WO2016158756A1 - Formulation intradermique pour la médecine régénérative - Google Patents
Formulation intradermique pour la médecine régénérative Download PDFInfo
- Publication number
- WO2016158756A1 WO2016158756A1 PCT/JP2016/059633 JP2016059633W WO2016158756A1 WO 2016158756 A1 WO2016158756 A1 WO 2016158756A1 JP 2016059633 W JP2016059633 W JP 2016059633W WO 2016158756 A1 WO2016158756 A1 WO 2016158756A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- intradermal
- regenerative medicine
- stem cells
- preparation
- skin
- Prior art date
Links
- 230000001172 regenerating effect Effects 0.000 title claims abstract description 135
- 239000003814 drug Substances 0.000 title claims abstract description 129
- 238000009472 formulation Methods 0.000 title claims abstract description 10
- 239000000203 mixture Substances 0.000 title claims abstract description 10
- 210000004623 platelet-rich plasma Anatomy 0.000 claims abstract description 72
- 210000000130 stem cell Anatomy 0.000 claims abstract description 59
- 239000003102 growth factor Substances 0.000 claims abstract description 57
- 206010025282 Lymphoedema Diseases 0.000 claims abstract description 32
- 208000002502 lymphedema Diseases 0.000 claims abstract description 32
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 230000008929 regeneration Effects 0.000 claims abstract description 20
- 238000011069 regeneration method Methods 0.000 claims abstract description 20
- 210000004369 blood Anatomy 0.000 claims abstract description 18
- 239000008280 blood Substances 0.000 claims abstract description 18
- 238000005469 granulation Methods 0.000 claims abstract description 18
- 230000003179 granulation Effects 0.000 claims abstract description 18
- 230000037380 skin damage Effects 0.000 claims abstract description 17
- 206010040943 Skin Ulcer Diseases 0.000 claims abstract description 15
- 210000003643 myeloid progenitor cell Anatomy 0.000 claims abstract description 15
- 231100000019 skin ulcer Toxicity 0.000 claims abstract description 15
- 210000004204 blood vessel Anatomy 0.000 claims abstract description 12
- 210000004263 induced pluripotent stem cell Anatomy 0.000 claims abstract description 12
- 208000004210 Pressure Ulcer Diseases 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims description 107
- 210000003491 skin Anatomy 0.000 claims description 77
- 210000001365 lymphatic vessel Anatomy 0.000 claims description 28
- 201000010099 disease Diseases 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 claims description 17
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 17
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 17
- 210000002615 epidermis Anatomy 0.000 claims description 17
- 239000007924 injection Substances 0.000 claims description 17
- 238000002347 injection Methods 0.000 claims description 17
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 claims description 16
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 claims description 16
- 108050007372 Fibroblast Growth Factor Proteins 0.000 claims description 12
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 12
- 229940126864 fibroblast growth factor Drugs 0.000 claims description 12
- 108090000190 Thrombin Proteins 0.000 claims description 11
- 210000004027 cell Anatomy 0.000 claims description 11
- 229960004072 thrombin Drugs 0.000 claims description 11
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 239000001110 calcium chloride Substances 0.000 claims description 9
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 108010009583 Transforming Growth Factors Proteins 0.000 claims description 6
- 102000009618 Transforming Growth Factors Human genes 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 230000004936 stimulating effect Effects 0.000 claims description 6
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 claims description 5
- 239000006202 intradermal dosage form Substances 0.000 claims description 5
- 230000009826 neoplastic cell growth Effects 0.000 claims description 5
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 claims description 5
- 206010011985 Decubitus ulcer Diseases 0.000 claims description 4
- 238000011276 addition treatment Methods 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 102000009024 Epidermal Growth Factor Human genes 0.000 claims description 3
- 101800003838 Epidermal growth factor Proteins 0.000 claims description 3
- 229940116977 epidermal growth factor Drugs 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 2
- 102100021866 Hepatocyte growth factor Human genes 0.000 claims 1
- 210000002751 lymph Anatomy 0.000 abstract description 37
- 238000000034 method Methods 0.000 abstract description 11
- 206010034576 Peripheral ischaemia Diseases 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 25
- 206010030113 Oedema Diseases 0.000 description 20
- 108090000623 proteins and genes Proteins 0.000 description 13
- 238000002271 resection Methods 0.000 description 13
- 239000013543 active substance Substances 0.000 description 12
- 230000002093 peripheral effect Effects 0.000 description 12
- 210000003141 lower extremity Anatomy 0.000 description 10
- 238000007920 subcutaneous administration Methods 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 210000004207 dermis Anatomy 0.000 description 9
- 238000004806 packaging method and process Methods 0.000 description 9
- 230000035876 healing Effects 0.000 description 8
