CN113209273A - 一种抗菌肽涂剂及其制备方法 - Google Patents
一种抗菌肽涂剂及其制备方法 Download PDFInfo
- Publication number
- CN113209273A CN113209273A CN202110482050.8A CN202110482050A CN113209273A CN 113209273 A CN113209273 A CN 113209273A CN 202110482050 A CN202110482050 A CN 202110482050A CN 113209273 A CN113209273 A CN 113209273A
- Authority
- CN
- China
- Prior art keywords
- antibacterial peptide
- paint
- percent
- buffer system
- amino acid
- 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.)
- Pending
Links
- 239000003910 polypeptide antibiotic agent Substances 0.000 title claims abstract description 86
- 239000003973 paint Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 239000007853 buffer solution Substances 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 12
- 239000003381 stabilizer Substances 0.000 claims abstract description 12
- 239000004094 surface-active agent Substances 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 241000894006 Bacteria Species 0.000 claims abstract description 9
- 239000003906 humectant Substances 0.000 claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 9
- 208000015181 infectious disease Diseases 0.000 claims abstract description 6
- 244000052616 bacterial pathogen Species 0.000 claims abstract description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 48
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 20
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 20
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 18
- 235000011187 glycerol Nutrition 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 10
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 10
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 10
- 150000001413 amino acids Chemical group 0.000 claims description 10
- 229920000136 polysorbate Polymers 0.000 claims description 10
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 8
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 8
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 229940024606 amino acid Drugs 0.000 claims description 6
- 235000001014 amino acid Nutrition 0.000 claims description 6
- 125000000539 amino acid group Chemical group 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 6
- 239000004472 Lysine Substances 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims description 4
- 229930195711 D-Serine Natural products 0.000 claims description 4
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 claims description 4
- 229930182819 D-leucine Natural products 0.000 claims description 4
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 claims description 4
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 claims description 4
