CN110870918A - Pharmaceutical composition containing amino acid nutrients and antitumor chemotherapeutic drugs and application thereof - Google Patents
Pharmaceutical composition containing amino acid nutrients and antitumor chemotherapeutic drugs and application thereof Download PDFInfo
- Publication number
- CN110870918A CN110870918A CN201811008756.5A CN201811008756A CN110870918A CN 110870918 A CN110870918 A CN 110870918A CN 201811008756 A CN201811008756 A CN 201811008756A CN 110870918 A CN110870918 A CN 110870918A
- Authority
- CN
- China
- Prior art keywords
- amino acid
- tumor
- pharmaceutical composition
- concentration
- chemotherapeutic
- 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
- 150000001413 amino acids Chemical class 0.000 title claims abstract description 152
- 235000015097 nutrients Nutrition 0.000 title claims abstract description 115
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 76
- 230000000259 anti-tumor effect Effects 0.000 title claims description 112
- 239000002246 antineoplastic agent Substances 0.000 title claims description 39
- 229940044683 chemotherapy drug Drugs 0.000 title claims description 29
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 131
- 239000012049 topical pharmaceutical composition Substances 0.000 claims abstract description 43
- 238000011282 treatment Methods 0.000 claims abstract description 32
- 239000004480 active ingredient Substances 0.000 claims abstract description 29
- 230000000699 topical effect Effects 0.000 claims abstract description 12
- 229940024606 amino acid Drugs 0.000 claims description 175
- 235000001014 amino acid Nutrition 0.000 claims description 175
- 239000003814 drug Substances 0.000 claims description 97
- 239000007788 liquid Substances 0.000 claims description 72
- 229940079593 drug Drugs 0.000 claims description 64
- 230000000973 chemotherapeutic effect Effects 0.000 claims description 62
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 39
- 229960002949 fluorouracil Drugs 0.000 claims description 39
- -1 amino acid compounds Chemical class 0.000 claims description 35
- 108010038807 Oligopeptides Proteins 0.000 claims description 31
- 102000015636 Oligopeptides Human genes 0.000 claims description 31
- 230000000694 effects Effects 0.000 claims description 30
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 28
- 229920001184 polypeptide Polymers 0.000 claims description 27
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 27
- 239000004475 Arginine Substances 0.000 claims description 19
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 19
- 229960003121 arginine Drugs 0.000 claims description 19
- 235000009697 arginine Nutrition 0.000 claims description 19
- 239000002417 nutraceutical Substances 0.000 claims description 19
- 235000021436 nutraceutical agent Nutrition 0.000 claims description 19
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 18
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 17
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 14
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 10
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 10
- 239000004472 Lysine Substances 0.000 claims description 10
- 229940127089 cytotoxic agent Drugs 0.000 claims description 10
- 235000018977 lysine Nutrition 0.000 claims description 10
- 239000004471 Glycine Substances 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 8
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 8
- 239000003242 anti bacterial agent Substances 0.000 claims description 8
- 229940088710 antibiotic agent Drugs 0.000 claims description 8
- 229960004397 cyclophosphamide Drugs 0.000 claims description 8
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 8
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 8
- 235000004554 glutamine Nutrition 0.000 claims description 8
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 7
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 7
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 7
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 7
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 7
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 7
- 229960003767 alanine Drugs 0.000 claims description 7
- 235000004279 alanine Nutrition 0.000 claims description 7
- 229960002433 cysteine Drugs 0.000 claims description 7
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 7
- 235000018417 cysteine Nutrition 0.000 claims description 7
- 229960001904 epirubicin Drugs 0.000 claims description 7
- 238000004108 freeze drying Methods 0.000 claims description 7
- 229960005277 gemcitabine Drugs 0.000 claims description 7
- 229910052697 platinum Inorganic materials 0.000 claims description 7
- 229960001153 serine Drugs 0.000 claims description 7
- 235000004400 serine Nutrition 0.000 claims description 7
- 229960001278 teniposide Drugs 0.000 claims description 7
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 7
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 6
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 6
- DATAGRPVKZEWHA-YFKPBYRVSA-N N(5)-ethyl-L-glutamine Chemical compound CCNC(=O)CC[C@H]([NH3+])C([O-])=O DATAGRPVKZEWHA-YFKPBYRVSA-N 0.000 claims description 6
- 229940123237 Taxane Drugs 0.000 claims description 6
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 6
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 6
- 235000013922 glutamic acid Nutrition 0.000 claims description 6
- 239000004220 glutamic acid Substances 0.000 claims description 6
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 6
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 5
- 229930012538 Paclitaxel Natural products 0.000 claims description 5
- 229960005261 aspartic acid Drugs 0.000 claims description 5
- 235000003704 aspartic acid Nutrition 0.000 claims description 5
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-aminopropionic acid Natural products NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 5
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 5
- 235000014304 histidine Nutrition 0.000 claims description 5
- 229960002885 histidine Drugs 0.000 claims description 5
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 5
- 229960001592 paclitaxel Drugs 0.000 claims description 5
- 238000001243 protein synthesis Methods 0.000 claims description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 5
- 230000014616 translation Effects 0.000 claims description 5
- 230000006820 DNA synthesis Effects 0.000 claims description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 4
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-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
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 4
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 4
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 4
- 239000004473 Threonine Substances 0.000 claims description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 4
- 229940000635 beta-alanine Drugs 0.000 claims description 4
- 229960002743 glutamine Drugs 0.000 claims description 4
- 229960000310 isoleucine Drugs 0.000 claims description 4
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 4
- 229960003136 leucine Drugs 0.000 claims description 4
- 229930182817 methionine Natural products 0.000 claims description 4
- 235000006109 methionine Nutrition 0.000 claims description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 4
- 229960005190 phenylalanine Drugs 0.000 claims description 4
- 229960002429 proline Drugs 0.000 claims description 4
- 235000008521 threonine Nutrition 0.000 claims description 4
- 229960002898 threonine Drugs 0.000 claims description 4
- 238000013518 transcription Methods 0.000 claims description 4
- 230000035897 transcription Effects 0.000 claims description 4
- 229960004441 tyrosine Drugs 0.000 claims description 4
- 235000002374 tyrosine Nutrition 0.000 claims description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 4
- 229960004295 valine Drugs 0.000 claims description 4
- 239000004474 valine Substances 0.000 claims description 4
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 3
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 3
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims description 3
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims description 3
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960001230 asparagine Drugs 0.000 claims description 3
- 235000009582 asparagine Nutrition 0.000 claims description 3
- 235000013477 citrulline Nutrition 0.000 claims description 3
- 229960002173 citrulline Drugs 0.000 claims description 3
- BBJIPMIXTXKYLZ-UHFFFAOYSA-N isoglutamic acid Chemical compound OC(=O)CC(N)CC(O)=O BBJIPMIXTXKYLZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229960003104 ornithine Drugs 0.000 claims description 3
- 229960003080 taurine Drugs 0.000 claims description 3
- 229940026510 theanine Drugs 0.000 claims description 3
- 241000408747 Lepomis gibbosus Species 0.000 claims description 2
- 244000269722 Thea sinensis Species 0.000 claims description 2
- 150000008442 polyphenolic compounds Chemical class 0.000 claims description 2
- 235000013824 polyphenols Nutrition 0.000 claims description 2
- 235000020236 pumpkin seed Nutrition 0.000 claims description 2
- SIUSQTBTBHUEBW-UHFFFAOYSA-N C1=COC2=CC(C(OC2=C1)C(=O)O)(C(=O)O)N Chemical compound C1=COC2=CC(C(OC2=C1)C(=O)O)(C(=O)O)N SIUSQTBTBHUEBW-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 16
- 239000007924 injection Substances 0.000 description 63
- 238000002347 injection Methods 0.000 description 63
- 239000000203 mixture Substances 0.000 description 58
- 230000005764 inhibitory process Effects 0.000 description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 33
- 239000000843 powder Substances 0.000 description 26
- 230000002195 synergetic effect Effects 0.000 description 26
- 239000013642 negative control Substances 0.000 description 24
- 210000001519 tissue Anatomy 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000000975 dye Substances 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 20
- 238000000034 method Methods 0.000 description 19
- 238000012360 testing method Methods 0.000 description 18
- 108010024636 Glutathione Proteins 0.000 description 17
- 150000001720 carbohydrates Chemical class 0.000 description 17
- 210000004881 tumor cell Anatomy 0.000 description 17
- 150000001875 compounds Chemical class 0.000 description 16
- 229960003180 glutathione Drugs 0.000 description 16
- 230000002601 intratumoral effect Effects 0.000 description 16
- 150000002772 monosaccharides Chemical class 0.000 description 16
- 229920001282 polysaccharide Polymers 0.000 description 16
- 235000014633 carbohydrates Nutrition 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 14
- XQAXGZLFSSPBMK-UHFFFAOYSA-M [7-(dimethylamino)phenothiazin-3-ylidene]-dimethylazanium;chloride;trihydrate Chemical compound O.O.O.[Cl-].C1=CC(=[N+](C)C)C=C2SC3=CC(N(C)C)=CC=C3N=C21 XQAXGZLFSSPBMK-UHFFFAOYSA-M 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 13
- 229960000907 methylthioninium chloride Drugs 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 201000011510 cancer Diseases 0.000 description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000008103 glucose Substances 0.000 description 11
- 241000699660 Mus musculus Species 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000011580 nude mouse model Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 235000000346 sugar Nutrition 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 8
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- 229960003646 lysine Drugs 0.000 description 8
- 150000007524 organic acids Chemical class 0.000 description 8
- 229920000642 polymer Polymers 0.000 description 8
- 230000008685 targeting Effects 0.000 description 8
- 238000011200 topical administration Methods 0.000 description 8
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 7
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 7
- 230000000202 analgesic effect Effects 0.000 description 7
- 230000006378 damage Effects 0.000 description 7
- 201000002528 pancreatic cancer Diseases 0.000 description 7
- 230000000144 pharmacologic effect Effects 0.000 description 7
- 206010006187 Breast cancer Diseases 0.000 description 6
- 208000026310 Breast neoplasm Diseases 0.000 description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 description 6
- 208000024770 Thyroid neoplasm Diseases 0.000 description 6
- 239000002535 acidifier Substances 0.000 description 6
- 230000000118 anti-neoplastic effect Effects 0.000 description 6
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 6
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 231100000433 cytotoxic Toxicity 0.000 description 6
- 230000001472 cytotoxic effect Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 208000020816 lung neoplasm Diseases 0.000 description 6
- 235000013336 milk Nutrition 0.000 description 6
- 210000004080 milk Anatomy 0.000 description 6
- 229920001542 oligosaccharide Polymers 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 230000001954 sterilising effect Effects 0.000 description 6
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 5
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 5
- 238000002679 ablation Methods 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 5
- RQFQJYYMBWVMQG-IXDPLRRUSA-N chitotriose Chemical compound O[C@@H]1[C@@H](N)[C@H](O)O[C@H](CO)[C@H]1O[C@H]1[C@H](N)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)[C@@H](CO)O1 RQFQJYYMBWVMQG-IXDPLRRUSA-N 0.000 description 5
- 230000000857 drug effect Effects 0.000 description 5
- 229960002989 glutamic acid Drugs 0.000 description 5
- 150000004676 glycans Chemical class 0.000 description 5
- 239000007928 intraperitoneal injection Substances 0.000 description 5
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 5
- 229960000511 lactulose Drugs 0.000 description 5
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 5
- 208000014018 liver neoplasm Diseases 0.000 description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 5
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 5
- 150000002482 oligosaccharides Chemical class 0.000 description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 description 5
- 239000005017 polysaccharide Substances 0.000 description 5
- 239000012730 sustained-release form Substances 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- 239000000811 xylitol Substances 0.000 description 5
- 235000010447 xylitol Nutrition 0.000 description 5
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 5
- 229960002675 xylitol Drugs 0.000 description 5
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 4
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 4
- 229930091371 Fructose Natural products 0.000 description 4