- 208000002874 Acne Vulgaris Diseases 0.000 description 7
- 206010000496 acne Diseases 0.000 description 7
- 230000006378 damage Effects 0.000 description 6
- 210000001165 lymph node Anatomy 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 206010063560 Excessive granulation tissue Diseases 0.000 description 5
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 5
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 5
- 241001442495 Mantophasmatodea Species 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 210000001126 granulation tissue Anatomy 0.000 description 5
- 201000002818 limb ischemia Diseases 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 4
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 4
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 4
- 102000029816 Collagenase Human genes 0.000 description 3
- 108060005980 Collagenase Proteins 0.000 description 3
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960002424 collagenase Drugs 0.000 description 3
- 230000002500 effect on skin Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 210000004880 lymph fluid Anatomy 0.000 description 3
- 230000035168 lymphangiogenesis Effects 0.000 description 3
- 230000035800 maturation Effects 0.000 description 3
- 206010033675 panniculitis Diseases 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000000087 stabilizing effect Effects 0.000 description 3
- 210000002536 stromal cell Anatomy 0.000 description 3
- 210000004304 subcutaneous tissue Anatomy 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000017423 tissue regeneration Effects 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 208000028990 Skin injury Diseases 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 230000001926 lymphatic effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004089 microcirculation Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 210000001778 pluripotent stem cell Anatomy 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000036560 skin regeneration Effects 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- FDQGNLOWMMVRQL-UHFFFAOYSA-N Allobarbital Chemical compound C=CCC1(CC=C)C(=O)NC(=O)NC1=O FDQGNLOWMMVRQL-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010007191 Capillary fragility Diseases 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000004044 Hypesthesia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 210000001736 capillary Anatomy 0.000 description 1
- POIUWJQBRNEFGX-XAMSXPGMSA-N cathelicidin Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C)C1=CC=CC=C1 POIUWJQBRNEFGX-XAMSXPGMSA-N 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000002316 cosmetic surgery Methods 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000002497 edematous effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 208000034783 hypoesthesia Diseases 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000005073 lymphatic endothelial cell Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000002906 medical waste Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000009707 neogenesis Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 231100000862 numbness Toxicity 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- -1 patches Substances 0.000 description 1
- 238000012335 pathological evaluation Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 229940041677 topical spray Drugs 0.000 description 1
- 108010078749 trafermin Proteins 0.000 description 1
- 229950009227 trafermin Drugs 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/16—Blood plasma; Blood serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/19—Platelets; Megacaryocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/48—Reproductive organs
- A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
- A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
Definitions
- the present invention relates to an intradermal preparation for regenerative medicine that is used to regenerate and treat tissues for diseases such as lymphedema, skin ulcer, skin acne, and skin damage by being administered intradermally.
- lymphedema skin ulcers caused by ischemia of the lower limbs, skin acne, skin damage, etc.
- lymph fluid skin inflammation, infection caused by loss of lymph vessels and blood vessels Is.
- lymphedema is surgically excised and dissected from the primary tumor and lymph nodes when removing cancer such as breast cancer or uterine cancer, and then treated with anticancer drugs or X-rays to prevent recurrence of the cancer. It is known that the lymphatic vessel disappears after the radiation treatment, and it occurs after the fact. Particularly in breast cancer patients, if the axillary lymph nodes are removed, brachial lymphedema frequently occurs after surgery. In patients with uterine cancer, lymphedema of the lower limb often occurs after surgery if the peripheral lymph nodes are removed.
- Lymphedema is a condition in which lymph accumulates at an early stage and infection or cellulitis occurs later. When edema develops, the upper arm and lower limbs are swollen, and the daily life of the patient is suppressed, and the quality of life (QOL) is significantly reduced. On the other hand, there are only symptomatic treatments such as massage for moving lymph fluid accumulated in the skin and compression therapy with a compression tape as treatment of lymphedema, and there is no curative treatment at present.