- 229930182831 D-valine Natural products 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 235000019766 L-Lysine Nutrition 0.000 claims description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 4
- 229960003767 alanine Drugs 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 229960002449 glycine Drugs 0.000 claims description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
- 239000008363 phosphate buffer Substances 0.000 claims description 4
- 239000004014 plasticizer Substances 0.000 claims description 4
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 4
- 229960001153 serine Drugs 0.000 claims description 4
- 229960004295 valine Drugs 0.000 claims description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 4
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical group CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 3
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- -1 nipagin methyl ester Chemical class 0.000 claims description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 102000003886 Glycoproteins Human genes 0.000 claims description 2
- 108090000288 Glycoproteins Proteins 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000008272 agar Substances 0.000 claims description 2
- 229940023476 agar Drugs 0.000 claims description 2
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 2
- 229940087168 alpha tocopherol Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 229960004365 benzoic acid Drugs 0.000 claims description 2
- ZWYAVGUHWPLBGT-UHFFFAOYSA-N bis(6-methylheptyl) decanedioate Chemical group CC(C)CCCCCOC(=O)CCCCCCCCC(=O)OCCCCCC(C)C ZWYAVGUHWPLBGT-UHFFFAOYSA-N 0.000 claims description 2
- 210000004899 c-terminal region Anatomy 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 239000000679 carrageenan Substances 0.000 claims description 2
- 235000010418 carrageenan Nutrition 0.000 claims description 2
- 229920001525 carrageenan Polymers 0.000 claims description 2
- 229940113118 carrageenan Drugs 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- TVACALAUIQMRDF-UHFFFAOYSA-N dodecyl dihydrogen phosphate Chemical compound CCCCCCCCCCCCOP(O)(O)=O TVACALAUIQMRDF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 229940014259 gelatin Drugs 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 229920002674 hyaluronan Polymers 0.000 claims description 2
- 229960003160 hyaluronic acid Drugs 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 229940067606 lecithin Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 230000035515 penetration Effects 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 229960003885 sodium benzoate Drugs 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims description 2