- 239000005715 Fructose Substances 0.000 description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- SJEYSFABYSGQBG-UHFFFAOYSA-M Patent blue Chemical compound [Na+].C1=CC(N(CC)CC)=CC=C1C(C=1C(=CC(=CC=1)S([O-])(=O)=O)S([O-])(=O)=O)=C1C=CC(=[N+](CC)CC)C=C1 SJEYSFABYSGQBG-UHFFFAOYSA-M 0.000 description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 150000007933 aliphatic carboxylic acids Chemical group 0.000 description 4
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 4
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 4
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 4
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 150000002016 disaccharides Chemical class 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000002224 dissection Methods 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 4
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 4
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 229930182830 galactose Natural products 0.000 description 4
- 229960002442 glucosamine Drugs 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 206010023841 laryngeal neoplasm Diseases 0.000 description 4
- 239000008267 milk Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 239000000176 sodium gluconate Substances 0.000 description 4
- 235000012207 sodium gluconate Nutrition 0.000 description 4
- 229940005574 sodium gluconate Drugs 0.000 description 4
- 150000005846 sugar alcohols Chemical class 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 201000003120 testicular cancer Diseases 0.000 description 4
- 206010046766 uterine cancer Diseases 0.000 description 4
- 206010046885 vaginal cancer Diseases 0.000 description 4
- 208000013139 vaginal neoplasm Diseases 0.000 description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 description 4
- 239000008158 vegetable oil Substances 0.000 description 4
- 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 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 108010016626 Dipeptides Proteins 0.000 description 3
- 206010061968 Gastric neoplasm Diseases 0.000 description 3
- 206010019695 Hepatic neoplasm Diseases 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 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 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229930183665 actinomycin Natural products 0.000 description 3
- 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 description 3
- 150000003862 amino acid derivatives Chemical class 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 3
- 229960004926 chlorobutanol Drugs 0.000 description 3
- HEBKCHPVOIAQTA-NGQZWQHPSA-N d-xylitol Chemical compound OC[C@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-NGQZWQHPSA-N 0.000 description 3
- 239000002612 dispersion medium Substances 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- FTSSQIKWUOOEGC-RULYVFMPSA-N fructooligosaccharide Chemical compound OC[C@H]1O[C@@](CO)(OC[C@@]2(OC[C@@]3(OC[C@@]4(OC[C@@]5(OC[C@@]6(OC[C@@]7(OC[C@@]8(OC[C@@]9(OC[C@@]%10(OC[C@@]%11(O[C@H]%12O[C@H](CO)[C@@H](O)[C@H](O)[C@H]%12O)O[C@H](CO)[C@@H](O)[C@@H]%11O)O[C@H](CO)[C@@H](O)[C@@H]%10O)O[C@H](CO)[C@@H](O)[C@@H]9O)O[C@H](CO)[C@@H](O)[C@@H]8O)O[C@H](CO)[C@@H](O)[C@@H]7O)O[C@H](CO)[C@@H](O)[C@@H]6O)O[C@H](CO)[C@@H](O)[C@@H]5O)O[C@H](CO)[C@@H](O)[C@@H]4O)O[C@H](CO)[C@@H](O)[C@@H]3O)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H]1O FTSSQIKWUOOEGC-RULYVFMPSA-N 0.000 description 3
- 229940107187 fructooligosaccharide Drugs 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 3
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000037841 lung tumor Diseases 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 229960004452 methionine Drugs 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 229960001309 procaine hydrochloride Drugs 0.000 description 3
- 208000023958 prostate neoplasm Diseases 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 229940126585 therapeutic drug Drugs 0.000 description 3
- 201000002510 thyroid cancer Diseases 0.000 description 3
- 208000013076 thyroid tumor Diseases 0.000 description 3
- 229960004799 tryptophan Drugs 0.000 description 3
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- MHOFGBJTSNWTDT-UHFFFAOYSA-M 2-[n-ethyl-4-[(6-methoxy-3-methyl-1,3-benzothiazol-3-ium-2-yl)diazenyl]anilino]ethanol;methyl sulfate Chemical compound COS([O-])(=O)=O.C1=CC(N(CCO)CC)=CC=C1N=NC1=[N+](C)C2=CC=C(OC)C=C2S1 MHOFGBJTSNWTDT-UHFFFAOYSA-M 0.000 description 2
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- JUQPZRLQQYSMEQ-UHFFFAOYSA-N CI Basic red 9 Chemical compound [Cl-].C1=CC(N)=CC=C1C(C=1C=CC(N)=CC=1)=C1C=CC(=[NH2+])C=C1 JUQPZRLQQYSMEQ-UHFFFAOYSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 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 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 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 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-MBMOQRBOSA-N D-mannonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O RGHNJXZEOKUKBD-MBMOQRBOSA-N 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 208000013452 Fallopian tube neoplasm Diseases 0.000 description 2
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 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 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- XXACTDWGHQXLGW-UHFFFAOYSA-M Janus Green B chloride Chemical compound [Cl-].C12=CC(N(CC)CC)=CC=C2N=C2C=CC(\N=N\C=3C=CC(=CC=3)N(C)C)=CC2=[N+]1C1=CC=CC=C1 XXACTDWGHQXLGW-UHFFFAOYSA-M 0.000 description 2
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 2
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 description 2
- 206010023825 Laryngeal cancer Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 208000003445 Mouth Neoplasms Diseases 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 229950000242 ancitabine Drugs 0.000 description 2
- KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical compound Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 229940052223 basic fuchsin Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036770 blood supply Effects 0.000 description 2
- 239000001045 blue dye Substances 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 229940077731 carbohydrate nutrients Drugs 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 238000000423 cell based assay Methods 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- ZXJXZNDDNMQXFV-UHFFFAOYSA-M crystal violet Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1[C+](C=1C=CC(=CC=1)N(C)C)C1=CC=C(N(C)C)C=C1 ZXJXZNDDNMQXFV-UHFFFAOYSA-M 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 2
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 229960001235 gentian violet Drugs 0.000 description 2
- 239000000174 gluconic acid Substances 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 229960002449 glycine Drugs 0.000 description 2
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 201000002313 intestinal cancer Diseases 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000000832 lactitol Substances 0.000 description 2
- 235000010448 lactitol Nutrition 0.000 description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 2
- 229960003451 lactitol Drugs 0.000 description 2
- 201000004959 laryngeal benign neoplasm Diseases 0.000 description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 229960005337 lysine hydrochloride Drugs 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000000845 maltitol Substances 0.000 description 2
- 235000010449 maltitol Nutrition 0.000 description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 2
- 229940035436 maltitol Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 208000025402 neoplasm of esophagus Diseases 0.000 description 2
- 208000025189 neoplasm of testis Diseases 0.000 description 2
- PGSADBUBUOPOJS-UHFFFAOYSA-N neutral red Chemical compound Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000003790 pyrimidine antagonist Substances 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- OARRHUQTFTUEOS-UHFFFAOYSA-N safranin Chemical compound [Cl-].C=12C=C(N)C(C)=CC2=NC2=CC(C)=C(N)C=C2[N+]=1C1=CC=CC=C1 OARRHUQTFTUEOS-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229950003937 tolonium Drugs 0.000 description 2
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 208000025421 tumor of uterus Diseases 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 description 1
- DWHMPBALQYTJFJ-DKWTVANSSA-N (2s)-2-aminobutanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CC(O)=O DWHMPBALQYTJFJ-DKWTVANSSA-N 0.000 description 1
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 1
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- VOXBZHOHGGBLCQ-UHFFFAOYSA-N 2-amino-3,7-dihydropurine-6-thione;hydrate Chemical compound O.N1C(N)=NC(=S)C2=C1N=CN2.N1C(N)=NC(=S)C2=C1N=CN2 VOXBZHOHGGBLCQ-UHFFFAOYSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- BUCXEFZXWKUCCY-UHFFFAOYSA-N 4-methyl-3-(2-phenylethyl)-1,2,4-oxadiazol-5-one Chemical compound O1C(=O)N(C)C(CCC=2C=CC=CC=2)=N1 BUCXEFZXWKUCCY-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 101150080924 CNE1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 description 1
- 108010087806 Carnosine Proteins 0.000 description 1
- 239000003390 Chinese drug Substances 0.000 description 1
- 241000579895 Chlorostilbon Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- QXKAIJAYHKCRRA-JJYYJPOSSA-N D-arabinonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(O)=O QXKAIJAYHKCRRA-JJYYJPOSSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- XBGGUPMXALFZOT-VIFPVBQESA-N Gly-Tyr Chemical compound NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-VIFPVBQESA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- VPZXBVLAVMBEQI-VKHMYHEASA-N Glycyl-alanine Chemical compound OC(=O)[C@H](C)NC(=O)CN VPZXBVLAVMBEQI-VKHMYHEASA-N 0.000 description 1
- 108010008488 Glycylglycine Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- HGNRJCINZYHNOU-LURJTMIESA-N Lys-Gly Chemical compound NCCCC[C@H](N)C(=O)NCC(O)=O HGNRJCINZYHNOU-LURJTMIESA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 description 1
- 108010079364 N-glycylalanine Proteins 0.000 description 1
- FCGPHOLYDUONKQ-UHFFFAOYSA-N NC1(C(OC=CC1)C(=O)O)C(=O)O Chemical compound NC1(C(OC=CC1)C(=O)O)C(=O)O FCGPHOLYDUONKQ-UHFFFAOYSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 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 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- FYGDTMLNYKFZSV-DZOUCCHMSA-N alpha-D-Glcp-(1->4)-alpha-D-Glcp-(1->4)-D-Glcp Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)O[C@H](O[C@@H]2[C@H](OC(O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-DZOUCCHMSA-N 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 229960003589 arginine hydrochloride Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000003157 cancerolytic effect Effects 0.000 description 1
- 150000001719 carbohydrate derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940044199 carnosine Drugs 0.000 description 1
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 108010079058 casein hydrolysate Proteins 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000235 effect on cancer Effects 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 229910052876 emerald Inorganic materials 0.000 description 1
- 239000010976 emerald Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960005144 gemcitabine hydrochloride Drugs 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 229960003707 glutamic acid hydrochloride Drugs 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- 229940043257 glycylglycine Drugs 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 230000008821 health effect Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- DLRVVLDZNNYCBX-RTPHMHGBSA-N isomaltose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)C(O)O1 DLRVVLDZNNYCBX-RTPHMHGBSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 150000003272 mannan oligosaccharides Chemical class 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 238000002229 photoelectron microspectroscopy Methods 0.000 description 1
- 230000007180 physiological regulation Effects 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000000649 purine antagonist Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003290 ribose derivatives Chemical class 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 210000002832 shoulder Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- IDBPBTCQINMQJK-PSRPMNHMSA-M sodium;(2s,3r,4r)-2,3,4,5-tetrahydroxypentanoate Chemical compound [Na+].OC[C@@H](O)[C@@H](O)[C@H](O)C([O-])=O IDBPBTCQINMQJK-PSRPMNHMSA-M 0.000 description 1
- 238000009214 sonodynamic therapy Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 235000021139 traditional diet Nutrition 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- GZXOHHPYODFEGO-UHFFFAOYSA-N triglycine sulfate Chemical compound NCC(O)=O.NCC(O)=O.NCC(O)=O.OS(O)(=O)=O GZXOHHPYODFEGO-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003741 xylose derivatives Chemical class 0.000 description 1
- 125000000969 xylosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)CO1)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to the use of amino acid based nutrients as a topical active ingredient for the preparation of a topical pharmaceutical composition for the treatment of solid tumors, and to a pharmaceutical composition comprising the amino acid based nutrient topical active ingredient.
Description
Technical Field
The present invention relates to the use of amino acid based nutrients as a topical active ingredient for the preparation of a topical pharmaceutical composition for the treatment of solid tumors, and to a pharmaceutical composition comprising the amino acid based nutrient topical active ingredient.
Background
A solid tumor is a neoplastic disease characterized by a tumor mass, which is a characteristic pathological tissue containing tumor cells. In the case of pancreatic cancer tumor bodies, pancreatic cancer cells account for only about 30% by volume of the tumor bodies. It can be seen that in addition to tumor cells, there are often a greater number of other components in tumor body tissue (sometimes also referred to as the microenvironment of the tumor cells), including other various cells, various intercellular substances, various ducts, etc.
One of the major problems faced in the development of antineoplastic drugs is specificity. The cytotoxic drug can target tumor cells through systemic administration based on the positive result of tumor cell inhibition experiment. However, since the target cells and normal cells cannot be sufficiently distinguished, and the difference between the effective dose and the safety limit is not large enough, there is a great risk of systemic toxicity while systemic therapeutic effects (tumor cell suppression effects in and out of tumor) are produced. Furthermore, the drug molecules need to penetrate effectively into the tumor tissue to interact with the tumor cells in between, which is not an obstacle-free event. For some tumors with a poor blood supply (e.g., pancreatic cancer), the chances of patient benefit are less.