- Lower limb ischemia is asymptomatic at an early stage, but symptoms such as numbness and cold sensation can be observed when the pathology progresses somewhat. As it progresses further, symptoms such as ulcers appear.
- Cutaneous pressure ulcers are irreversible tissue necrosis caused by continuous pressure on the skin and soft tissues, and disruption of blood flow, increased circulatory disturbance, and continued ischemia.
- Skin damage may occur due to burns or physical damage, but it is often caused by a combination of damages such as venous capillaries and lymphatic networks, mainly in the destruction of arterial capillaries. It is thought to occur.
- HGF human growth factor
- FGF fibroblast growth factor
- VEGF vascular endothelial growth factor
- sprays, patches, ointments and the like containing bioactive ingredients such as these growth factors (proteins) produced using these genes by biotechnology are being developed.
- These genes and their growth factors have been studied for their roles using animal models and are known to be involved in angiogenesis and lymphangiogenesis (Non-patent Document 1).
- FGF fibroblast growth factor
- PDGF platelet-derived growth factor
- VEGF vascular endothelial growth factor
- these gene therapies have just begun to be applied clinically and are in the clinical research stage, and it is not clear about long-term safety.
- these genes and proteins derived from them are used for the treatment of diseases such as lymphedema, skin ulcers caused by ischemia of the lower limbs, skin acne, and skin damage by subcutaneous and intramuscular administration.
- diseases such as lymphedema, skin ulcers caused by ischemia of the lower limbs, skin acne, and skin damage by subcutaneous and intramuscular administration.
- the details of internal distribution and localization are not clear, and it is thought that the pharmacological effect disappears quickly because it is quickly washed away from the target site by simple diffusion rather than distribution / localization.
- lymph node transplantation In the field of plastic surgery in the treatment of lymphedema, treatment is performed by lymph node transplantation. It has been reported in rat experiments that lymphatic tissues such as lymphatic vessels including import / export lymphatic vessels are born by administering platelet-rich plasma around transplanted lymph nodes by the Manto method (Non-patent Document 2).
- the present inventors have administered specific platelet-rich plasma (PRP) and stem cells into the skin, so that capillary lymphatic vessels, capillaries, and skin are injected into the skin. It was found that granulation tissue was regenerated, regenerated and matured.
- specific platelet-rich plasma or stem cells are administered into the skin, multiple proteins possessing physiological activities such as growth factors are released, and capillary lymphatic vessels grow in the skin and skin fibroblasts migrate Regeneration of capillary lymph vessels, capillaries, and dermal granulation tissue was confirmed by experiments, and the present invention was completed.
- the present invention has been made in order to solve the above-mentioned problems, and has not been effective for diseases such as lymphedema, skin ulcers, skin pressure ulcers, and skin injuries that have occurred during lower limb ischemia. It is an object of the present invention to provide an intradermal preparation for regenerative medicine for inducing maturation by inducing regeneration and neoplasia of lymphatic vessels, blood vessels and granulations in a safe, simple and reliable manner. Furthermore, the present invention provides a production method capable of easily preparing an intradermal preparation for regenerative medicine, and an intradermal administration device for regenerative medicine for safely, simply and reliably administering the intradermal preparation for regenerative medicine into the skin. For the purpose.
- the intradermal preparation for regenerative medicine of the present invention which has been made to achieve the above object, is an intradermal preparation, comprising platelet-rich plasma, adipose stem cells, myeloid stem cells, blood stem cells, and artificial It contains a growth factor released from at least one of at least one stem cell selected from pluripotent stem cells.
- the intradermal preparation for regenerative medicine is a therapeutic preparation for at least any disease selected from, for example, lymphedema, skin ulcer, skin acne, and skin damage.
- the intradermal preparation for regenerative medicine can induce, for example, regeneration or neoplasia of lymphatic vessels, blood vessels, and / or granulations.
- the growth factor is at least selected from platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor, epidermal growth factor, fibroblast growth factor, and hepatocyte growth factor Either is preferable.
- the intradermal preparation for regenerative medicine is preferably administered into the skin having a depth of 1 to 4 mm from the surface of the skin epidermis.
- the growth factor is preferably released by stimulating the platelet-rich plasma and / or the stem cells.
- the intradermal preparation for regenerative medicine is a product in which the growth factor is released from the platelet-rich plasma by either cooling treatment or addition treatment of thrombin and / or calcium chloride, or the fat
- the growth factor is released from at least one of the stem cells selected from a stem cell, the myeloid stem cell, the blood stem cell, and the induced pluripotent stem cell.