- 235000010334 sodium propionate Nutrition 0.000 claims description 2
- 239000004324 sodium propionate Substances 0.000 claims description 2
- 229960003212 sodium propionate Drugs 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229960000984 tocofersolan Drugs 0.000 claims description 2
- 239000001069 triethyl citrate Substances 0.000 claims description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000013769 triethyl citrate Nutrition 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 2
- 239000002076 α-tocopherol Substances 0.000 claims description 2
- 235000004835 α-tocopherol Nutrition 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims 2
- MRBKEAMVRSLQPH-UHFFFAOYSA-N 3-tert-butyl-4-hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1 MRBKEAMVRSLQPH-UHFFFAOYSA-N 0.000 claims 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims 1
- 239000002826 coolant Substances 0.000 claims 1
- MIMDHDXOBDPUQW-UHFFFAOYSA-N dioctyl decanedioate Chemical compound CCCCCCCCOC(=O)CCCCCCCCC(=O)OCCCCCCCC MIMDHDXOBDPUQW-UHFFFAOYSA-N 0.000 claims 1
- 239000000796 flavoring agent Substances 0.000 claims 1
- 235000013355 food flavoring agent Nutrition 0.000 claims 1
- 239000003755 preservative agent Substances 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 229940001584 sodium metabisulfite Drugs 0.000 claims 1
- 239000002966 varnish Substances 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 6
- 239000011248 coating agent Substances 0.000 abstract description 5
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 102000044503 Antimicrobial Peptides Human genes 0.000 description 14
- 108700042778 Antimicrobial Peptides Proteins 0.000 description 14
- 239000000243 solution Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 8
- 229940040145 liniment Drugs 0.000 description 7
- 239000000865 liniment Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000011159 matrix material Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- VNYMOTCMNHJGTG-JBDRJPRFSA-N Ala-Ile-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O VNYMOTCMNHJGTG-JBDRJPRFSA-N 0.000 description 3
- AWZKCUCQJNTBAD-SRVKXCTJSA-N Ala-Leu-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN AWZKCUCQJNTBAD-SRVKXCTJSA-N 0.000 description 3
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 3
- OHZIZVWQXJPBJS-IXOXFDKPSA-N Leu-His-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OHZIZVWQXJPBJS-IXOXFDKPSA-N 0.000 description 3
- YCJCEMKOZOYBEF-OEAJRASXSA-N Lys-Thr-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O YCJCEMKOZOYBEF-OEAJRASXSA-N 0.000 description 3