Topical administration has the advantage of physically targeting the drug. It has therefore been thought that topical administration of cytotoxic drugs can increase the intratumoral concentration and thus the efficacy of the drug. However, topical administration of cytotoxic drugs has not shown a significant improvement in efficacy. Merely increasing its intratumoral concentration does not appear to significantly improve its efficiency in targeting cancer cells in intratumoral tissues. In addition to resorting to their sustained release forms, cytotoxic drugs are still almost systemically administered clinically. Chemical ablators (high purity ethanol, high concentration of acids and bases) are not characterized by cell destruction but by tissue destruction. Compared with cytotoxic drugs, it has almost no systemic effect of targeting cancer cells, but often shows higher local effect. However, they are often strong disrupters that do not sufficiently distinguish the target tissue from other tissues. This makes their practical application of intervention volumes (e.g., acid-base doses not exceeding 0.2ml/kg) and intervention sites very limited (e.g., restrictions on the organs in which the tumor resides, limited ablation of the tumor margins, etc.). Thus, chemical ablative agents have been clinically faded out of malignant solid tumors in the last decade. In fact, at present, there are few local drugs with high local safety and local curative effect in clinic.
Thus, there is still a need to develop new anti-solid tumor drugs, especially topical drugs, to meet various clinical needs that the prior art has not yet met.
Disclosure of Invention
The invention aims to provide a local medicinal composition for preventing and treating solid tumors, and a method for treating the solid tumors by using the medicinal composition and application of the medicinal composition.
According to one aspect of the present application, there is provided a topical pharmaceutical composition for the treatment of solid tumors comprising an amino acid based nutrient, an anti-tumor chemotherapeutic, and a pharmaceutically acceptable liquid carrier, wherein the concentration (w/v) of said amino acid based nutrient in the topical pharmaceutical composition is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%; the concentration (w/v) of the anti-tumor chemotherapeutic is greater than 30% of its saturation concentration, preferably 50% -100% of its saturation concentration, wherein the saturation concentration refers to the saturation concentration of the anti-tumor chemotherapeutic in the liquid carrier.
According to another aspect of the present application there is provided the use of an amino acid based nutrient as a topically active ingredient in combination with an anti-tumour chemotherapeutic agent in the manufacture of a topical pharmaceutical composition for the treatment of a solid tumour.
In a specific embodiment, the topical pharmaceutical composition comprises said amino acid based nutrient, said anti-tumor chemotherapeutic, and a pharmaceutically acceptable liquid carrier, and wherein the concentration (w/v) of said amino acid based nutrient is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25%, or 10-25%; the concentration of the anti-tumor chemotherapeutic is greater than 30% of its saturation concentration, preferably 50% -100% of its saturation concentration, wherein the saturation concentration refers to the saturation concentration of the anti-tumor chemotherapeutic in the liquid carrier.
According to a further aspect of the present application, there is provided a method for the prevention and treatment of solid tumors comprising topically administering to an individual in need thereof a pharmaceutical composition according to the present application comprising an amino acid based nutrient as a topically active ingredient together with an anti-tumor chemotherapeutic.
Compared with the single medicine containing the amino acid nutrient and the anti-tumor chemotherapeutic medicine, the composition containing the amino acid nutrient and the anti-tumor chemotherapeutic medicine has the following advantages: provides a synergistic effect against solid tumors to improve efficacy, while possibly providing an antagonistic effect against non-specific tissue destruction to improve safety.
Embodiments according to the present invention have the following advantages over the prior art of solid tumor treatment: compared with the existing cytotoxic drugs, the compound has obviously higher tumor curative effect; compared with the existing molecular targeted drugs, the compound shows less rigorous screening of indications and great potential for rapidly growing tumor bodies, large tumor bodies and blood-poor tumor donors. Compared with the existing chemical ablation agent, the chemical ablation agent has higher specificity, namely, the chemical ablation agent has higher effectiveness on tumor bodies and obviously lower local irritation on non-pathological tissues, so that the chemical ablation agent has larger intervention adaptability and higher application volume. Compared with the existing hardening agent, the compound has higher curative effect and safety. The applications and compositions of the present invention are also not plagued by the problem of drug resistance encountered with existing cytotoxic drugs and existing molecular targeted drugs. In addition, the application and the composition are convenient to prepare and low in cost, and are particularly beneficial to leading the vast population who is difficult to bear high expense to enjoy safe and effective treatment.
Detailed Description
The inventor of the invention finds that the amino acid nutrient can be used as a local active ingredient for a local medicament applied to solid tumors in a tumor-bearing animal test. In the context of the present invention, the term "local active ingredient" is used to refer to an active ingredient in a topical medicament that provides a local effect, typically a destructive effect on local tissues.
The inventors of the present invention have further found that the combination of amino acid based nutrients with an anti-tumour chemotherapeutic drug has a synergistic effect in the treatment of solid tumours, especially when their concentrations in the topical pharmaceutical composition for the treatment of solid tumours have the quantitative ratios as defined below.
In the context of the present invention, the term "local effect" or "local activity" is used to mean that the pharmacological effect or pharmacological activity is produced at the target area primarily by the agent itself, rather than by the blood with the agent. The term "topical drug (composition)" refers to a therapeutic drug (composition) that exerts its pharmacological effects primarily through local action. The term "target area" as used herein refers to the target site of administration, e.g., adjacent, interfacial, internal (preferably internal) to a localized lesion, etc.
In the context of the present invention, the term "synergistic effect" means that the combination of active ingredients shows a more favorable pharmaceutical effect on the treatment than their individual use alone, which includes, for example, synergistic efficacy and synergistic safety. The term "synergistic efficacy" refers to the combined display of the active ingredients that exhibits a higher desired efficacy than either ingredient alone and/or the combined display that does not exhibit the desired efficacy (e.g., a novel immune effect) of either ingredient alone. The term "synergistic safety" means that the active ingredients in combination exhibit a desired safety higher than that of either ingredient alone, for example, even if the efficacy of the combination is not more than the maximum efficacy of the single ingredient, it is an effective efficacy, and the safety of the combination is significantly higher than that of the single ingredient (e.g., antagonism of side effects) of the maximum efficacy of the single ingredient.
Thus, according to one aspect of the present invention, there is provided a topical pharmaceutical composition for the treatment of solid tumors comprising an amino acid based nutrient, an anti-tumor chemotherapeutic, and a pharmaceutically acceptable liquid carrier, wherein the concentration (w/v) of said amino acid based nutrient in the topical pharmaceutical composition is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%; the concentration of the anti-tumor chemotherapeutic is greater than 30% of its saturation concentration, preferably 50% -100% of its saturation concentration, wherein the saturation concentration refers to the saturation concentration of the anti-tumor chemotherapeutic in the liquid carrier.
According to another aspect of the present invention there is provided the use of an amino acid based nutrient as a topically active ingredient in combination with an anti-tumour chemotherapeutic agent in the manufacture of a topical pharmaceutical composition for the treatment of a solid tumour. In a specific embodiment, the topical pharmaceutical composition comprises said amino acid based nutrient, said anti-tumor chemotherapeutic, and a pharmaceutically acceptable liquid carrier, and wherein the concentration (w/v) of said amino acid based nutrient is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25%, or 10-25%; the concentration of the anti-tumor chemotherapeutic is greater than 30% of its saturation concentration, preferably 50% -100% of its saturation concentration, wherein the saturation concentration refers to the saturation concentration of the anti-tumor chemotherapeutic in the liquid carrier.
According to a further aspect of the present invention there is provided a method for the prevention and treatment of solid tumors comprising topically administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an amino acid based nutrient as a topically active ingredient in combination with an anti-tumor chemotherapeutic according to the present disclosure.
Within the scope of the present invention, the term "therapeutically effective amount" refers to an amount of a drug that is used to treat a disease (e.g., a tumor) and achieve an effective effect (e.g., reduce or/and alleviate symptoms of the disease).
In the context of the present invention, unless otherwise indicated, the term "concentration" refers to the weight/volume percent concentration% (w/v) of the specified component in the topical pharmaceutical composition. The term "local administration concentration" refers to the concentration of a specified component at the time the drug is administered locally, which may be the concentration of the specified component at the site where the drug contacts the target area (e.g., injection needle hole or infusion tube outlet).
In the scope of the present invention, the term "amino acid nutrient" is used to refer to an amino acid compound having a nutraceutical effect, preferably selected from amino acids, amino acid polymers and amino acid derivatives having a nutraceutical effect, more preferably selected from amino acid nutraceuticals and amino acid adjuvants having a nutraceutical effect, as carried in the chinese, us or european official pharmacopoeia or guidelines. In the context of the present invention, the term "nutraceutical effect" is used to refer to an in vivo effect resulting from the action of one or more of the following organisms: providing energy, participating in the synthesis of bioactive substances (e.g., proteins), participating in part of the metabolism, maintaining the intestinal micro-ecological balance of animals, and participating in other physiological regulation beneficial to the health of the body (e.g., regulating protein synthesis, regulating immune response).
In the scope of the present invention, the amino acid polymer, and the amino acid derivative as the amino acid nutrient are preferably amino acids selected from the group consisting of: proteinogenic amino acids and nonproteinogenic amino acids.
In the context of the present invention, the term "proteinogenic amino acids" refers to the main amino acids that make up a protein; the term "non-proteinogenic amino acids" refers to amino acids other than proteinogenic amino acids that may also be used as nutraceutical functional components in nutraceuticals, traditional diets and functional diets (e.g., health diets).
Specifically, in the present disclosure, the proteinogenic amino acids include amino acids selected from the group consisting of nonpolar amino acids (e.g., alanine, valine, leucine, isoleucine, phenylalanine, proline), polar neutral amino acids (e.g., tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine), basic amino acids (e.g., lysine, arginine, histidine), acidic amino acids (e.g., aspartic acid, glutamic acid), the above are L-type α -amino acids except glycine.
The amino acid polymer may be selected from oligopeptides and polypeptides comprising amino acids as described above.
In the present disclosure, the term "oligopeptide" is used to refer to an amino acid polymer comprising 2 to 10 identical or different amino acids linked by peptide bonds, while the term "polypeptide" is used to refer to an amino acid polymer comprising 11 to 100 identical or different amino acids linked by peptide bonds, for the amino acids making up the oligopeptide or polypeptide, all of one or more of the above amino acids may be present, as well as additional amino acids.
The amino acid derivative may, for example, be selected from amino acid salts comprising the amino acids as described above. In the context of the present invention, the term "amino acid salt" is used to indicate salts of amino acids with acids or bases as described above, for example sodium, calcium, potassium, iron, magnesium, zinc, magnesium salts with bases and the like, as well as salts with acids, for example hydrochloride, hydrobromide, sulphate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulphonate, p-toluenesulphonate, amino acid salts and the like. More specifically, for example, lysine hydrochloride, histidine hydrochloride, glutamic acid hydrochloride, cysteine hydrochloride, arginine hydrochloride, glycine sulfate, lysine hydrochloride, aspartic acid hydrochloride, etc.
In the present disclosure, the amino acid nutrient includes one or more of the following amino acid compounds having a nutraceutical effect: amino acids, amino acid salts, oligopeptides, and polypeptides. In the pharmaceutical composition of the present invention, the amino acid nutrient may be one or more of amino acids, amino acid salts, oligopeptides and polypeptides, for example, 2, 3, 4 or 5 or more.
In the present disclosure, the amino acids, amino acid salts, oligopeptides and polypeptides as the amino acid nutrients are preferably amino acids selected from the group consisting of alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, tyrosine, serine, cysteine, methionine, threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, β -alanine, taurine, gamma-aminobutyric acid (GABA), theanine, citrulline and ornithine or salts thereof or oligopeptides and polypeptides comprising or consisting of amino acids selected from the group consisting of arginine, lysine, glycine, cysteine, alanine, serine, aspartic acid and glutamic acid.
In one embodiment, the amino acid nutrient is selected from arginine, an arginine salt, or an oligopeptide or polypeptide containing arginine.
In one embodiment, the amino acid nutrient is selected from lysine, a lysine salt, or an oligopeptide or polypeptide containing lysine.
In one embodiment, the amino acid nutrient is selected from glycine, a glycine salt, or an oligopeptide or polypeptide containing glycine.
In one embodiment, the amino acid nutrient is selected from glutamic acid, a glutamate, or an oligopeptide or polypeptide containing glutamic acid.
In one embodiment, the amino acid based nutrient is selected from the group consisting of amino acids or amino acid salts having a nutraceutical effect and the concentration (w/v) of the amino acid or amino acid salt in the topical pharmaceutical composition is ≥ 2%,. gtoreq.2.5%,. gtoreq.5%,. gtoreq.7.5%, 10-25% or 18-25%, preferably 15% -25% or 20% -25%.
