0.000 description 1
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011746 zinc citrate Substances 0.000 description 1
- 235000006076 zinc citrate Nutrition 0.000 description 1
- 229940068475 zinc citrate Drugs 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
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- A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
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Abstract
本发明涉及用杀菌剂功能化的碳酸羟基磷灰石，所述杀菌剂选自氯己定及其盐、苯甲烷铵卤化物、二异丁基苯氧基乙氧基乙基二甲基苄基铵卤化物、烷基二甲基乙基苄基铵卤化物和十六烷基吡啶鎓卤化物及其混合物。本发明还涉及化妆品组合物，例如口腔护理组合物或皮肤护理组合物，其包含所述功能化碳酸羟基磷灰石。
Description
技术领域
本发明涉及用杀菌剂功能化的碳酸羟基磷灰石(carbonate-hydroxyapatite)，所述杀菌剂选自氯己定及其盐、苯甲烷铵卤化物、二异丁基苯氧基乙氧基乙基二甲基苄基铵卤化物、烷基二甲基乙基苄基铵卤化物和十六烷基吡啶鎓卤化物及其混合物。
本发明还涉及化妆品组合物，例如口腔护理组合物或皮肤护理组合物，其包含所述功能化碳酸羟基磷灰石。
背景技术
羟基磷灰石，Ca10(PO4)6(OH)2，是一种存在于人体中的化合物，是骨组织和牙釉质(enamel)的主要矿物成分。事实上，人体中99％的钙以羟基磷灰石的形式储存在骨组织中。由于其优异的生物相容性，合成羟基磷灰石被用于人造骨、人造牙根、骨填充物、药物载体等。近年来，合成羟基磷灰石也被应用于化妆品，如牙膏、防晒霜等。
例如，在口腔护理中，目前羟基磷灰石作为再矿化剂材料被用在牙膏、口香糖和牙齿美白后处理中；作为复合聚合物材料中的填充材料用于制备牙科零件；提供牙齿的长期再矿化。
近来，羟基磷灰石已被提出作为抗微生物剂(如金属离子或季铵盐和其他杀菌活性物质)的载体。
EP 0 539 651公开了一种洁牙剂(牙膏或粉末)，其含有钙化合物，例如羟基磷灰石，以及由钙化合物携带的抗菌金属离子。优选的金属是银、锌和铜。
KR 2004/0081936涉及一种牙膏组合物，其含有基于组合物总重量的0.01至5重量％的十六烷基吡啶鎓氯化物，其中十六烷基吡啶鎓氯化物被涂覆在颗粒的表面上，该颗粒选自沉淀碳酸钙、二氧化硅、沸石、胶体二氧化硅和无水磷酸钙。使用流化床造粒机或使用浸渍法获得涂层。
Carlos A.Soriano deSouza等人在Colloids Surf.B,87(2),310-318(2011)中评估了氯己定在合成羟基磷灰石(HA)上的吸附及其抗微生物活性。他们证明，将氯己定与HA结合不会影响其对粪肠球菌(Enterococcus faecalis)生长的抗微生物活性，还能减少细菌附着。
EP 3 484 435涉及一种包含复合颗粒的口腔护理组合物，所述颗粒包含：
-具有式Can(X)x(AOy)z的水不溶性无机组分，其中：X选自OH、F和Cl；A选自C、P、Si及其组合；n＝1至5；x＝0或1；y＝3或4；z＝1至3；