- YUTZYVTZDVZBJJ-IHPCNDPISA-N Lys-Trp-Lys Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 YUTZYVTZDVZBJJ-IHPCNDPISA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- UPLYXVPQLJVWMM-KKUMJFAQSA-N Ser-Phe-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O UPLYXVPQLJVWMM-KKUMJFAQSA-N 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 239000003429 antifungal agent Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 108010034529 leucyl-lysine Proteins 0.000 description 3
- 108010043322 lysyl-tryptophyl-alpha-lysine Proteins 0.000 description 3
- 206010040872 skin infection Diseases 0.000 description 3
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HKXSZKJMDBHOTG-CIUDSAMLSA-N Lys-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN HKXSZKJMDBHOTG-CIUDSAMLSA-N 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- 230000002924 anti-infective effect Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 206010016936 Folliculitis Diseases 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- VHTOGMKQXXJOHG-RHYQMDGZSA-N Lys-Thr-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O VHTOGMKQXXJOHG-RHYQMDGZSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- 235000010787 Rubus niveus Nutrition 0.000 description 1
- 244000157378 Rubus niveus Species 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 241000589970 Spirochaetales Species 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 230000002951 depilatory effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003410 keratolytic agent Substances 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- FYKDNWHPKQOZOT-UHFFFAOYSA-M sodium;dihydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].OP(O)([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FYKDNWHPKQOZOT-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960000580 terconazole Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
本发明公开了一种抗菌肽涂剂及其制备方法。所述抗菌肽涂剂，包括下述质量百分含量的组分：抗菌肽0.5‰～0.5％、成膜材料5％～10％、保湿剂2％～5％、稳定剂1％～5％、表面活性剂1％～5％；以及pH值4.0～6.0的缓冲体系。本发明提供的抗菌肽外用涂剂具有抗菌，消炎功效，可适用于致病菌尤其是耐药菌引起的各种感染。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一种用于抗感染的抗菌肽涂剂及其制备方法。
背景技术
上世纪二三十年代以来，抗生素的发现和应用拯救了无数人的生命。抗生素是由细菌或其他微生物在生活过程中所产生的物质，具有抑制或杀灭细菌、螺旋体、支原体、衣原体等致病微生物的作用。但由于抗生素的滥用，超级细菌产生了对抗生素不敏感现象，耐药细菌的阵容也愈发强大。
已发现的抗真菌药物包括两性霉素B，克霉唑，咪康唑，酮康唑，制霉素，特康唑等等。CN1324607A公开了一种将上述抗真菌药物和溶角蛋白剂组成的组合物涂剂，提供了一种抗真菌剂的可控释放系统，用于指甲和周围组织真菌感染局部治疗。CN110496133A公开了一种克林霉素甲硝唑搽剂可用于寻常痤疮，脂溢性皮炎，酒渣鼻，毛囊炎等。CN100464728C公开了一种牙釉质表面抗菌涂剂，该涂剂包括固体粉末和混合溶液两部分。结合其临床应用，该涂剂组合具有较好的治疗效果，但对于局部组织的感染等问题，该制剂临床使用操作繁琐。综上，已公开的涂剂均体现了涂剂局部应用的优势，但文献或专利公开的涂剂多是小分子化药，或者是化学药物复方涂剂。
随着生物医药技术的发展，抗生素替代品的研发已成为生物医药领域的热点话题。抗菌肽用于抗菌研究的报道日渐增多。抗菌肽是以细胞膜为主要靶点，通过其独特的特点致使细胞膜丧失其屏障功能，现已成为了生物医药领域的焦点。但抗菌肽涂剂组合物用于局部感染治疗并未查询到相关报道。且抗菌肽涂剂组合物的研究开发并未见相关报道。
发明内容
本发明提供了一种抗菌肽涂剂，其能够有效的涂敷于患者创面，直接发挥抗菌消炎作用，为广大患者减轻痛苦。