In one embodiment, the amino acid based nutrients are selected from oligopeptides and polypeptides having nutraceutical effects and the concentration (w/v) of said oligopeptides and polypeptides in the topical pharmaceutical composition is ≥ 5%, preferably 7.5-25%, more preferably 10% -25%.
In one embodiment, the amino acid based nutrient is a combination of the amino acid and/or amino acid salt and the oligopeptide and/or polypeptide and the concentration (w/v) of the combination in the topical pharmaceutical composition is ≥ 5%, preferably 7.5% -25%, more preferably 10-25%.
In the present disclosure, the term "anti-tumor chemotherapeutic" is used to refer to a drug that is effective in inhibiting a solid tumor by absorption at a safe dose, and is selected from any pharmaceutically acceptable anti-tumor chemotherapeutic, preferably from anti-tumor chemotherapeutic known in the art, and more preferably from anti-tumor chemotherapeutic approved or to be approved by or loaded in the official pharmacopoeia of china, the united states or europe (e.g., FDA or chinese drug administration). The term "absorption" as used herein refers to a pharmacological effect resulting from the formation of drug-bearing blood into the target area by blood absorption of the drug; the term "absorbed drug" refers to a therapeutic drug that exerts its pharmacological effect primarily through absorption.
In the present disclosure, the anti-tumor chemotherapeutic may be one or more selected from the group consisting of: drugs that disrupt the structure and function of DNA, drugs that interfere with the transcription of RNA that intercalate into DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis. Such drugs that disrupt the structure and function of DNA include, for example, alkylating agents (e.g., cyclophosphamide, carmustine, etc.), metal platinum complexes (e.g., cisplatin, carboplatin, etc.), DNA topoisomerase inhibitors (e.g., doxorubicin, topotecan, irinotecan, etc.), and the like. The drugs that are inserted into the DNA to interfere with the transcription of RNA include, for example, antitumor antibiotics such as actinomycins, daunorubicin, doxorubicin, and the like. The drug which interferes with DNA synthesis includes, for example, pyrimidine antagonists (e.g., uracil derivatives 5-fluorouracil, furacil, difuracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine, etc.), purine antagonists (e.g., carcinolytic, thioguanine, etc.), folic acid antagonists (e.g., methotrexate, etc.), and the like. The drugs affecting protein synthesis include, for example, colchicines, vinblastines, taxanes (e.g., paclitaxel, docetaxel, etc.), and the like.
In the pharmaceutical compositions disclosed herein, the pharmaceutically acceptable liquid carrier is water and/or ethanol. The pharmaceutically acceptable liquid carrier is selected primarily based on the properties of the anti-tumor chemotherapeutic drug to achieve the corresponding concentration of the drug.
The anti-tumor chemotherapeutic is selected from water-soluble anti-tumor chemotherapeutic and alcohol-soluble anti-tumor chemotherapeutic. In the scope of the present invention, the term "alcohol-soluble antitumor chemotherapeutic" means an antitumor chemotherapeutic having a solubility in ethanol or aqueous ethanol at normal temperature greater than or equal to the concentration required for its effective local action, and includes, for example, taxanes, vinblastines and the like. The term "water-soluble antitumor chemotherapeutic" is used to mean an antitumor chemotherapeutic having a solubility in aqueous solution at normal temperature greater than or equal to the concentration required for its effective local action, and includes, for example, one or more water-soluble compounds selected from the group consisting of: uracil derivatives, cyclic phosphoramides, gemcitabine (e.g., gemcitabine hydrochloride), epirubicin (e.g., epirubicin hydrochloride), antitumor antibiotics (e.g., doxorubicin, actinomycin, etc.), vinblastines (e.g., vinblastine sulfate), teniposide, metal platinum complexes, and the like.
In the pharmaceutical composition according to the present disclosure, the anti-tumor chemotherapeutic may be one or more selected from the group consisting of: uracil derivatives, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complex, and taxanes; preferably one or more selected from the following drugs and their analogous derivatives: 5-fluorouracil, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complex, paclitaxel.
In the topical pharmaceutical composition according to the present disclosure, the concentration of the anti-tumor chemotherapeutic is greater than 30% of its saturation concentration, preferably 50-100%, or 60-100%, 70-100%, 80-100%, 90-100% of its saturation concentration, wherein the saturation concentration refers to the saturation concentration of the anti-tumor chemotherapeutic in the liquid carrier.
In a specific embodiment, the concentration (w/v) of the antineoplastic chemotherapeutic agent selected from said alkylating agents, such as cyclophosphamide, carmustine, etc., in said topical pharmaceutical composition is between 0.5-6%, preferably between 0.75-1.5%.
In a specific embodiment, the concentration (w/v) of the antineoplastic chemotherapeutic agent (e.g., cisplatin, carboplatin, etc.) selected from said metal platinum complex in said topical pharmaceutical composition is 0.03-0.08%, preferably 0.03-0.06%.
In a specific embodiment, the concentration (w/v) of the antineoplastic chemotherapeutic selected from said DNA topoisomerase inhibitors (e.g. doxorubicin, topotecan, irinotecan, etc.) in said topical pharmaceutical composition is between 0.05-0.20%, preferably between 0.75-0.15%.
In a particular embodiment, the concentration (w/v) of the antineoplastic chemotherapeutic drug selected from said antineoplastic antibiotics (e.g. actinomycins, daunorubicin, etc.) in said topical pharmaceutical composition is between 1-4%, preferably between 1-2%.
In a specific embodiment, the concentration (w/v) of the antineoplastic chemotherapeutic agent selected from said pyrimidine antagonists, e.g. uracil derivatives 5-fluorouracil, fururofluorouracil, bifurofluorouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine, etc., is in the range of 0.5-2%, preferably 0.75-1.5% in said topical pharmaceutical composition.
In a particular embodiment, the concentration (w/v) of the anti-tumor chemotherapeutic selected from the taxanes (e.g. paclitaxel, docetaxel, etc.) in the topical pharmaceutical composition is 0.5-2%, preferably 0.75-1.5%.
The compositions according to the present disclosure may optionally further comprise one or more substances selected from the group consisting of: excipient, analgesic, sustained release carrier, vital dye, saccharide nutrient, lipid nutrient, and organic acid acidifying agent.
The pharmaceutical composition according to the present disclosure may further optionally comprise an analgesic. The analgesic is used to reduce the pain experienced by the patient and may be any suitable one known to those skilled in the art, such as benzyl alcohol, procaine hydrochloride, chlorobutanol, lidocaine hydrochloride, and the like. The concentration of the analgesic in the pharmaceutical composition may be, for example, 0.1-4% by weight. For example, benzyl alcohol may be present in the pharmaceutical composition at a concentration of 1 to 4% by weight, and procaine hydrochloride, chlorobutanol, and lidocaine hydrochloride may be present in the pharmaceutical composition at a concentration of 1 to 3% by weight, respectively.
The pharmaceutical compositions according to the present disclosure may further optionally comprise a slow release carrier. The sustained release carrier may be any suitable one known to those skilled in the art, including, for example, a gel matrix, a microparticle carrier, a micelle matrix, and the like. The concentration (w/v) of the slow release carrier in the pharmaceutical composition may be, for example, 0.5-13%, preferably 1-12% or 1-15%.
The pharmaceutical composition according to the present disclosure may further optionally comprise a vital dye. In the context of the present invention, the term "vital dye" refers to an organic substance capable of coloring the structure in the target area upon topical administration, but with side effects within a pharmaceutically acceptable range, selected from any pharmaceutically acceptable vital dye, preferably from vital dyes known in the art, more preferably from vital dyes approved or to be approved by or loaded in the chinese, us or european official administrative department, such as the FDA or the chinese medical administration.
Specifically, in the disclosure of the present application, the vital dye may be one or more selected from the following compounds and derivatives thereof: methylene blue (including its hydrates), patent blue, isothio blue, toluidine blue, trypan blue, basic blue, eosin, basic fuchsin, crystal violet, gentian violet, neutral red, janus green B, safranin, bengal red, and the like. In one embodiment, the concentration (w/v) of the vital dye in the topical pharmaceutical composition disclosed herein is > 0.35%, preferably 0.5-10%.
The vital dyes are preferably selected from methylene blue dyes and bengal, wherein the methylene blue dyes are selected from one or more of the following vital dyes and derivatives thereof: methylene blue, patent blue, isothio blue. In the composition according to the invention, the vital dye is more preferably methylene blue.
The concentration (w/v) of the methylene blue coloring agent in the pharmaceutical composition is less than or equal to 2 percent, preferably 0.35 to 2 percent, more preferably 0.35 to 1.5 percent or 0.5 to 1 percent. The concentration (w/v) of the Monglazole in the pharmaceutical composition is more than or equal to 3 percent, and preferably 5-10 percent.
The pharmaceutical composition according to the present disclosure may further optionally comprise a carbohydrate nutrient, wherein the carbohydrate nutrient is present in a concentration (w/v) of greater than 5%, ≧ 10%, preferably 10-40%, 15-50% or 25-50%
In the context of the present invention, the term "carbohydrate nutrient" is used to mean a carbohydrate compound having a nutraceutical effect, preferably selected from monosaccharides, carbohydrate polymers and carbohydrate derivatives having a nutraceutical effect, more preferably selected from carbohydrate nutraceuticals and carbohydrate excipients having a nutraceutical effect as carried in the chinese, us or european official pharmacopoeia or guidelines.
In the present disclosure, the monosaccharide, the sugar polymer, and the sugar derivative as the saccharide nutrient are preferably a monosaccharide selected from the following group, a sugar polymer containing a monosaccharide selected from the following group, or a derivative thereof: glucose, ribose, deoxyribose, xylose, fructose, galactose and fucose.
The sugar polymer may be selected from disaccharides, oligosaccharides and polysaccharides comprising monosaccharides as described above. In the context of the present invention, the term "disaccharide" is used to indicate a polymer comprising 2 monosaccharides linked by glycosidic bonds; the term "oligosaccharide" is used to mean a polymer comprising 3 to 10 monosaccharides linked by glycosidic linkages; and the term "polysaccharide" is used to refer to a polymer comprising more than 10 monosaccharides linked by glycosidic linkages. The monosaccharides that constitute the disaccharide, oligosaccharide or polysaccharide may be all one or more of the monosaccharides described above, or may additionally contain other monosaccharides. In one embodiment, the disaccharide may be one or more selected from: lactulose, maltose, sucrose, lactose, trehalose. In one embodiment, the oligosaccharide may be one or more selected from: chitosan oligosaccharide, xylo-oligosaccharide, fructo-oligosaccharide, mannooligosaccharide, maltooligosaccharide and isomalto-oligosaccharide. In one embodiment, the polysaccharide may be one or more selected from the group consisting of: starch, cellulose, dextran, glycosaminoglycan.
The sugar derivative may for example be the following sugar derivatives selected from the group of monosaccharides or sugar polymers as described above: sugar acid, sugar acid salt and sugar alcohol. In the context of the present invention, the term "sugar acid" is used to indicate an acid derivative of a monosaccharide or sugar polymer; the term "sugar acid salt" refers to salt derivatives of monosaccharides or sugar polymers; the term "sugar alcohol" refers to an alcoholic derivative of a monosaccharide or sugar polymer. In one embodiment, the sugar acid may be one or more selected from the group consisting of: gluconic acid, mannonic acid, arabinonic acid. In one embodiment, the sugar acid salt may be one or more selected from the group consisting of: sodium gluconate, sodium mannonate and sodium arabinonate. In one embodiment, the sugar alcohol may be one or more selected from the group consisting of: mannitol, maltitol, lactitol, xylitol.
In the pharmaceutical composition of the present invention, the carbohydrate nutrient may be one or more of monosaccharide, oligosaccharide, polysaccharide, sugar acid salt, sugar alcohol, for example, 2, 3, 4, or 5 or more.
In one embodiment, the carbohydrate nutrient is selected from glucose, a glucose-containing carbohydrate polymer, or a glucose derivative.
In one embodiment, the carbohydrate nutrient is selected from ribose, a ribose-containing sugar polymer, or a ribose derivative.
In one embodiment, the carbohydrate nutrient is selected from xylose, a carbohydrate polymer comprising xylose, or a xylose derivative.