-和阳离子杀菌剂，
其中，所述颗粒为薄片状，具有15至80nm的厚度。羟基磷灰石是优选的水不溶性的无机组分，氯己定和十六烷基吡啶鎓氯化物是优选的阳离子杀菌剂。
Okada M.等人(Dent.Mater.J.35(4),651–658(2016))评估了十六烷基吡啶鎓氯化物(CPC)在各种形态(球形、短棒、长棒和纤维形态)的HAp纳米颗粒上的吸附/解吸行为，以开发具有抗菌特性的纳米颗粒牙釉质修复剂。
然而，在本领域中仍然存在提供载体的需要，该载体能够逐渐释放杀菌物质和响应于特定条件，这可以保证随着时间推移的持续和受控的抗菌作用，从而达到持久的保护活性。
我们惊讶地发现，特定杀菌剂功能化的碳酸羟基磷灰石(C-HAp)在掺入的杀菌剂的释放动力学方面显示出有利的特征：在形成C-HAp颗粒后掺入的杀菌剂，其释放更慢且更受控，而在C-Hap颗粒的形成过程中掺入的杀菌剂更容易响应pH改变而释放。因此，根据应用和所需的释放动力学，可以为取代的C-Hap选择更合适的合成方法，从而分别获得缓慢或快速释放的产物。
此外，与未功能化的羟基磷灰石相比，本发明的功能化C-Hap显示出更均匀的颗粒组织以形成球状微聚集体。特别是对于口腔护理应用，具有均匀表面的材料是优选的，因为它改善了生物相容性、与天然组织的接触和物质交换，从而提高了再矿化活性。
此外，钙离子可以被其他金属阳离子(例如锌、铜和银)部分取代，从而增加杀菌物质的释放和本发明的功能化C-Hap的抗菌活性。
碳酸羟基磷灰石是其中羟基或磷酸根阴离子被碳酸根阴离子取代的羟基磷灰石。通过仔细选择操作条件(温度、浓度等)和试剂，可以成功合成碳酸羟基磷灰石。合成的C-HAp模仿骨磷灰石晶体的组成、结构、尺寸和形态比纯合成Hap更接近，因此它也被定义为“仿生”羟基磷灰石。
据申请人所知，之前没有人描述过本公开的功能化C-Hap及其有利性质。
在本发明中，“用杀菌剂功能化的碳酸羟基磷灰石”的定义是指杀菌剂“吸附在”C-HAp上或(部分地)“掺入在”C-HAp的结构中，这取决于生产工艺。
发明内容
因此，本发明的一个目的是一种碳酸羟基磷灰石(C-Hap)，基于功能化C-Hap的总重量，其含有0.3至20重量％(wt％)的碳酸根并且由0.01至10重量％的杀菌剂功能化，其中所述杀菌剂选自氯己定及其盐、苯甲烷铵卤化物、二异丁基苯氧基乙氧基乙基二甲基苄基铵卤化物、烷基二甲基乙基苄基铵卤化物，十六烷基吡啶鎓卤化物及其混合物。
本发明的另一目的是包含0.05至35重量％的所述功能化C-HaP的化妆品组合物。
本发明的又一个目的是制备所述功能化碳酸羟基磷灰石的方法，该方法包括以下步骤：
i)提供包含Ca阳离子源和任选的取代钙的金属阳离子源的水性溶液或悬浮液；
ii)将步骤i的水性溶液或悬浮液与包含磷酸根源的水性溶液或者悬浮液混合；
iii)在二氧化碳或碳酸根存在的情况下，搅拌所得的混合物，以允许形成C-HAp颗粒的悬浮液，
其中，将杀菌剂添加到步骤i.-iii.的溶液/悬浮液中或吸附在预先制备的C-Hap颗粒上，所述杀菌剂选自氯己定及其盐、苯甲烷铵卤化物、二异丁基苯氧基乙氧基乙基二甲基苄基铵卤化物、烷基二甲基乙基苄基铵卤化物和十六烷基吡啶鎓卤化物及其混合物。
附图说明
图1.实施例1的功能化C-HAP的X射线衍射光谱。
图2.C-Hap的SEM图像。
图3.实施例1的功能化C-Hap的SEM图像。
具体实施方式
优选地，基于功能化C-Hap的总重量，用0.05至5重量％的所述杀菌剂对本发明的功能化碳酸羟基磷灰石进行功能化。