本发明所提供的抗菌肽涂剂，包括下述质量百分含量的组分：抗菌肽0.5‰～0.5％、成膜材料5％～10％、保湿剂2％～5％、稳定剂1％～5％、表面活性剂1％～5％；以及pH值4.0～6.0的缓冲体系、余量为水。
其中，所述抗菌肽为如下通式的多肽：
区段甲-Ⅰ-A-Ⅱ-区段乙；
Ⅰ选自下述任意氨基酸残基：L-亮氨酸、D-亮氨酸、L-缬氨酸、D-缬氨酸、L-丙氨酸、D-丙氨酸、甘氨酸、L-丝氨酸、D-丝氨酸、L-赖氨酸及D-赖氨酸(L-和D-光学异构形式的L、A、S、V和K，以及G)；
Ⅱ选自下述任意氨基酸残基：选自下述任意氨基酸残基：L-亮氨酸、D-亮氨酸、L-缬氨酸、D-缬氨酸、L-丙氨酸、D-丙氨酸、甘氨酸、L-丝氨酸、D-丝氨酸、L-赖氨酸及D-赖氨酸(L-和D-光学异构形式的L、A、S、V和K，以及G)；
区段甲如SEQ ID No：1所示，其序列为：KWKSFLKTFK；
区段乙如SEQ ID No：2所示，其序列为：KTVLHTALKAISS；
A代表丙氨酸残基；
所述通式中，方向为自N端至C端。
优选的，所述抗菌肽为NAL以及D-NAL。
所述NAL具有SEQ ID No：3的序列，其氨基酸序列为：KWKSFLKTFKSAAKTVLHTALKAISS；
所述D-NAL具有SEQ ID No：4的序列，其氨基酸序列为：KWKSFLKTFKSAAKTVLHTALKAISS(除了第13位的A为L构型外，所有氨基酸都是D-构型)。
所述抗菌肽涂剂中的成膜材料可选自聚乙烯醇、羧甲基纤维素钠、羟丙甲基纤维素衍生物、卡拉胶、卡波姆、明胶、琼脂中的一种或几种；优选聚乙烯醇，羧甲基纤维素钠，羟丙基甲基纤维素衍生物，更优选聚乙烯醇(如聚乙烯醇L100)。
所述抗菌肽涂剂中的保湿剂可以选自甘油，丙二醇，聚乙二醇，木糖醇，山梨醇，氨基酸，透明质酸，糖蛋白等中的一种或多种，优选甘油。
所述抗菌肽涂剂中的表面活性剂可以选自司盘类(司盘20，司盘80等)，吐温类(吐温20，吐温40，吐温80等)，单月桂基磷酸酯，卵磷脂，硬脂酸等，优选吐温类，如吐温40。
所述抗菌肽涂剂中的稳定剂可以选自甘露醇，甘油，糊精，海藻糖，氨基酸等，优选海藻糖。
所述抗菌肽涂剂中的缓冲体系可以选自磷酸盐水溶液缓冲体系，醋酸盐水溶液缓冲体系，枸橼酸盐水溶液缓冲体系等等，优选磷酸盐水溶液缓冲体系，进一步的，所述磷酸盐水溶液缓冲体系的浓度为0.02M。
优选的，所述抗菌肽涂剂包括下述质量百分含量的组分：抗菌肽1‰～2‰、成膜材料5％～8％、保湿剂2％～3％、稳定剂3％～4％、表面活性剂4％～5％；以及pH值4.0～6.0的缓冲体系。
更优选的，所述抗菌肽涂剂包括下述质量百分含量的组分：抗菌肽1‰～2‰、聚乙烯醇L100 5％～8％、甘油2％～3％、海藻糖3％～4％、吐温40 4％～5％；以及0.02M、pH值4.0～6.0的磷酸盐缓冲体系。
除上述优选的组合物体系组分，还可以考虑在抗菌肽涂剂中增加增塑剂，改善涂剂的粘附性，增塑剂可以选自癸二酸二异辛酯，邻苯二甲酸甲酯，邻苯二甲酸二丁酯，聚乙二醇PEG，柠檬酸三乙酯等，或者选自上述的混合物。
抗菌肽涂剂中可考虑再增加防腐剂，防腐剂可以选自苯甲酸，苯甲醇，苯甲酸钠，丙酸钠，山梨酸，尼波金甲酯(丙酯)等，或者选自上述的混合物。
抗菌肽涂剂中可考虑增加抗氧化剂，抗氧化剂可以选自丁基羟基甲苯(BHA)，丁基羟基茴香醚(BHT)，抗坏血酸(钠)，焦亚硫酸钠，α-生育酚等，或者选自上述的混合物。
还可考虑在抗菌肽涂剂的缓冲体系中加入一种或多种挥发性溶剂或者促渗透剂，可以选自乙醇，丙酮，异丙醇等，或者选自上述的混合物。
当然，考虑到外用部位及制剂的特点，可以考虑在处方中加入一定量的芳香剂或者清凉剂。
本发明还提供了上述抗菌肽涂剂的制备方法。
本发明所提供的抗菌肽涂剂的制备方法，包括下述步骤：
配制缓冲液体系，然后加入抗菌肽搅拌溶解；再加入成膜材料、保湿剂、稳定剂以及表面活性剂，搅拌溶解，最后加水定容至100％。
本发明提供的抗菌肽涂剂，具有抗菌，消炎功效，可适用于致病菌(如金黄色葡萄球菌)尤其是耐药菌引起的各种原发性感染。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述原材料如无特别说明均能从公开商业途径获得。
下述实施例中使用的抗菌肽的序列(具有SEQ ID No：3的序列)能够通过人工合成。
下述实施例中的“％”均为质量百分含量。
实施例1抗菌肽涂剂成膜性考察
选择聚乙烯醇L100(PVA-L100)，羧甲基纤维素钠(CMC-Na)和甘油进行组合考察，考察指标包括成膜时间(涂于皮肤表面考察成膜时间)和黏度(NDJ-8S数显黏度计测定黏度)等，结果见表1。
表1抗菌肽涂剂成膜性考察
| 成膜时间/min | 黏度/Pa·S | |
| PVA L100(5％)+甘油(3％) | 7 | 2.859 |
| PVA L100(8％)+甘油(2％) | 8 | 2.798 |
| CMC-Na(3％)+甘油(2％) | 12 | 1.798 |
| CMC-Na(2％)+甘油(3％) | 13 | 1.950 |
| PVA L100(5％)+CMC-Na(3％) | 10 | 7.511 |
| PVA L100(8％)+CMC-Na(2％) | 11 | 7.180 |
由表1可见，PVA L-100与甘油的组合能够在涂于皮肤表面10分钟内成膜，成膜具有良好的可塑性。
实施例2、抗菌肽涂剂稳定剂筛选
选择海藻糖(3％)和赖氨酸(3％)等作为抗菌肽的稳定剂，分别制备抗菌肽溶液(抗菌肽浓度为2‰)，考察抗菌肽溶液的稳定性，检测指标包括有关物质(总杂)和含量。
1)有关物质：照高效液相色谱法(中国药典2010年版二部附录V D)试验，用十八烷基硅烷键合硅胶为填充剂，取溶液20μL注入液相色谱仪，记录色谱图。有关物质及限度：面积归一化法总杂质不得超过3.0％。
2)含量：照高效液相色谱法(中国药典2015年版四部通则0512)测定，精密量取本品适量，加水溶解并定量稀释制成每1ml中含0.25mg的溶液，作为供试品溶液，精密量取10μl注入液相色谱仪，记录色谱图；另取抗菌肽(原料药作为对照品)适量，同法测定。
表2抗菌肽溶液稳定性考察结果
由表2可知，选择海藻糖作为抗菌肽溶液中的稳定剂，可以保证抗菌肽在25℃条件下放置3个月，抗菌肽含量的仍在98％以上。