In one embodiment, the carbohydrate nutrient is preferably selected from one or more of the following: glucose, fructose, chitosan oligosaccharide, glucosamine, lactulose, sorbitol, ribose, sorbose, mannose, galactose, sucrose, lactose, trehalose, xylo-oligosaccharide, fructo-oligosaccharide, manno-oligosaccharide, xylitol, more preferably selected from one or more of the following: glucose, sodium gluconate, chitosan oligosaccharide, glucosamine, lactulose, ribose, mannan oligosaccharide and xylitol. In one embodiment, the concentration (w/v) of the carbohydrate nutrient in the pharmaceutical composition is ≥ 10%, preferably 10-40%, 15-50% or 25-50%.
The pharmaceutical composition according to the present disclosure may further optionally comprise a liponutrient, wherein the concentration (w/v) of the liponutrient is ≥ 4%, preferably 4-25%.
The lipid nutrient is one or more selected from the following group: fatty acids, fatty milks and lipids, more preferably one or more selected from the group consisting of: vegetable oil, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), long-chain fat milk, medium-chain fat milk and phospholipid.
The pharmaceutical compositions according to the present disclosure may further optionally comprise an organic acid acidifying agent which is a C1-10 aliphatic carboxylic acid optionally substituted with 1-3 hydroxyl groups. The aliphatic carboxylic acid may be a mono-, di-or tri-aliphatic carboxylic acid. In one embodiment, the concentration (w/v) of the organic acid acidifying agent in the present disclosure is greater than 0.8% and less than 20%, 1.5-20%, preferably 3.5-15% or 3.5-10%, and still preferably 1.5-10% or 1.5-7.5%.
In one embodiment, the organic acid acidifying agent can be one or more selected from the group consisting of: acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, glycolic acid, lactic acid, citric acid, malic acid, tartaric acid, preferably acetic acid.
The pharmaceutical composition according to the present disclosure may be in any form suitable for topical administration, preferably an injection, more preferably a topical injection, which may comprise the active ingredient (the amino acid based nutrient, the anti-tumor compound, and optionally other active ingredients as described above) and a liquid carrier, such as water, ethanol, or a water/ethanol mixture, etc.
In the context of the present invention, the term "injectable formulation" refers to a sterile formulation containing an active ingredient and a liquid carrier and intended for in vivo administration. Injections are classified into local injections, intravenous injections, etc. according to administration modes, and intravenous injections can be used as local injections only after a given local administration concentration. The injection is classified into liquid injection, powder injection for injection, etc. according to its commercial form. The powder injection for injection comprises sterile dry powder and a solvent, wherein the sterile dry powder contains part or all of active ingredients, and the solvent contains all of liquid carriers. The concentration of the active ingredient in an injection is the concentration of the active ingredient in its mixture with the entire liquid carrier, usually in the liquid drug at the end point (e.g. needle hole, catheter outlet, etc.) of the topical administration device (syringe, piercer, infusion catheter, etc.). For injectable powder injections, the concentration of the active ingredient is the concentration of the active ingredient in a mixture (e.g., a reconstituted solution) of sterile dry powder and vehicle (or the pharmaceutically acceptable liquid carrier).
Therefore, the pharmaceutical composition disclosed by the application can be in the form of injection, and the injection comprises liquid injection and powder injection for injection.
The powder injection for injection can comprise sterile dry powder and a solvent, wherein one part or all of the amino acid nutrient and the antitumor chemotherapeutic drug are contained in the sterile dry powder, the liquid carrier is contained in the solvent, and the concentrations of the amino acid nutrient and the antitumor chemotherapeutic drug are respectively the concentrations of the amino acid nutrient and the antitumor chemotherapeutic drug in a mixture of the sterile dry powder and the solvent.
According to another aspect of the present disclosure there is provided a topical pharmaceutical composition for the treatment of solid tumors in lyophilized or semi-lyophilized form obtained by lyophilizing or semi-lyophilizing a portion or all of one of the pharmaceutical compositions comprising the amino acid based nutrient, the anti-tumor chemotherapeutic and a pharmaceutically acceptable carrier according to the present disclosure.
The pharmaceutical composition according to the present disclosure may further optionally comprise an excipient. The excipient may be any suitable one known to those skilled in the art and may include, for example, one or more of the following: dispersion media, preservatives, stabilizers, wetting and/or emulsifying agents, solubilizers, viscosity-increasing agents, and the like. The viscosity-increasing agent is, for example, sodium carboxymethylcellulose, polyvinylpyrrolidone or gelatin. Such as an antioxidant (e.g., ascorbic acid).
It will be appreciated by those skilled in the art that the compositions according to the present disclosure should be formulated for local administration to the target area, preferably as an injection, more preferably as a local injection.
The pharmaceutical compositions according to the present disclosure may be prepared as follows: a liquid medicament is prepared containing the topically active ingredient, a vehicle (pharmaceutically acceptable liquid carrier), and optionally other substances. The liquid medicament may be a solution (e.g. a solution in a hydrophilic vehicle, preferably an aqueous solution), a suspension, or an emulsion comprising the topically active ingredient. When the liquid drug is a suspension, the dispersion medium may be any suitable medium known to those skilled in the art, such as a micro-material or a nano-material. When the liquid drug is an emulsion, the dispersion medium may be any suitable one known to those skilled in the art, such as a vegetable oil, a synthetic oil or a semi-synthetic oil which may be used for injection. The vegetable oil may be, for example, cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and peanut oil.
According to the preparation method of the invention, the concentrations of the amino acid nutrients, the antitumor chemotherapeutic and optionally other ingredients are greater than or equal to the local administration concentration thereof in the composition of the invention. When the concentration is more than that in the pharmaceutical composition of the present invention, it can be further diluted for use.
According to one embodiment disclosed herein, the liquid injection of the pharmaceutical composition of the present invention can be prepared by a method comprising the steps of: 1) adding amino acid nutrients and anti-tumor chemotherapeutic drugs with required amounts according to local administration concentrations into a solvent to prepare liquid; 2) adding other optional components (such as carbohydrate nutrients, vital dyes, analgesics, organic acids such as acetic acid) in required amounts according to the concentration for topical administration to the liquid prepared in step 1) and mixing uniformly to obtain a liquid medicament; 3) sterilizing the liquid medicine prepared in the step 2) and preparing the liquid injection. When in use, the bacteria-removing liquid medicine in the liquid injection can be directly used as a local administration liquid medicine or used as a diluted liquid medicine.
According to one embodiment disclosed herein, the liquid injection of the pharmaceutical composition of the present invention can be prepared by a method comprising the steps of: 1) adding amino acid nutrients, anti-tumor chemotherapeutic drugs and optionally other components which are required according to the local administration concentration into a solvent (or a pharmaceutically acceptable liquid carrier), uniformly mixing, and sterilizing to prepare a sterilization liquid I; 2) the desired amount of optional other components (e.g., acetic acid) depending on the topical concentration is added to the vehicle (or pharmaceutically acceptable liquid carrier) and mixed well and sterilized to prepare sterile liquid II. When the liquid medicine is used, the sterilization liquid I and the sterilization liquid II form a mixed liquid before or after entering a local administration instrument, and the mixed liquid can be directly used as a local administration liquid medicine or diluted liquid medicine.
According to one embodiment disclosed herein, the powder injection for injection of the pharmaceutical composition of the present invention may be prepared by a method comprising the steps of: preparing sterile dry powder containing the amino acid nutrients and the anti-tumor chemotherapeutic drugs in required amounts according to the local administration concentration; and preparing a sterile vehicle containing the required amounts of the other components (e.g., carbohydrate nutrients, vital dyes, analgesics, organic acids such as acetic acid) according to the concentration to be topically administered. The sterile dry powder is preferably sterile freeze-dried powder, and the preparation method comprises the following steps: 1) preparing a solution comprising amino acid nutrients, an anti-tumor chemotherapeutic and optionally other components; 2) sterilizing, filtering and packaging; 3) freeze drying; 4) and (5) plugging and capping. The freeze-drying process conditions include, for example: the pre-freezing condition is that the temperature is kept at minus 45 ℃ for 4 hours; sublimation drying condition is that the heating rate is 0.1 ℃/min, and the heating is kept for at least 10 hours when the temperature is raised to-15 ℃; the desorption drying conditions were 30 ℃ for 6 hours. When in use, the sterile dry powder of the powder injection for injection is redissolved in a sterile solvent to form a redissolved liquid medicine which can be directly used as a local administration liquid medicine or diluted.
In accordance with the principles of these methods described above, one skilled in the art can prepare a variety of specific dosage forms comprising the compositions of the present invention by any suitable specific method. For example, variations in the compositions of the present invention include: containing different kinds and concentrations of the anti-tumor chemotherapeutic drugs, amino acid nutrients, other drugs containing different kinds and concentrations, and other additives (such as analgesics and activators).
In the present disclosure, the pharmaceutical composition is primarily for use in the prevention and treatment of solid tumors by local administration, wherein the solid tumors include malignant tumors and non-malignant tumors.
In the use and method for the topical treatment and prevention of solid tumors according to the present disclosure, the amino acid based nutrients and the anti-tumor chemotherapeutic are administered topically at their concentration or amount ratio in the topical pharmaceutical composition. The concentration or amount provides a synergistic effect on the local response compared to local administration.
In the context of the present invention, the term "solid tumor" is used to mean a tumor having a tumor body, which may be due to any pathology (malignant and non-malignant) and at any stage of the tumor, including for example the following groups classified according to the tumor cell type: epithelial cell tumors, sarcomas, lymphomas, germ cell tumors, blastomas; and tumors named as the organ or tissue in which the tumor cell foci are located, including, for example, tumors named as the following organs or tissues: skin, bone, muscle, breast, kidney, liver, lung, gall bladder, pancreas, brain, esophagus, muscle of the shoulder, large intestine, small intestine, spleen, stomach, prostate, emerald, ovary, or uterus.
Specifically, the malignant tumor includes, for example, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, intestinal cancer, oral cancer, esophageal cancer, stomach cancer, laryngeal cancer, testicular cancer, vaginal cancer, uterine cancer, ovarian cancer, and the like.
The non-malignant tumor includes, for example, breast tumor, pancreatic tumor, thyroid tumor, prostate tumor, liver tumor, lung tumor, intestinal tumor, oral tumor, esophageal tumor, stomach tumor, nasopharyngeal tumor, laryngeal tumor, testicular tumor, vaginal tumor, uterine tumor, fallopian tube tumor, ovarian tumor, etc.
The topical drug in the present invention is a therapeutic drug, which, when used for the prevention and treatment of a localized disease, can also be administered in combination with other interventions, systemic chemotherapy, immunotherapy, photodynamic therapy, sonodynamic therapy, surgical intervention or a combination of such therapies to further enhance the therapeutic effect.
The present disclosure includes the following items:
item 1, a topical pharmaceutical composition for the treatment of a solid tumor comprising an amino acid based nutrient, an anti-tumor chemotherapeutic, and a pharmaceutically acceptable liquid carrier, wherein the concentration (w/v) of the amino acid based nutrient in the topical pharmaceutical composition is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%; the concentration of the anti-tumor chemotherapeutic is greater than 30% of its saturation concentration, preferably 50% -100% of its saturation concentration, wherein the saturation concentration refers to the saturation concentration of the anti-tumor chemotherapeutic in the liquid carrier.
Item 2, use of a combination of amino acid nutrients as a local active ingredient with an anti-tumor chemotherapeutic for the preparation of a topical pharmaceutical composition for the treatment of solid tumors.
Item 3, the use according to item 2, wherein the topical pharmaceutical composition comprises the amino acid based nutrient, the anti-tumor chemotherapeutic, and a pharmaceutically acceptable liquid carrier, and wherein the concentration (w/v) of the amino acid based nutrient is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%; the concentration of the anti-tumor chemotherapeutic is greater than 30% of its saturation concentration, preferably 50% -100% of its saturation concentration, wherein the saturation concentration refers to the saturation concentration of the anti-tumor chemotherapeutic in the liquid carrier.
Item 4, the pharmaceutical composition or use according to one of items 1 to 3, wherein the amino acid nutrient comprises one or more of the following amino acid compounds having a nutraceutical effect, amino acid salts, oligopeptides and polypeptides, preferably amino acids or salts thereof or oligopeptides and polypeptides comprising or consisting of amino acids selected from the group consisting of alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, β -alanine, taurine, gamma aminobutyric acid (GABA), tea polyphenols (theanine), pumpkin seed amino acids (3-amino-3-carboxypyranate), glutamine, citrulline, ornithine, more preferably amino acids or salts thereof selected from the group or oligopeptides and polypeptides comprising or consisting of arginine, lysine, glycine, cysteine, alanine, serine, glutamic acid.