基于功能化C-HAP的总重量，根据本发明的功能化C-HAP中碳酸根的含量可为0.3至20重量％，优选1.0至12重量％。碳酸根阴离子可以在C-HAp结构中占据两个不同的位点：即，它可以部分取代OH-阴离子(位点A)和/或磷酸根阴离子(位点B)。根据本发明，碳酸根离子优选在位点B。
本发明的碳酸羟基磷灰石可以用下式I表示：
Ca(10-x)Mx(PO4)(6-2/3y)(CO3)y(OH)2I
其中：
M是金属阳离子，选自下组：Cu、Mg、Al、Zn、Co、Fe、Ag、Mn、Sr和Ti阳离子或这些阳离子的组合；
x为0至2.5，优选为0.05至2.5，更优选为0.1至2；
y为0.1至3，优选为0.2至1.5。
在本发明的一个优选实施方式中，在式I中，x为零并且碳酸羟基磷灰石不包含取代钙的金属阳离子。这种碳酸羟基磷灰石可以由下式II表示：
Ca10(PO4)(6-2/3y)(CO3)y(OH)2II
其中y可以具有与上述相同的值。
在另一个优选实施方式中，在式I中，x为0.05至2.5，更优选为0.1至2。
可以将具有抗菌活性的多种金属阳离子部分取代钙阳离子掺入C-HAp结构中。这些金属阳离子的示例是铜(Cu2+)、铝(Al3+)、镁(Mg2+)、锌(Zn2+)、钴(Co2+)、铁(Fe3+和Fe2+)、银(Ag+)、锰(Mn2+)、锶(Sr2+)、钛(Ti4+)或其组合。
根据本发明的一个优选实施方式，金属取代的C-Hap中包含的阳离子选自Cu、Zn、Ag阳离子和这些阳离子的组合。
根据本发明的一个更优选的实施方式，金属取代的C-Hap包含Zn或Cu阳离子或其组合。
最优选的金属取代的C-Hap包含Cu阳离子。
优选地，杀菌剂选自氯己定及其盐、苯甲烷铵卤化物、十六烷基吡啶鎓卤化物及其混合物。
更优选地，杀菌剂是十六烷基吡啶鎓卤化物。
十六烷基吡啶鎓氯化物(CPC)是优选的十六烷基吡啶鎓卤化物。
根据本发明的一个优选实施方式，功能化C-HAP的结晶度为15％至85％，优选为15％至70％。
可根据以下方程式计算结晶度：
％结晶度＝100·(C/(A+C))
其中，C和A分别是尖锐峰面积之和，以及非晶峰面积(即X射线衍射光谱中尖锐峰和背景之间的面积，见图1)之和。
优选地，本发明的功能化C-HAp是颗粒形式，其尺寸小于5μm，优选尺寸为0.01至0.5μm。通常，C-HAp颗粒结合在一起形成颗粒的聚集体(团簇)。该聚集体可以具有微米尺度，其尺寸为0.1至50μm，更特别地为0.5至25μm。
本发明的功能化碳酸羟基磷灰石的制备可以通过在制备C-Hap颗粒的过程中加入杀菌剂作为试剂，或者通过将杀菌剂吸附在预先制备的C-Hap颗粒上进行。
制备碳酸羟基磷灰石的方法在本领域中是众所周知的。通常，C-HAp是通过在二氧化碳或碳酸根阴离子源的存在下使钙阳离子源与磷酸根阴离子源接触而获得的。
根据本发明的一个实施方式，制备本发明的功能化碳酸羟基磷灰石的方法包括以下步骤：
i)提供包含Ca阳离子源和任选的取代钙的金属阳离子源的水性溶液或悬浮液；
ii)将步骤i)的水性溶液或悬浮液与包含磷酸根源的水性溶液或者悬浮液混合；
iii)在二氧化碳或碳酸根存在的情况下搅拌混合物，以允许形成C-HAp颗粒的悬浮液；
其中，将杀菌剂添加到步骤i)-iii)的溶液/悬浮液中，所述杀菌剂选自氯己定及其盐、苯甲烷铵卤化物、二异丁基苯氧基乙氧基乙基二甲基苄基铵卤化物、烷基二甲基乙基苄基铵卤化物和十六烷基吡啶鎓卤化物及其混合物。
合适的钙阳离子源是氟化钙、氯化钙、硝酸钙、碳酸钙、氢氧化钙、乙酸钙或其组合。优选地，钙阳离子源是氢氧化钙或氯化钙。更优选钙阳离子源是氢氧化钙。