实施例3、
抗菌肽涂剂处方1：
制备工艺：首先将聚乙烯醇L-100加水搅拌均匀；配制罐中加入一定体积的水，加入磷酸盐缓冲体系(0.02M，调节pH值4.0～6.0)，搅拌溶解，加入抗菌肽搅拌溶解；加入聚乙烯醇L-100，甘油，吐温40和海藻糖，搅拌溶解，加入水定容至目标值，分装(10ml/瓶，15ml/瓶，20ml/瓶)。
实施例4、
抗菌肽涂剂处方2：
制备工艺：首先将聚乙烯醇L-100加水搅拌均匀；配制罐中加入一定体积的水，加入柠檬酸-磷酸二氢钠缓冲体系(0.02M，调节pH值4.0～6.0)，搅拌溶解，加入抗菌肽搅拌溶解；加入聚乙烯醇L-100，甘油，吐温40和海藻糖，搅拌溶解，加入水定容至目标值，分装(10ml/瓶，15ml/瓶，20ml/瓶)。
抗菌肽涂剂质量评价方法：
1)有关物质：照高效液相色谱法(中国药典2010年版二部附录V D)试验，用十八烷基硅烷键合硅胶为填充剂，取溶液20μL注入液相色谱仪，记录色谱图。有关物质及限度：面积归一化法总杂质不得超过3.0％。
2)含量：照高效液相色谱法(中国药典2015年版四部通则0512)测定，精密量取本品适量，加水溶解并定量稀释制成每1ml中含0.25mg的溶液，作为供试品溶液，精密量取10μl注入液相色谱仪，记录色谱图；另取抗菌肽对照品适量，同法测定。
对实施例3及实施例4的抗菌肽涂剂进行了稳定性考察，结果见表3。
表3抗菌肽涂剂(4℃条件下)稳定性考察结果
由表3可见，实施例3和实施例4处方在4℃条件下，在12个月内抗菌肽的含量均能够维持在97％以上。
实施例5、抗菌肽涂剂抗皮肤感染试验
ICR小鼠，20±2g，雄性。按体重随机分组。每组10只，共5组，分为模型组，百多邦阳性对照组，抗菌肽实施例3制剂组、空白涂剂基质组(实施例3空白基质)。普通级动物房饲养，喂以普通饲料，自由摄水，光照12小时明暗交替。
试验菌株：金黄色葡萄球菌CMCC(B)26003
抗感染皮肤外用剂：
实施例3抗菌肽涂剂，空白涂剂基质(实施例3空白基质)，百多邦(中美史克)。实验步骤：
(1)取保存于液氮的表皮葡萄球菌菌株，接种于血液平板，37℃过夜培养。
(2)次日将生长于血平板的单个菌落接种于MH液体培养基中，于控温摇床中37℃震荡培养2h。
(3)将被测定菌液与0.5麦氏比浊标准液比色，稀释至5×106CFU/ml，备用。
(4)皮肤造模：将小鼠背部剪毛，脱毛膏脱毛，待毛全部褪去后，用600目砂纸打磨至渗血。渗血皮肤皮下注射浓度为5×106CFU/ml的菌液，0.1ml。
(5)给药：抗菌肽涂剂及空白涂剂基质的给药剂量均为0.5g，每天早晚各外用1次，连续3天一疗程。百多邦的给药剂量为0.5g，每天早晚各外用1次，连续3天一疗程。(6)3天后，无菌取感染部位皮肤，按体积1:10稀释并研磨匀浆，取20μl涂皿，检测活菌并计数统计。
实验结果
感染皮肤检测结果见表4。
表4抗菌肽涂剂对金葡菌CMCC(B)26003皮肤感染影响(CFU/皿n＝3)
由表4可知，抗菌肽涂剂与模型对照组以及基质对照组相比较效果较明显，对抗表皮葡萄球菌皮肤感染效果较好。
抗菌肽涂剂的应用：
本发明的抗菌肽涂剂可以一天多次至一天一次的喷涂于患处或者患处周围组织。喷涂的次数和喷涂的液体量可以根据被治疗个体的年龄和条件调整。本发明的抗菌肽涂剂可适用于致病菌尤其是耐药菌引起的各种感染。
序列表
<110> 江苏普莱医药生物技术有限公司
<120> 一种抗菌肽涂剂及其制备方法
<130> GNCZJ211213
<160> 4
<170> SIPOSequenceListing 1.0
<210> 1
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Lys Trp Lys Ser Phe Leu Lys Thr Phe Lys
1 5 10
<210> 2
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Lys Thr Val Leu His Thr Ala Leu Lys Ala Ile Ser Ser
1 5 10
<210> 3
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Lys Trp Lys Ser Phe Leu Lys Thr Phe Lys Ser Ala Ala Lys Thr Val
1 5 10 15
Leu His Thr Ala Leu Lys Ala Ile Ser Ser
20 25
<210> 4
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Lys Trp Lys Ser Phe Leu Lys Thr Phe Lys Ser Ala Ala Lys Thr Val
1 5 10 15
Leu His Thr Ala Leu Lys Ala Ile Ser Ser
20 25
Claims (8)
1.一种抗菌肽涂剂，包括下述质量百分含量的组分：抗菌肽0.5‰～0.5％、成膜材料5％～10％、保湿剂2％～5％、稳定剂1％～5％、表面活性剂1％～5％；以及pH值4.0～6.0的缓冲体系、余量为水；
其中，所述抗菌肽为如下通式的多肽：
区段甲-Ⅰ-A-Ⅱ-区段乙；
Ⅰ选自下述任意氨基酸残基：L-亮氨酸、D-亮氨酸、L-缬氨酸、D-缬氨酸、L-丙氨酸、D-丙氨酸、甘氨酸、L-丝氨酸、D-丝氨酸、L-赖氨酸及D-赖氨酸(L-和D-光学异构形式的L、A、S、V和K，以及G)；
Ⅱ选自下述任意氨基酸残基：选自下述任意氨基酸残基：L-亮氨酸、D-亮氨酸、L-缬氨酸、D-缬氨酸、L-丙氨酸、D-丙氨酸、甘氨酸、L-丝氨酸、D-丝氨酸、L-赖氨酸及D-赖氨酸(L-和D-光学异构形式的L、A、S、V和K，以及G)；
区段甲如SEQ ID No：1所示，其序列为：KWKSFLKTFK；
区段乙如SEQ ID No：2所示，其序列为：KTVLHTALKAISS；
A代表丙氨酸残基；
所述通式中，方向为自N端至C端。
2.根据权利要求1所述的抗菌肽涂剂，其特征在于：
所述抗菌肽为NAL或D-NAL；
所述NAL具有SEQ ID No：3的序列，其氨基酸序列为：KWKSFLKTFKSAAKTVLHTALKAISS；