Item 5, the pharmaceutical composition or the use according to item 4, wherein the amino acid nutrient is selected from the group consisting of amino acids or amino acid salts having a nutritional and health effect, and the concentration (w/v) of the amino acid or amino acid salt in the topical pharmaceutical composition is ≥ 2%, ≥ 2.5% >, ≥ 5% >, ≥ 7.5%, 10-25% or 18-25%, 15% -25% or 20% -25%.
Item 6, the pharmaceutical composition or use according to item 4, wherein the amino acid based nutrients are selected from oligopeptides and polypeptides with nutraceutical effect and the concentration (w/v) of the oligopeptides and polypeptides in the topical pharmaceutical composition is ≥ 5%, preferably 7.5-25%, more preferably 10-25%.
Item 7, the pharmaceutical composition or use according to item 4, wherein the amino acid based nutrient is a combination of the amino acid and/or amino acid salt and the oligopeptide and/or polypeptide and the concentration (w/v) of the combination in the topical pharmaceutical composition is ≥ 5%, preferably 7.5-25%, more preferably 10-25%.
Item 8, the pharmaceutical composition or use according to item 4, wherein the oligopeptide is one or more selected from the group consisting of glycyl-L-tyrosine, glycylalanine, glycylglycine, lysine-glycine dipeptide, glutamine dipeptide, carnosine (β -alanine histidine copolymer), glutathione, collagen oligopeptide, casein hydrolysate peptide, soybean oligopeptide, oligoarginine, oligoglycine, oligolysine, and the polypeptide is one or more selected from the group consisting of polyaspartic acid, polyglutamic acid, polylysine.
Item 9, a pharmaceutical composition or use according to one of items 1 to 3, wherein the anti-tumor chemotherapeutic is selected from one or more of the following group: drugs that disrupt the structure and function of DNA, drugs that interfere with the transcription of RNA that intercalate into DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis.
Item 10, the pharmaceutical composition or use according to item 9, wherein the anti-tumor chemotherapeutic is one or more selected from the group consisting of: uracil derivatives, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complex, and taxanes; preferably one or more selected from the following drugs and their analogous derivatives: 5-fluorouracil, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complex, paclitaxel.
Item 11, the pharmaceutical composition or use according to item 9 or 10, wherein the anti-tumor chemotherapeutic is selected from a water-soluble anti-tumor chemotherapeutic or an alcohol-soluble anti-tumor chemotherapeutic.
Item 12, a pharmaceutical composition or use according to one of items 1 to 11, wherein the pharmaceutically acceptable liquid carrier is water and/or ethanol.
Item 13, a pharmaceutical composition or use according to one of items 1 to 12, wherein the pharmaceutical composition further optionally comprises one or more of the following groups: analgesic, sustained release carrier, vital dye, saccharide nutrient, lipid nutrient, and organic acid acidifying agent.
Item 14, the pharmaceutical composition or use according to item 13, wherein the analgesic is one or more selected from the group consisting of: benzyl alcohol, procaine hydrochloride, chlorobutanol and lidocaine hydrochloride, and the concentration of the analgesic in the pharmaceutical composition is 0.1-4% by weight.
Item 15, the pharmaceutical composition or use according to item 13, wherein the vital dye is one or more selected from the group consisting of: methylene blue (including hydrates thereof), patent blue, isothio blue, toluidine blue, trypan blue, basic blue, eosin, basic fuchsin, crystal violet, gentian violet, neutral red, janus green B, safranin, bengal red, wherein the concentration (w/v) of said vital dye in said topical pharmaceutical composition is > 0.35%, preferably 0.5-10%.
Item 16, the pharmaceutical composition or use according to item 15, wherein the vital dyes are selected from the group consisting of methylene blue type dyes and bengal, wherein the methylene blue type dyes are selected from one or more of the following vital dyes and derivatives thereof: methylene blue, patent blue, isothio blue, more preferably the vital dye is methylene blue.
Item 17, the pharmaceutical composition or use according to item 16, wherein the pharmaceutical concentration (w/v) of the methylene blue stain in the pharmaceutical composition is ≦ 2%, preferably 0.35-2%, more preferably 0.35-1.5% or 0.5-1%; and the concentration (w/v) of the bengal in the pharmaceutical composition is more than or equal to 3%, preferably 5-10%.
Item 18, the pharmaceutical composition or use according to item 13, wherein the carbohydrate nutrient is a carbohydrate compound selected from the group consisting of one or more of the following saccharide units: glucose, ribose, xylose, fructose, galactose, fucose, preferably selected from one or more of the following: glucose, fructose, chitosan oligosaccharide, glucosamine, lactulose, sorbitol, ribose, sorbose, mannose, galactose, sucrose, lactose, trehalose, xylooligosaccharide, fructooligosaccharide, mannooligosaccharide, gluconic acid, sodium gluconate, xylitol, mannitol, maltitol, lactitol, more preferably one or more selected from the group consisting of: glucose, sodium gluconate, chitosan oligosaccharide, glucosamine, lactulose, ribose, mannose oligomer and xylitol; and the concentration (w/v) of the carbohydrate nutrient in the pharmaceutical composition is not less than 10%, preferably 10-40%, 15-50% or 25-50%.
Item 19, the pharmaceutical composition or use according to item 13, wherein the liponutrient is one or more selected from the group consisting of: fatty acids, fatty milks and lipids, preferably selected from one or more of the following: vegetable oil, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), long-chain fat milk, medium-chain fat milk, phospholipids, and the concentration (w/v) of the lipid nutrient in the pharmaceutical composition is not less than 4%, preferably 4-25%.
Item 20, the pharmaceutical composition or use according to item 13, wherein the organic acid acidifying agent is a C1-10 aliphatic carboxylic acid optionally substituted with 1-3 hydroxyl groups, preferably selected from one or more of the following: acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, glycolic acid, lactic acid, citric acid, malic acid, tartaric acid, preferably acetic acid; wherein the concentration (w/v) of the aliphatic carboxylic acid in the topical pharmaceutical composition is greater than 0.8% and less than 20%, 1.5-20%, preferably 3.5-15% or 3.5-10%, further preferably 1.5-10% or 1.5-7.5%.
Item 21, the pharmaceutical composition according to one of items 1 to 20, or the application, wherein the pharmaceutical composition is in the form of an injection, and the injection includes a liquid injection and a powder injection for injection.
Item 22, the pharmaceutical composition or the use according to item 21, wherein the powder for injection comprises a sterile dry powder and a vehicle, and one or both of the amino acid nutrient and the anti-tumor chemotherapeutic is contained in the sterile dry powder, and the liquid carrier is contained in the vehicle, and the concentrations of the amino acid nutrient and the anti-tumor chemotherapeutic are the concentrations thereof in a mixture of the sterile dry powder and the vehicle, respectively.
Item 23, a topical pharmaceutical composition for the treatment of solid tumors obtained by lyophilization or semi-lyophilization of a part or all of the pharmaceutical composition according to one of items 1 and 4 to 10.
Item 24, a method for the prevention and treatment of solid tumors comprising the local administration of a pharmaceutical composition according to one of items 1 and 4 to 13 to an individual in need thereof.
Item 25, a pharmaceutical composition, use or method according to one of items 1 to 24, wherein the solid tumor comprises a malignant tumor and a non-malignant tumor.
Item 26, the pharmaceutical composition, use or method of item 25, wherein the malignant tumor comprises breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, intestinal cancer, oral cancer, esophageal cancer, gastric cancer, laryngeal cancer, testicular cancer, vaginal cancer, uterine cancer, ovarian cancer.
Item 27, the pharmaceutical composition, use or method according to item 25, wherein the non-malignant tumor comprises a breast tumor, a pancreatic tumor, a thyroid tumor, a prostate tumor, a liver tumor, a lung tumor, an intestinal tumor, an oral tumor, an esophageal tumor, a stomach tumor, a nasopharyngeal tumor, a laryngeal tumor, a testicular tumor, a vaginal tumor, a uterine tumor, a fallopian tube tumor, an ovarian tumor.
Examples
The present invention is further illustrated by the following specific examples, which are not to be construed as limiting the invention thereto. In the following examples, all experimental animals were performed according to the relevant regulations and industry discipline. Unless otherwise specified, all tests were carried out according to the usual methods.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified. Some of the amino acid nutrients, antineoplastic chemotherapeutic agents and other ingredients used in the following examples are listed in table 1.
TABLE 1
In the present invention, L-amino acids are abbreviated as amino acids (for example, L-arginine is abbreviated as arginine), reduced glutathione is abbreviated as glutathione, and alanyl-glutamine dipeptide is abbreviated as glutamine dipeptide.
In the following examples, tests of subcutaneous transplanted tumor animals were performed according to the test guidelines issued by the drug administration, unless otherwise indicated. The test animal is Balb/c nude mouse or mouse with age of 6-8 weeks and weight of 17.5-20.5 g. The subcutaneous transplantation is carried out according to the conventional subcutaneous inoculation method of tumor cells. Unless otherwise stated, the tumor is grown to a desired volume (e.g., 75-500 mm)3) This was randomly divided into several groups of 6 animals each using PEMS 3.2 software (compiled by the national institute of public health, western Sichuan university). Items observed, measured and analyzed in the test, including general condition, body weight, intakeFood intake, tumor volume, tumor weight, thymus weight, spleen weight, etc.
The tumor volume calculation formula is as follows:
tumor volume (V) ═ l/2 × a × b2Wherein a represents the tumor length and b represents the tumor width.
The tumor growth inhibition rate (abbreviated as tumor inhibition rate in the invention) is calculated by the following formula:
tumor inhibition rate Y (%) ═ (TW-CW)/CW × 100%, where TW is the average tumor weight of the study group; CW is the average tumor weight of the negative control group.
In the following examples, the tests were each statistically tested for group differences in mean index using Repeated measures analysis of variance (Repeated Meas μ res ANOVA). When the group difference has statistical significance (P is less than or equal to 0.05), the difference between each group and the negative control group is compared by adopting a minimum significant difference method. Quantitative indices are described as mean ± standard error (X ± SEM). When the LEVENE homogeneity test indicates that the variance is not uniform (P is less than 0.05), the difference between the groups is compared by using Mann-Whitney M rank sum test (M-W method). All statistical analyses were performed under SPSS for Windows 13.0 software.
Example 1: preparation of the composition
A number of different compositions of the present invention can be formulated according to the above-described method of preparing the compositions of the present invention, and the compositions of some of the compositions of the present invention prepared in this example are listed in Table 2.
TABLE 2
Several examples of the preparation tests of the compositions according to the invention are listed below.
1. Preparation of liquid injection (1)
Amino acid nutrients (e.g. 10g glutathione), anti-tumour chemotherapeutic drugs (e.g. 1g 5-fluorouracil), optional other components and a liquid carrier (e.g. water for injection) are measured according to the required concentration (as shown in table 2), slowly mixed uniformly, sterilized, filtered and then dispensed into the required amount (e.g. 10 ml/bottle) for storage. The preparation (e.g. 10% glutathione/1% 5-fluorouracil in water) can be administered topically as a liquid medicament.
2. Preparation of liquid injection (2)
1) Amino acid nutrients (e.g. 10g glutathione), anti-tumour chemotherapeutic drugs (e.g. 1g 5-fluorouracil), optionally other components (e.g. 30g glucose) and a liquid carrier (e.g. water for injection) are measured at the required concentration (as described in table 2) and brought to a total volume (e.g. 85ml) and mixed slowly and homogeneously, sterile filtered and aliquoted into the required volume (e.g. 8.5ml per bottle) for storage as solution I.
2) The acidulant (e.g. 5g of acetic acid), optional other components and vehicle (e.g. water for injection) are measured out at the desired concentration (as described in table 2), brought to a total volume (e.g. 15ml) and mixed slowly until homogeneous, sterile filtered and stored in aliquots of the desired volume (e.g. 1.5 ml/vial) as solution II.
3) The solution I and the solution II are mixed uniformly (for example, 8.5ml of the solution I and 1.5ml of the solution II are mixed) according to the required concentration of each component to form a mixed solution (for example, 10% glutathione/1% 5-fluorouracil/30% glucose/5% acetic acid aqueous solution), and then the mixed solution can be used as a liquid medicine for local administration.
3. Preparation of powder injection for injection
1) The amino acid nutrients (such as 10g of glutathione), the antitumor chemotherapeutic drugs (such as 1g of 5-fluorouracil), other optional components and a liquid carrier (such as water for injection) which is constant to the total volume (such as 100ml) are measured according to the required concentration (shown in the table 2), and are slowly mixed uniformly, sterilized, filtered and then subpackaged into the required amount (such as 10 ml/bottle), and the required amount is subjected to freeze drying, tamponade and capping to prepare the sterilized dry powder for later use.