在制备功能化C-HAP的方法中，步骤i)的水性溶液或悬浮液中钙阳离子的浓度可为0.15至10mol/l，优选0.5至5mol/l。
根据本发明方法的一个优选实施方式，步骤i)的水性溶液或悬浮液还可包含选自以下的金属阳离子源：Cu、Mg、Al、Zn、Co、Fe、Ag、Mn、Sr和Ti阳离子或这些阳离子的组合。合适源是这些阳离子的氧化物或盐或其混合物。
合适的锌阳离子源是乙酸锌、硝酸锌、柠檬酸锌、氟化锌、氯化锌、氢氧化锌、碳酸锌或其组合。优选地，锌阳离子源是碳酸锌。
在制备功能化的Zn取代的C-HAP的方法中，锌阳离子的浓度可为0.01至5mol/l，优选0.1至1.5mol/l。
合适铜的阳离子源是乙酸铜、硝酸铜、柠檬酸铜、硫酸铜、氯化铜、氢氧化铜、碳酸铜或其组合。优选的铜阳离子源是氯化铜。
在制备功能化的Cu取代的C-HAP的方法中，铜阳离子的浓度可为0.01至5mol/l，优选0.1至1.5mol/l。
合适的银阳离子源是氧化银、硝酸银、乙酸银、硫酸银、苯甲酸银、水杨酸银、碳酸银、柠檬酸银或磷酸银。
在制备功能化的Ag取代的C-HAP的方法中，银阳离子的浓度可为0.01至5mol/l，优选0.1至1.5mol/l。
合适的铝阳离子源是氯化铝、氯化羟铝、硫酸铝、硝酸铝或其混合物。优选地，铝阳离子源是氯化铝。
在步骤i)的水性溶液或悬浮液中，铝阳离子的浓度可为0.02至5.0mol/l，优选0.1至3.0mol/l。
合适的镁阳离子源是磷酸氢镁、磷酸三镁、磷酸二氢镁、氯化镁、六水合氯化镁、甘油磷酸镁、氢氧化镁、碳酸氢氧化镁、氧化镁、柠檬酸镁、硅酸镁或其混合物。优选地，镁阳离子源是六水合氯化镁。
在制备功能化的Mg取代的C-HAp的方法中，使用的镁阳离子的初始浓度可为0.005至3.0mol/l，优选0.05至1.0mol/l。
优选地，步骤i)的水性溶液或悬浮液的pH为7-13，更优选8-12。
合适的磷酸根阴离子源是磷酸氢二钠、磷酸二氢钠、正磷酸、磷酸氢二钾、磷酸二氢钾、磷酸氢二铵或其组合。优选地，磷酸根阴离子源是正磷酸。
在制备功能化C-HAP的方法中，步骤ii)的水性溶液或悬浮液中磷酸根阴离子的浓度可为0.05至10mol/l，优选0.5至5mol/l。
步骤ii)可以在低于60℃，优选30-50℃的温度下进行30分钟至2小时的时间。
在本发明的方法中，步骤iii)允许功能化碳酸羟基磷灰石的颗粒生长到所需的尺寸和结构。通常，步骤iii)在低于60℃的温度下进行至少6小时。优选地，步骤iii)在25至45℃的温度下进行6至36小时，更优选12至24小时。
碳酸根对磷酸根的取代可以有利地通过，例如，在二氧化碳气体存在的情况下简单地通过机械搅拌器搅拌溶液或悬浮液来实现，或者可以通过将二氧化碳气体鼓泡到液相中来实现，或者通过将机械搅拌与气体鼓泡组合来实现。
所述二氧化碳气体可以是含有二氧化碳的气体。可以使用纯的二氧化碳气体或空气来作为二氧化碳气体。
或者，可以预先将碳酸盐添加到步骤i)的水性溶液或悬浮液中，或者添加到包含磷酸根源的溶液或悬浮液中。否则，可以将碳酸盐添加到步骤ii)中获得的混合物中。
此外，步骤ii)可以通过同时向步骤i)的水性溶液或悬浮液中加入含有碳酸盐的溶液或悬浮液以及含有磷酸根阴离子的另外的溶液或悬浮液来进行。
可以使用碳酸铵、碳酸氢钠、碳酸钠、碳酸钾或碳酸氢钾作为碳酸盐。或者，在金属取代的C-Hap的情况下，碳酸根源可以是取代金属的碳酸盐。
碳酸盐的浓度可为，例如0.01至3.0mol/l。
类似地，可以将杀菌剂添加到步骤i)和ii)的溶液或悬浮液中，或添加到步骤iii)的混合物中，或可以在步骤ii)中作为单独的溶液添加。优选地，在步骤iii)开始时将杀菌剂添加到混合物中。