所述D-NAL具有SEQ ID No：4的序列，其氨基酸序列为：KWKSFLKTFKSAAKTVLHTALKAISS，且除了第13位的A为L构型外，所有氨基酸都是D-构型。
3.根据权利要求1或2所述的抗菌肽涂剂，其特征在于：
所述成膜材料选自聚乙烯醇、羧甲基纤维素钠、羟丙甲基纤维素衍生物、卡拉胶、卡波姆、明胶、琼脂中的一种或几种；优选聚乙烯醇，羧甲基纤维素钠，羟丙基甲基纤维素衍生物，更优选聚乙烯醇；
所述保湿剂选自甘油，丙二醇，聚乙二醇，木糖醇，山梨醇，氨基酸，透明质酸，糖蛋白中的一种或多种，优选甘油；
所述表面活性剂选自司盘类表面活性剂，吐温类表面活性剂，单月桂基磷酸酯，卵磷脂，硬脂酸，优选吐温类表面活性剂；
所述稳定剂选自甘露醇，甘油，糊精，海藻糖，氨基酸，优选海藻糖；
所述缓冲体系选自磷酸盐水溶液缓冲体系、醋酸盐水溶液缓冲体系、枸橼酸盐水溶液缓冲体系，优选磷酸盐水溶液缓冲体系。
4.根据权利要求1-3中任一项所述的抗菌肽涂剂，其特征在于：所述抗菌肽涂剂包括下述质量百分含量的组分：抗菌肽1‰～2‰、成膜材料5％～8％、保湿剂2％～3％、稳定剂3％～4％、表面活性剂4％～5％；以及pH值4.0～6.0的缓冲体系。
5.根据权利要求4所述的抗菌肽涂剂，其特征在于：所述抗菌肽涂剂包括下述质量百分含量的组分：抗菌肽1‰～2‰、聚乙烯醇L100 5％～8％、甘油2％～3％、海藻糖3％～4％、吐温40 4％～5％；以及0.02M、pH值4.0～6.0的磷酸盐缓冲体系。
6.根据权利要求1-5中任一项所述的抗菌肽涂剂，其特征在于：所述抗菌肽涂剂中还包括增塑剂，所述增塑剂选自癸二酸二异辛酯，邻苯二甲酸甲酯，邻苯二甲酸二丁酯，聚乙二醇PEG，柠檬酸三乙酯，或者选自上述的混合物；
和/或，所述抗菌肽涂剂中还包括防腐剂，防腐剂选自苯甲酸，苯甲醇，苯甲酸钠，丙酸钠，山梨酸，尼波金甲酯(丙酯)，或者选自上述的混合物；
和/或，所述抗菌肽涂剂中还包括抗氧化剂，所述抗氧化剂选自丁基羟基甲苯，丁基羟基茴香醚，抗坏血酸(钠)，焦亚硫酸钠，α-生育酚，或者选自上述的混合物；
和/或，所述抗菌肽涂剂的缓冲体系中还加入一种或多种挥发性溶剂或者促渗透剂，选自乙醇，丙酮，异丙醇，或者选自上述的混合物；
和/或，所述抗菌肽涂剂中还包括芳香剂或者清凉剂。
7.根据权利要求1-6中任一项所述的抗菌肽涂剂，其特征在于：所述抗菌肽涂剂适用于治疗致病菌尤其是耐药菌引起的各种感染。
8.权利要求1-7中任一项所述抗菌肽涂剂的制备方法，包括下述步骤：
配制缓冲液体系，然后加入抗菌肽搅拌溶解；再加入成膜材料、保湿剂、稳定剂以及表面活性剂，搅拌溶解，最后加水定容至100％。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110482050.8A CN113209273A (zh) | 2021-04-30 | 2021-04-30 | 一种抗菌肽涂剂及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110482050.8A CN113209273A (zh) | 2021-04-30 | 2021-04-30 | 一种抗菌肽涂剂及其制备方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113209273A true CN113209273A (zh) | 2021-08-06 |
Family
ID=77090676
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110482050.8A Pending CN113209273A (zh) | 2021-04-30 | 2021-04-30 | 一种抗菌肽涂剂及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113209273A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113827503A (zh) * | 2021-11-09 | 2021-12-24 | 浙江臻艾控股(集团)有限公司 | 一种含玻尿酸的面膜精华液及其制备方法 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1899600A (zh) * | 2005-07-22 | 2007-01-24 | 上海高科联合生物技术研发有限公司 | 抗菌肽喷雾成膜剂及其制备方法 |
| CN101111256A (zh) * | 2004-12-15 | 2008-01-23 | 科罗拉多大学 | 抗菌肽及其使用方法 |
| CN102219831A (zh) * | 2011-04-18 | 2011-10-19 | 江阴普莱医药生物技术有限公司 | 一种抗菌肽及其制备方法和应用 |
| CN105288586A (zh) * | 2015-08-28 | 2016-02-03 | 广东海纳川生物科技股份有限公司 | 一种抗菌肽菌丝霉素成膜剂及其制备方法与应用 |
| US20190381136A1 (en) * | 2017-02-21 | 2019-12-19 | Tearsolutions, Inc. | Stable peptide compositions |
-
2021
- 2021-04-30 CN CN202110482050.8A patent/CN113209273A/zh active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101111256A (zh) * | 2004-12-15 | 2008-01-23 | 科罗拉多大学 | 抗菌肽及其使用方法 |
| CN1899600A (zh) * | 2005-07-22 | 2007-01-24 | 上海高科联合生物技术研发有限公司 | 抗菌肽喷雾成膜剂及其制备方法 |
| CN102219831A (zh) * | 2011-04-18 | 2011-10-19 | 江阴普莱医药生物技术有限公司 | 一种抗菌肽及其制备方法和应用 |