2) The remaining optional other components (if any) and a liquid carrier (e.g. water for injection) are measured according to the required concentration (as shown in table 2) and added to a total volume (e.g. 100ml), and the components are slowly mixed uniformly, sterilized, filtered and then distributed into required amount (e.g. 10 ml/bottle) to prepare a sterilized liquid for later use.
3) And the required amount of sterile dry powder (for example, 1 bottle of the dry powder) is dissolved in the required amount of sterile liquid (for example, 1 bottle of the solvent) according to the required concentration of each component to obtain the required compound solution (for example, 10 percent glutathione/1 percent 5-fluorouracil aqueous solution), and then the compound solution can be used as a liquid medicine for local administration.
Example 2: preferred synergistic technical scheme of the composition
1. Synergistic pharmacological preferences
Test animals (S180-cell-bearing mice, tumor body mean volume 131 mm)3) The groups were randomized into 2 negative control groups and 14 study groups. The negative control was physiological saline and 7 study drugs were administered intraperitoneally and intratumorally as shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. The medicine is taken once every 3 days for 3 times, and the injection amount is less than or equal to 150 mu l/injection. On day 5 after the completion of the administration, the animals were euthanized, and the tumor weights were measured after dissection, and the tumor inhibition ratios were calculated from the negative control groups for each administration pattern, and the results are shown in table 3.
TABLE 3
Research medicine | Tumor inhibition rate of intraperitoneal injection | Tumor inhibition rate of intratumoral injection |
1% 5-Fluorouracil | 54% | 59% |
20% arginine | 2% | 31% |
20% Glycine | 3% | 32% |
10% glutathione | 1% | 35% |
1% 5-Fluorouracil/20% arginine | 55% | 85% |
1% 5-Fluorouracil/20% Glycine | 53% | 79% |
1% 5-Fluorouracil/10% glutathione | 56% | 77% |
In table 3, 5-fluorouracil is in line with its expectation as an anti-tumor chemotherapeutic. The results of the intraperitoneal injection group show that the anti-tumor chemotherapeutic drug can target tumor cells in a blood drug form so as to inhibit the growth of tumor bodies. Once generally accepted, the local drug concentration of the antitumor chemotherapeutic drug can be improved by the in vivo administration of the tumor, and the drug effect of the antitumor chemotherapeutic drug can be greatly improved. However, as shown in Table 3, intratumoral injection did not greatly increase the tumor inhibition rate of 5-fluorouracil. The targeting property (tumor cells) and the pharmacology (tumor cell inhibition) of the medicine are not changed substantially during intratumoral injection, and the medicine also faces the same targeting barrier in tissues, so that the medicine shows consistent curative effect. Thus, conventional anti-tumor chemotherapeutic drugs have heretofore been administered primarily by absorption rather than topically, unless placed in a sustained release system.
In table 3, the group of intraperitoneal amino acid nutrient injections meets the expectation of conventional application (absorption by blood), and the tumor inhibition rates are all less than 20%, which belongs to the ineffective range. The tumor inhibition rate of the intratumoral injection group is obviously improved, and the intratumoral injection group can be applied as a local active component.
In table 3, the group of amino acid-based nutrient/antitumor chemotherapeutic composition for intraperitoneal injection meets the expectations in conventional applications (absorption through blood), and shows the drug effects of the individual components under experimental conditions, without showing synergistic drug effects. Surprisingly, the tumor volume increase of the intratumoral injection group at the 3 rd day after the first medication is lower than that of the intraperitoneal injection group, and the obvious synergistic medicinal effect is shown under the same experimental conditions, so that the targeting and pharmacology of the composition in the intraperitoneal injection group are obviously different.
Similar results can be obtained with experiments with other compositions of the invention, such as the compositions in table 2.
In another experiment, successfully modeled test animals (S180-bearing mice, tumor body mean volume 163 mm)3) Randomized into blank control and 5 study groups (A, B, C, D, E). The negative control was physiological saline, and the composition and injection pattern of the 4 study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. The medicine is taken once, and the injection amount is less than or equal to 130 mu l per unit. The following day after the end of drug administration, animals were euthanized and tumor anatomy was histologically observed, with intratumoral tissue destruction distinguished by a blank control group of 0 and a 5% acetic acid group of 5, and the results are shown in table 4.
TABLE 4
Test group | Research medicine | Injection mode | Intratumoral tissue destruction |
A | 1% 5-Fluorouracil/20% arginine | Abdominal injection | 0 |
B | 1% 5-Fluorouracil/20% arginine | Intratumoral injection | 3 |
C | 20% arginine | Intratumoral injection | 1 |
D | 1% 5-Fluorouracil | Intratumoral injection | 1 |
E | 5% acetic acid | Intratumoral injection | 5 |
Blank control group | - | - | 0 |
2. Preference for synergistic composition
Test animals successfully modeled (S180 cell-bearing mice, average tumor volume 124mm3) The groups were randomized into negative control and 14 study groups. The negative control was physiological saline and the composition of the 14 study drugs included as shown in the table below: 4 kinds of 5-fluorouracil single drugs with variable concentrations (X% 5-fluorouracil), 4 kinds of amino acid nutrients with variable concentrations (Y% amino acid nutrients), and 6 compositions respectively composed of 5-fluorouracil with variable concentrations and amino acid nutrients with variable concentrations (X% 5-fluorouracil/Y% amino acid nutrients). The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Saturation concentration of 5-Fluorouracil used (C)Resist against) About 1.5%. Each group is injected intratumorally, the medicine is taken once every 3 days for 3 times in total, the dosage of each time of medicine is 50mg/kg of 5-fluorouracil, the glutathione is less than or equal to 1g/kg, and the injection amount is less than or equal to 150 mu l per group. The animals were euthanized 5 days after the end of the administration, tumor weights were measured after dissection, and the tumor inhibition rates were calculated from the negative control groups, and the results are shown in table 5.
TABLE 5
*: the data in parentheses in the horizontal bar is the average tumor inhibition rate of the X% 5-fluorouracil group, for example, the average tumor inhibition rate of the 0.5% 5-fluorouracil group is 43%
**: the data in parentheses in the column is the average tumor inhibition for the Y% amino acid nutrient group, e.g., the average tumor inhibition for the 20% arginine group is 35%
***: the parenthesized data is the average tumor inhibition of the X% 5-fluorouracil/Y% amino acid nutrient group, e.g., the average tumor inhibition of the 0.5% 5-fluorouracil/20% arginine group is 45%
According to the above and more similar studies, the synergistic technical solution of the composition of the present invention is:
1. local administration to diseased tissue;
2. is administered topically in a synergistic combination wherein
The concentration of the anti-tumor chemotherapeutic drug is more than 30 percent of the saturation concentration of the anti-tumor chemotherapeutic drug, and preferably 50 to 100 percent of the saturation concentration of the anti-tumor chemotherapeutic drug; and
the concentration of the amino acid nutrient is more than 2.5%, preferably 5% -25%.
By adopting the above-mentioned synergistic technical scheme, the synergistic effect of the composition of the present invention is not in the inhibition effect on cancer cells nor indiscriminate tissue destruction effect, but in which the components synergistically enhance the drug effect and reduce local damage. Conversely, the compositions of the invention significantly increase the specificity of local action.
Example 3: the condition of ultra-effective synergistic action of the composition is preferably
A breakthrough in the technical solution is needed to make the composition of the present invention not only produce a synergistic effect, but also make the synergistic effect so strong as to be clinically competitive. The following test examples were conducted to investigate this.
Test animals (S180-cell-bearing mice, average tumor volume 129 mm)3) The groups were randomly divided into a negative control group, a positive control group and 12 study groups. The negative control was physiological saline and the study drug contained 1% 5-fluorouracil and varying concentrations (X%) of arginine and glutathione as shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was injected intratumorally, once every 3 days for 3 times in total, and the dose for each time was: 50mg/kg of 5-fluorouracil, less than or equal to 1.5g/kg of arginine, less than or equal to 1g/kg of glutathione and less than or equal to 150 mul of injection volume. Animals were euthanized 5 days after the end of dosing, tumor weights were determined after dissection, and tumor inhibition rates were calculated from negative controls. The tumor inhibition rates of the study groups are shown in Table 6.
TABLE 6
In Table 6, only the groups having arginine concentration of not less than 10% or glutathione concentration of not less than 7.5% showed super-potent synergistic efficacy (compared with 1% 5-fluorouracil group) when the synergistic technical scheme given in example 2 was satisfied. When the local administration concentration of the amino acid nutrient is more than or equal to the threshold value, the super-effective synergistic drug effect becomes sensitive to the local administration concentration and then becomes less sensitive again, and even the tumor inhibition rate can be reduced.
Based on these results and more similar studies, a super-effective synergistic efficacy solution of the composition of the present invention is: the composition is such that the composition can provide a topical administration concentration of the amino acid based nutrient of 3% or more, preferably 5-25% or 3-25%, wherein:
when the amino acid nutrient comprises an acidic amino acid salt, the local administration concentration of the amino acid nutrient is 3% -25%;
when the amino acid nutrient is selected from one or more of amino acid or/and amino acid salt except acidic amino acid salt, the local administration concentration of the amino acid nutrient is 10% -25%, preferably 15% -25% or 20% -25%;
when the amino acid nutrient is selected from one or more oligopeptides, the amino acid nutrient is locally administered at a concentration of 5% to 25%, preferably 7.5% to 25%;
when the amino acid based nutrient comprises one or more of oligopeptides, amino acids or/and amino acid salts other than acidic amino acid salts, the amino acid based nutrient is administered topically at a concentration of 5% to 25%, preferably 7.5-25% or 10-25%.
The results of the above studies of examples 2 and 3 illustrate that: compared with the absorption pharmaceutical composition (intra-tumor injection in experiment) which is applied conventionally, the local pharmaceutical composition (intra-tumor injection in experiment) which uses the amino acid nutrients and the anti-tumor chemotherapeutic drugs as local active ingredients has essential differences:
1) the targeting is different. After the amino acid nutrients and the anti-tumor chemotherapeutic medicine in the pharmaceutical composition are absorbed into the body, the amino acid nutrients and the anti-tumor chemotherapeutic medicine are respectively dispersed in the blood to run. After the medicated blood has passively entered the target area, they can only be targeted under conditions controlled by vascular wall penetration and other tissue barriers, such as targeting tumor cells. The topical pharmaceutical compositions of the present invention are directed to diseased tissues (e.g., intratumoral tissues) including, for example, blood supply vessels, matrix, and other micro-environmental structures within tumor body tissues.
2) Different compositions of the target area drugs. After absorbing amino acid nutrients and antitumor chemotherapeutic medicines in the pharmaceutical composition into the body, the composition of the substances in the blood with the medicine in the target area is greatly different from that in the composition due to different effects of the substances in the blood. Such compositions are not based on any other composition. The composition of the amino acid nutrient and the anti-tumor chemotherapeutic drug in the local medicinal composition of the invention in the liquid medicine in the target area is basically consistent with the composition in the composition.
3) Different target and different composition cause different pharmacology. It has been shown in the literature that nutrients delivered by blood have a nutritional effect on tumor cells and other cells, while anti-tumor chemotherapeutic drugs are delivered by blood to target areas to inhibit tumor cells. In the above tests, the absorption pharmaceutical composition of amino acid nutrients and antitumor chemotherapeutic drugs did not show a synergistic effect. In the local medicinal composition, the amino acid nutrients and the anti-tumor chemotherapeutic drugs are used as local active components to synergistically destroy tumor body tissues so as to enable tumor cells to lose survival and proliferation basis. The two different pharmacologies produce distinct pharmacological effects at the same dose.
4) Different in pharmacokinetics. Absorption of drugs (e.g., anti-tumor chemotherapeutic drugs) is often based on the results of cellular assays, with the pharmacokinetic key parameter being the blood concentration of the active ingredient (often approaching the effective concentration in cellular assays). This blood level is generally not guaranteed by the administered concentration (which is often given by dilution), but by the administered dose. Whereas the amino acid based nutrients and the anti-tumor chemotherapeutic in the composition of the present invention show completely different pharmacokinetics as local active ingredients. In the above test, there is a local administration concentration threshold and a local administration concentration interval, and it is only possible to produce their synergistic effect, especially a super-effective synergistic effect, above the concentration threshold and within a specific concentration interval.