杀菌剂的浓度可为，例如0.001至1.0mol/l。
在本发明的一个实施方式中，制备功能化C-Hap的方法还包括以下步骤：
iv)从步骤iii)获得的悬浮液中分离功能化的碳酸羟基磷灰石颗粒；
v)以及对湿颗粒进行干燥。
使用本领域技术人员熟知的技术进行步骤iv)的分离，例如通过倾析、离心、过滤、喷雾干燥等。
在步骤v)中，对粉末进行干燥，例如通过冷冻干燥或在通风或真空烘箱中在40-90℃的温度下干燥，以及将其减小到适用于所需用途的粒度。
在一个优选的实施方式中，该方法还可以包括在干燥步骤v)之前用水或碱性溶液洗涤分离的颗粒的额外步骤。如果需要，可以重复几次洗涤操作。有利地，任选的洗涤步骤对于去除可能被颗粒聚集体吸附或捕获的任何试剂残留物是有用的。
在另一个实施方式中，本发明的功能化C-Hap的制备可以通过，在不添加任何杀菌剂的情况下，对根据上述方法制备的C-HAp颗粒(任选金属取代的)进行功能化。这些C-Hap颗粒可以通过吸附自杀菌剂的浓缩溶液进行功能化，例如在Okada M.等人,Dent.Mater.J.35(4),651–658(2016)中所述的。
用本发明的杀菌剂功能化的C-HAp可用于制备化妆品组合物，该化妆品组合物包含0.05至35重量％，优选0.5至25重量％的所述功能化的碳酸羟基磷灰石。
优选的化妆品组合物是口腔护理组合物或皮肤护理组合物。
皮肤护理组合物的示例是洗手液、足部乳液、除臭剂、唇膏等。
口腔护理组合物的示例是牙膏、牙粉、用于口腔和牙齿卫生的口香糖、漱口水和口腔浴浓缩液(mouth bath concentrate)以及漱喉液(gargle)。
实施例
实施例1
在37℃的温度下，在搅拌中将含有0.013摩尔H3PO4和0.0022摩尔十六烷基吡啶鎓氯化物一水合物的45ml去离子水滴加到含有0.2摩尔Ca(OH)2和0.015摩尔CaCO3的50ml去离子水中。在约60分钟的时间内加入磷酸溶液。
在37℃的温度下将所得的悬浮液搅拌保持24小时。
通过离心(以每分钟6000转持续20分钟)回收功能化的C-Hap颗粒，并用去离子水洗涤三次。
在制备结束时，将功能化的C-Hap颗粒置于80℃的真空烘箱中干燥。
实施例2
在37℃的温度下，在搅拌中将含有0.013摩尔H3PO4的30ml去离子水滴加到含有0.2摩尔Ca(OH)2和0.015摩尔CaCO3的50ml去离子水中。在约60分钟的时间内加入磷酸溶液。
在添加结束时，在搅拌中将含有0.0022摩尔十六烷基吡啶鎓氯化物一水合物的15ml去离子水滴加到反应物质中。
在37℃的温度下将所得的悬浮液轻柔搅拌保持24小时。
通过离心(以每分钟6000转持续20分钟)回收功能化的C-Hap颗粒，并用去离子水洗涤三次。
在制备结束时，将功能化的C-Hap颗粒置于80℃的真空烘箱中干燥。
实施例3
在37℃的温度下，在搅拌中将含有0.013摩尔H3PO4的30ml去离子水滴加到含有0.18摩尔Ca(OH)2、0.02摩尔硫酸铜和0.02摩尔Na2CO3的50ml去离子水中。在约60分钟的时间内加入磷酸溶液。
继续制备，在搅拌中将含有0.0022摩尔十六烷基吡啶鎓氯化物一水合物的15ml去离子水滴加到反应物质中。
在37℃的温度下将所得的悬浮液轻柔搅拌保持24小时。
通过离心(以每分钟6000转持续20分钟)回收功能化的Cu取代的C-Hap颗粒，并用去离子水洗涤三次。
在制备结束时，将功能化的Cu取代的C-Hap颗粒置于80℃的真空烘箱中干燥。
表1报告了实施例1-3的功能化C-HAp中CPC的量。
表1.