| CN105288586A (zh) * | 2015-08-28 | 2016-02-03 | 广东海纳川生物科技股份有限公司 | 一种抗菌肽菌丝霉素成膜剂及其制备方法与应用 |
| US20190381136A1 (en) * | 2017-02-21 | 2019-12-19 | Tearsolutions, Inc. | Stable peptide compositions |
Non-Patent Citations (2)
| Title |
|---|
| CHEN YUXIN 等: "Rational design of α-helical antimicrobial peptides with enhanced activities and specificity/therapeutic index", 《JOURNAL OF BIOLOGICAL CHEMISTRY》, vol. 280, no. 13, pages 12316 - 12329 * |
| Q FENG ET AL.: "Functional synergy of α-helical antimicrobial peptides and traditional antibiotics against Gram-negative and Gram-positive bacteria in vitro and in vivo", 《EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES》, vol. 34, no. 1, pages 1, XP036270529, DOI: 10.1007/s10096-014-2219-3 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113827503A (zh) * | 2021-11-09 | 2021-12-24 | 浙江臻艾控股(集团)有限公司 | 一种含玻尿酸的面膜精华液及其制备方法 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69835279T2 (de) | Zusammensetzungen und verfahren zur behandlung von infektionen unter verwendung von kationischen peptiden allein oder in kombination mit antibiotika | |
| WO1997018827A1 (en) | Compositions and methods for the prevention and treatment of oral mucositis | |
| KR101629386B1 (ko) | 왕지네로부터 유래한 항균 펩타이드 스콜로펜드라신-7 및 그의 조성물 | |
| KR101700603B1 (ko) | 바퀴벌레에서 유래한 항균 펩타이드 페리플라네타신-1 및 그의 조성물 | |
| KR20180052178A (ko) | 흰점박이꽃무지에서 유래한 항균 펩타이드 프로테티아마이신 1 및 그의 조성물 | |
| KR101444257B1 (ko) | 왕지네로부터 분리한 신규 스콜로펜드라신ⅱ 펩타이드 및 그의 조성물 | |
| EP2750689B1 (de) | Modifizierte apidaecinderivate als antibiotische peptide | |
| CN113209273A (zh) | 一种抗菌肽涂剂及其制备方法 | |
| KR20160013328A (ko) | 왕지네로부터 분리한 항균 펩타이드 스콜로펜드라신-6 및 그의 조성물 | |
| KR20180117792A (ko) | 왕귀뚜라미에서 유래한 항균 펩타이드 테레오그릴루신 1 및 그의 조성물 | |
| KR20170053879A (ko) | 벼메뚜기에서 유래한 항균 펩타이드 옥시야신-1 및 그의 조성물 | |
| KR101444256B1 (ko) | 왕지네로부터 분리한 신규 스콜로펜드라신ⅲ 펩타이드 및 그의 조성물 | |
| EP1519951B1 (fr) | Peptides lineaires cationiques ayant des proprietes antifongiques | |
| DE60125809T2 (de) | Diastereomere peptide und diese umfassende arzneimittel | |
| CN112755175A (zh) | 一种抗菌肽液体组合物及其制剂 | |
| KR101825952B1 (ko) | 벼메뚜기에서 유래한 항균 펩타이드 옥시야신-3 및 그의 조성물 | |
| EP4282400A1 (en) | Antimicrobial peptide liquid composition and formulation thereof | |
| CN113081953B (zh) | 一种局部用抗菌肽凝胶剂及其制备方法 | |
| KR101889404B1 (ko) | 바퀴벌레에서 유래한 항균 펩타이드 페리플라네타신-5 및 그의 조성물 | |
| KR101851134B1 (ko) | 바퀴벌레에서 유래한 항균 펩타이드 페리플라네타신-6 및 그의 조성물 | |
| CN113081977B (zh) | 一种抗感染的抗菌肽冻干制剂及其制备方法 | |
| CN113134075B (zh) | 一种抗菌肽乳膏及其制备方法 | |
| KR101773351B1 (ko) | 바퀴벌레에서 유래한 항균 펩타이드 페리플라네타신-3 및 그의 조성물 | |
| CN113134075A (zh) | 一种抗菌肽乳膏及其制备方法 | |
| CN113717267B (zh) | 一种抗菌肽pHTP-1及其应用和包含抗菌肽pHTP-1的产品 |
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 |