Example 4: further application of composition in tumor treatment
In the following experiments, successfully modeled human cancer cell-bearing nude mice were each randomly divided into 1 negative control group and 6 study groups (A, B, C, D, E, F groups). The corresponding negative control was normal saline, and the 6 study drugs were: 1% 5-fluorouracil/20% arginine, 1% 5-fluorouracil/10% glutamine dipeptide, 1% 5-fluorouracil/10% glutathione, 1% 5-fluorouracil/10% glycine/10% acetic acid, 1% 5-fluorouracil/10% glutathione/10% glucose/5% acetic acid, 1% 5-fluorouracil/20% lysine/1% methylene blue. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was injected intratumorally, once every 3 days for a total of 3 times, 100. mu.l/dose. On the following day after the end of the administration, the animals were euthanized, and tumor weights were determined after dissection, and the tumor inhibition rates were calculated from the respective negative control groups.
1) Application of the compound in treating breast tumor
The nude mice (tumor body average volume 187 mm) with human breast cancer cells (MDA-MB231) successfully modeled3) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 77%, 73%, 71%, 82%, 86%, 89%, all meet the commonly recognized effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).
2) Application of the compound in lung tumor treatment
The successfully modeled nude mice bearing human lung cancer cells (A549) (tumor average volume is 203 mm)3) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 71%, 75%, 72%, 81%, 85%, 87% all meet the generally recognized effective anti-tumor standard (tumor inhibition rate is more than or equal to 40%).
3) Application of the compound in thyroid tumor treatment
The nude mice (tumor body average volume 211 mm) with successfully modeled human thyroid cancer cells (SW579)3) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 75 percent of77%, 73%, 85%, 89% and 93% which all meet the commonly considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).
4) Use in the treatment of prostate tumors
The successfully modeled nude mice (tumor body average volume 194 mm) with human prostate cancer cells (LNCaP/AR)3) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 73%, 71%, 75%, 87%, 85%, 91% all meet the generally recognized effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).
5) Application of the compound in liver tumor treatment
The successfully modeled nude mice (average tumor volume 214 mm) with human hepatoma cells (HepG2)3) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 73%, 75%, 72%, 81%, 87%, 93% all meet the generally recognized effective anti-tumor standard (tumor inhibition rate is more than or equal to 40%).
6) Application of the compound in treating head and neck tumors
The successfully modeled nude mice with human head and neck cancer cells (F mu da) (average tumor volume 172 mm)3) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 76%, 72%, 71%, 81%, 89%, 95% all meet the generally recognized effective anti-tumor standard (tumor inhibition rate is more than or equal to 40%).
7) Application of the compound in treatment of nasopharyngeal tumors
The nude mice (tumor body average volume is 203 mm) with successfully modeled human nasopharyngeal carcinoma cells (CNE1)3) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 73%, 71%, 75%, 83%, 87%, 85%, all of which meet the generally recognized effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).
8) Application of the compound in treating gastric tumor
The successfully modeled nude mice (tumor body average volume) with human gastric cancer cells (BGC823)218mm3) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 71%, 72%, 75%, 83%, 87%, 91% all meet the generally recognized effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).
9) Application of the compound in ovarian tumor treatment
The nude mice (tumor body average volume 186 mm) with successfully modeled human ovarian cancer cells (PA1)3) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 72%, 71%, 73%, 81%, 87%, 92%, all of which meet the generally recognized effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).
Similar results were obtained with some other compositions of the invention prepared in example 1 (e.g. the compositions in table 2), for each of the above tumor treatments.
Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.
Claims (10)
1. A topical pharmaceutical composition for the treatment of a solid tumor comprising an amino acid based nutrient at a concentration (w/v) > 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%, an anti-tumor chemotherapeutic, and a pharmaceutically acceptable liquid carrier; the concentration of the anti-tumor chemotherapeutic is greater than 30% of its saturation concentration, preferably 50% -100% of its saturation concentration, wherein the saturation concentration refers to the saturation concentration of the anti-tumor chemotherapeutic in the liquid carrier.
2. Use of an amino acid nutrient as a topical active ingredient in combination with an anti-tumour chemotherapeutic agent for the manufacture of a topical pharmaceutical composition for the treatment of a solid tumour.
3. Use according to claim 2, wherein the topical pharmaceutical composition comprises the amino acid based nutrient, the anti-tumour chemotherapeutic drug, and a pharmaceutically acceptable liquid carrier, and wherein the concentration (w/v) of the amino acid based nutrient is > 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%; the concentration of the anti-tumor chemotherapeutic is greater than 30% of its saturation concentration, preferably 50% -100% of its saturation concentration, wherein the saturation concentration refers to the saturation concentration of the anti-tumor chemotherapeutic in the liquid carrier.
4. Pharmaceutical composition or use according to any of claims 1 to 3, wherein the amino acid nutrient comprises one or more of the amino acid compounds, amino acid salts, oligopeptides and polypeptides having a nutraceutical effect, preferably amino acids or salts thereof or oligopeptides and polypeptides comprising or consisting of amino acids alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, β -alanine, taurine, gamma-aminobutyric acid (GABA), tea polyphenols (theanine), pumpkin seed amino acids (3-amino-3-carboxypyranopyranic acid), glutamine, citrulline, ornithine, more preferably amino acids or salts thereof selected from the group or oligopeptides and polypeptides comprising or consisting of amino acids arginine, lysine, glycine, cysteine, alanine, serine, glutamic acid.
5. The pharmaceutical composition or use according to claim 4, wherein the amino acid based nutrient is selected from the group consisting of amino acids or amino acid salts with nutraceutical effect and the concentration (w/v) of the amino acid or amino acid salt in the topical pharmaceutical composition is ≥ 2%, ≧ 2.5%, ≧ 5%, ≧ 7.5%, 10-25% or 18-25%, 15% -25% or 20% -25%.
6. The pharmaceutical composition or use according to claim 4, wherein the amino acid based nutrients are selected from oligopeptides and polypeptides with nutraceutical effect and the concentration (w/v) of said oligopeptides and polypeptides in the topical pharmaceutical composition is ≥ 5%, preferably 7.5-25%, more preferably 10% -25%.
7. The pharmaceutical composition or use according to claim 4, wherein the amino acid based nutrient is a combination of the amino acid and/or amino acid salt and the oligopeptide and/or polypeptide and the concentration (w/v) of the combination in the topical pharmaceutical composition is ≥ 5%, preferably 7.5-25%, more preferably 10-25%.
8. The pharmaceutical composition or use according to any one of claims 1 to 3, wherein the anti-tumour chemotherapeutic agent is selected from one or more of the following groups: drugs that disrupt the structure and function of DNA, drugs that interfere with the transcription of RNA that intercalate into DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis.
9. The pharmaceutical composition or use according to claim 8, wherein the anti-tumour chemotherapeutic agent is one or more selected from the group consisting of: uracil derivatives, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complex, and taxanes; preferably one or more selected from the following drugs and their analogous derivatives: 5-fluorouracil, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complex, paclitaxel.
10. A topical pharmaceutical composition for the treatment of solid tumors obtained by lyophilization or semi-lyophilization of a part or all of the pharmaceutical composition according to one of claims 1 and 4 to 9.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811008756.5A CN110870918A (en) | 2018-08-31 | 2018-08-31 | Pharmaceutical composition containing amino acid nutrients and antitumor chemotherapeutic drugs and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811008756.5A CN110870918A (en) | 2018-08-31 | 2018-08-31 | Pharmaceutical composition containing amino acid nutrients and antitumor chemotherapeutic drugs and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110870918A true CN110870918A (en) | 2020-03-10 |
Family
ID=69714582
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811008756.5A Pending CN110870918A (en) | 2018-08-31 | 2018-08-31 | Pharmaceutical composition containing amino acid nutrients and antitumor chemotherapeutic drugs and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110870918A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110870860A (en) * | 2018-08-31 | 2020-03-10 | 成都夸常奥普医疗科技有限公司 | Pharmaceutical composition comprising amino acid nutrients and conventional ineffective compounds and use thereof |
CN113559058A (en) * | 2021-07-30 | 2021-10-29 | 石家庄学院 | Gemcitabine amino acid injection |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101234122A (en) * | 2008-03-03 | 2008-08-06 | 中国科学院化学研究所 | New purpose of polylysine |
-
2018
- 2018-08-31 CN CN201811008756.5A patent/CN110870918A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101234122A (en) * | 2008-03-03 | 2008-08-06 | 中国科学院化学研究所 | New purpose of polylysine |
Non-Patent Citations (8)
Title |
---|
刘太峰等主编: "《各系统常见种类的综合诊治》", 31 March 2016, 吉林科学技术出版社 * |
刘广宣等: "5-氟尿嘧啶与肠外营养液配伍制剂的体外稳定性和体内抗肿瘤活性", 《山东医药》 * |
周雪峰主编: "谷氨酰胺和5-氟尿嘧啶对荷瘤大鼠肿瘤生长的影响", 《现代医药卫生》 * |
宋建国主编: "《泌尿及男性生殖系统:恶性肿瘤:现代非手术治疗》", 30 September 2008, 北京科技文献出版社 * |
尹晓燕等: "5-氟尿嘧啶联合L-精氨酸治疗裸鼠人肝癌移植瘤及其机制", 《世界华人消化杂志》 * |
张志义主编: "《恶性肿瘤化学治疗学》", 30 November 1981, 上海科学技术出版社出 * |
查文良等: "不平衡氨基酸肠内营养联合5_氟尿嘧啶对大鼠Walker-256癌肉瘤生长的影响", 《实用医学杂志》 * |
金正均: "等概率和曲线与"Q50", 《上海第二医学院学报》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110870860A (en) * | 2018-08-31 | 2020-03-10 | 成都夸常奥普医疗科技有限公司 | Pharmaceutical composition comprising amino acid nutrients and conventional ineffective compounds and use thereof |
CN113559058A (en) * | 2021-07-30 | 2021-10-29 | 石家庄学院 | Gemcitabine amino acid injection |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110870914A (en) | Use of amino acid nutrients and pharmaceutical compositions containing same | |
WO2021164706A1 (en) | Pharmaceutical composition containing methylene blue dye and application thereof | |
CN110870868A (en) | Pharmaceutical composition containing methylene blue dye, nutrient or/and anti-tumor compound and application thereof | |
CN110870869A (en) | Pharmaceutical composition comprising carbohydrate nutrients and conventional ineffective compounds and use thereof | |
CN110665003A (en) | Double-drug-loading carrier-free nanoparticle and preparation method thereof | |
WO2021163897A1 (en) | Pharmaceutical composition containing methylene blue dye, nutrient or/and conventional antitumor drug, and application thereof | |
CN110870918A (en) | Pharmaceutical composition containing amino acid nutrients and antitumor chemotherapeutic drugs and application thereof | |
WO2022068918A1 (en) | Pharmaceutical composition comprising acid-base neutralization combination and application thereof | |
US20230074885A1 (en) | Bortezomib-loaded nanoparticles | |
CN110870858A (en) | Pharmaceutical compositions comprising organic acid acidifying agents and conventional ineffective compounds and uses thereof | |
CN110870860A (en) | Pharmaceutical composition comprising amino acid nutrients and conventional ineffective compounds and use thereof | |
CN109069472A (en) | Medical composition containing producing high-molecular drug | |
CN112438942A (en) | Pharmaceutical composition containing alkalizer and its synergist and its application | |
CN110870913A (en) | Use of amino acid nutrients as vaccine adjuvants and vaccines comprising amino acid nutrients as adjuvants | |
JP2023544310A (en) | Use of probiotic ingredients and pharmaceutical compositions containing probiotic ingredients | |
CN102526714B (en) | Medicine composition for curing tumour and preparation method thereof | |
CN110870919A (en) | Pharmaceutical composition containing acidifier and anti-tumor chemotherapeutic drug and application thereof | |
CN100377712C (en) | Cucurbitacin lipsome preparation method and formulation | |
CN101559037B (en) | Binary solution type preparation for intravenous injection and intracerebral injection | |
CN112439066A (en) | Pharmaceutical composition comprising chemical ablation agent and pH adjusting agent and use thereof | |
CN1838942A (en) | Compositions and methods for hydrophobic drug delivery | |
CN102716465B (en) | Pharmaceutical composite for treating tumor and preparation method of pharmaceutical composite | |
CN100431605C (en) | Anticarcinogen composition | |
CN113230420A (en) | Water-based emulsion containing methylene blue vital dye, application of the emulsion and pharmaceutical composition containing the emulsion | |
CN114306392A (en) | Use of probiotic components and pharmaceutical compositions comprising probiotic components |
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 | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200310 |
|
RJ01 | Rejection of invention patent application after publication |