| CPC％ | |
| 实施例1 | 0.6 |
| 实施例2 | 0.6 |
| 实施例3 | 0.6 |
根据欧洲药典，通过UV-Vis分光光度分析测定功能化C-Hap中CPC的浓度。
简言之，将1mg功能化的C-Hap溶解在1ml 0.1M的HCl中，并通过读取259nm处的吸光度来测定溶液中CPC的量。
X射线衍射表征
对实施例1的用CPC功能化的C-HAP进行干燥并用MiniFlex X射线衍射仪(Rigaku)表征，参数设置如下：
-电压：30kV
-电流：15mA
-辐射类型：Cu
-辐射波长：
-2θ范围：10°至60°，步长为0.02°
-扫描速度：2°(2θ)/分钟
衍射光谱(图1)显示了文献中报道的羟基磷灰石的典型峰(存放在ICDD衍射数据数据库中的标准羟基磷灰石，文件编号01-086-1199)。然而，样品结晶性较差；检测到的大衍射(扩散)峰是由于合成条件引起的低结晶度。
实施例1的功能化C-HAP的结晶度为30±5％。
扫描电子显微镜表征
通过扫描电子显微镜(SEM)对功能化的C-Hap进行了进一步的表征。
SEM成像强调，与碳酸羟基磷灰石(图2)相比，实施例1的CPC功能化C-Hap(图3)显示出更均匀的颗粒组织，在悬浮液中形成球状微聚集体。
这一行为允许形成复合物的规则交换表面，与较低的结晶度和较高的反应性一起，导致了十六烷基吡啶鎓氯化物的受控释放。
十六烷基吡啶鎓氯化物的释放
通过将150mg功能化C-Hap颗粒放入两种不同pH的5ml缓冲液中，评估了CPC随时间从功能化C-Hap中的释放。通过UV-Vis分光光度法测定缓冲溶液中CPC浓度的变化。
结果示于表2中。
表2
表2中总结的结果显示根据实施例1和实施例2获得的功能化C-Hap以pH依赖的方式随时间释放CPC。
事实上，较低的pH(6.3至5.5)促进了CPC从C-Hap的释放，从而诱导在施用部位更快地达到十六烷基吡啶鎓氯化物的活性浓度(在30分钟后已达到)。
当用于皮肤和个人护理的化妆品，如除臭剂、洗手液、足部乳液、唇膏等时，由于皮肤的pH值(约5.5)，功能化C-Hap可以更快地释放CPC，从而有效但持久地保护皮肤免受微生物的侵害。
当施用于pH值较高的区域时，例如通过口腔护理产品施用在口腔中，CPC会缓慢释放。功能化的C-Hap将有足够的时间固定在牙釉质表面，防止形成构成牙菌斑的生物膜。餐后口腔粘膜的pH降低(由于食物的消耗)，将允许增加CPC的释放，有利地减少导致牙菌斑形成的微生物群体。
Claims (10)
1.一种功能化碳酸羟基磷灰石，基于功能化C-Hap的总重量，其含有0.3至20重量％(wt％)的碳酸根并且由0.01至10重量％的杀菌剂功能化，其中所述杀菌剂选自氯己定及其盐、苯甲烷铵卤化物、二异丁基苯氧基乙氧基乙基二甲基苄基铵卤化物、烷基二甲基乙基苄基铵卤化物，十六烷基吡啶鎓卤化物及其混合物。
2.如权利要求1)所述的功能化碳酸羟基磷灰石，基于功能化C-Hap的总重量，用0.05至5重量％的所述杀菌剂对其进行功能化。
3.如权利要求1)所述的功能化碳酸羟基磷灰石，其中所述杀菌剂是十六烷基吡啶鎓卤化物。
4.如权利要求1)所述的功能化碳酸羟基磷灰石，其中所述碳酸羟基磷灰石由式I表示：
Ca(10-x)Mx(PO4)(6-2/3y)(CO3)y(OH)2I
其中：
M是金属阳离子，选自下组：Cu、Mg、Al、Zn、Co、Fe、Ag、Mn、Sr和Ti阳离子或这些阳离子的组合；
x为0至2.5；
y为0.1至3。
5.如权利要求4)所述的功能化碳酸羟基磷灰石，其中在式I中x为零。
6.如权利要求4)所述的碳酸羟基磷灰石，其中，在式I中，x为0.1至2。
7.如权利要求4)所述的碳酸羟基磷灰石，其中金属阳离子M选自Cu、Zn、Ag阳离子及其组合。
8.一种化妆品组合物，其包含0.05至35重量％的碳酸羟基磷灰石，基于功能化C-Hap的总重量，所述碳酸羟基磷灰石含有0.5至20重量％的碳酸根并且由0.01至10重量％的杀菌剂功能化，其中所述杀菌剂选自氯己定及其盐、苯甲烷铵卤化物、二异丁基苯氧基乙氧基乙基二甲基苄基铵卤化物、烷基二甲基乙基苄基铵卤化物、十六烷基吡啶鎓卤化物及其混合物。
9.如权利要求8)所述的化妆品组合物，其包含0.5至25重量％的所述功能化碳酸羟基磷灰石。
10.如权利要求8)所述的化妆品组合物，其中所述组合物是口腔护理组合物或皮肤护理组合物。
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| CN202280033052.1A Pending CN117255617A (zh) | 2021-05-05 | 2022-05-04 | 功能化仿生羟基磷灰石 |
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| JP (1) | JP2024516866A (zh) |
| KR (1) | KR20240004881A (zh) |
| CN (1) | CN117255617A (zh) |
| IT (1) | IT202100011492A1 (zh) |
| WO (1) | WO2022233986A1 (zh) |
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|---|---|---|---|---|
| JP3157563B2 (ja) | 1991-10-29 | 2001-04-16 | 株式会社サンギ | 歯磨剤 |
| KR100951396B1 (ko) | 2003-03-17 | 2010-04-07 | 동아제약주식회사 | 구취제거, 플라그제거 및 항균효과가 우수한 치약 조성물 |
| KR20080101954A (ko) * | 2007-05-17 | 2008-11-24 | 김기영 | 은입자가 함유된 분말치약 조성물 |
| JP5973585B2 (ja) * | 2011-11-08 | 2016-08-23 | コスウェル・エス・ペー・アーＣｏｓｗｅｌｌ Ｓ．Ｐ．Ａ． | ラクトフェリン機能化表面を有する生体模倣ヒドロキシアパタイト粒子を含有するデンタルケア製品 |
| EP3484435A1 (en) | 2016-07-14 | 2019-05-22 | Unilever N.V. | Oral care composition comprising composite particles containing cationic germicide |
-
2021
- 2021-05-05 IT IT102021000011492A patent/IT202100011492A1/it unknown
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2022
- 2022-05-04 WO PCT/EP2022/062069 patent/WO2022233986A1/en active Application Filing
- 2022-05-04 JP JP2023568405A patent/JP2024516866A/ja active Pending
- 2022-05-04 CN CN202280033052.1A patent/CN117255617A/zh active Pending
- 2022-05-04 EP EP22728079.9A patent/EP4333617A1/en active Pending
- 2022-05-04 KR KR1020237041615A patent/KR20240004881A/ko unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR20240004881A (ko) | 2024-01-11 |
| IT202100011492A1 (it) | 2022-11-05 |
| WO2022233986A1 (en) | 2022-11-10 |
| EP4333617A1 (en) | 2024-03-13 |
| JP2024516866A (ja) | 2024-04-17 |
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