- the stem cells release the growth factor even if they are not activated.
- the adipose stem cells are separated by collagenase at the time of collection and release the growth factor.
- the intradermal preparation for regenerative medicine is derived from the platelet-rich plasma and / or the stem cells collected from a patient who is subjected to regenerative medicine.
- the platelet count of the platelet-rich plasma and / or the number of stem cells is preferably 1 ⁇ 10 ⁇ 5 to 1 ⁇ 10 ⁇ 7 cells / ⁇ l.
- the amount of the intradermal preparation for regenerative medicine is preferably 1 to 40 ml.
- the platelet-rich plasma and / or the stem cells may be uncultured.
- the method for producing the intradermal preparation for regenerative medicine of the present invention made to achieve the above object is selected from platelet-rich plasma, adipose stem cells, myeloid stem cells, blood stem cells, and induced pluripotent stem cells. It is prepared by stimulating at least one of at least one kind of stem cells to release growth factors.
- the method for producing an intradermal preparation for regenerative medicine comprises the step of releasing the growth factor by stimulating the platelet-rich plasma with either cooling and addition of thrombin and / or calcium chloride, or fat
- the growth factor is released from at least one stem cell selected from a stem cell, a myeloid stem cell, a blood stem cell, and an induced pluripotent stem cell.
- the adipose stem cells are separated by collagenase at the time of collection and release the growth factor.
- the intradermal administration device for regenerative medicine of the present invention made to achieve the above object is a device for intradermal administration, comprising platelet-rich plasma, adipose stem cells, myeloid stem cells, blood stem cells, and artificial multiples.
- a drug room containing a regenerative medical intradermal preparation containing a released growth factor from at least one of at least one stem cell selected from pluripotent stem cells, and administering the regenerative medical intradermal preparation A needle and / or a cannula.
- the injection needle and / or the cannula are adjusted to a length capable of administering the intradermal preparation for regenerative medicine into the skin having a depth of 1 to 4 mm from the skin epidermis. Preferably it is.
- the intradermal preparation for regenerative medicine of the present invention is a release of growth factors such as platelet-rich plasma, stem cells such as adipose stem cells, myeloid stem cells, blood stem cells, and induced pluripotent stem cells.
- growth factors such as platelet-rich plasma, stem cells such as adipose stem cells, myeloid stem cells, blood stem cells, and induced pluripotent stem cells.
- the capillary lymph network and the capillary network can be efficiently regenerated by locally reaching the inner compartment and locally distributing within the skin skin.
- intradermal preparation for regenerative medicine for lymphedema, skin ulcer, skin acne, skin damage, by intradermal administration, compared to intradermal and external administration such as subcutaneous, muscle, topical spray, etc. Since the capillary lymphatic network and the capillary network can be locally distributed to the pathological site in the skin to be regenerated, a high therapeutic effect can be expected.
- capillary vessels such as skin capillary lymph vessels and capillaries, and lymphedema, skin ulcer, skin pressure ulcer, skin damage Skin regeneration, early recovery, and healing of patients with such diseases are possible.
- the therapeutic method using this intradermal preparation for regenerative medicine is to selectively administer growth factors derived from specific platelet-rich plasma or hepatocytes to the skin, for example, to the dermis to regenerate capillaries and capillaries.
- this is a new treatment method in which capillary lymph vessels and capillaries regenerate and regenerate in the dermis to induce thicker lymph vessels and blood vessels. Lymphedema, in particular, develops due to broken capillary tubules due to radiation therapy after cancer treatment or anticancer drug treatment. Therefore, it is necessary to quickly regenerate this microcirculation. Also, if the microcirculation is regenerated, the lymph fluid flows in a certain direction, leading to thicker lymphatic vessels.
- a preparation containing a growth factor as an active ingredient for regenerating capillary lymphatic vessels and capillaries while maintaining high safety in a simple and reliable manner It can be quickly prepared with good reproducibility.
- the intradermal administration device for regenerative medicine according to the present invention can be applied to the intradermal area for regenerative medicine into a very limited skin having a depth of 1 to 4 mm from the skin epidermis without the need for advanced and specialized skilled administration skills. It is possible to selectively administer the administration preparation without leakage, and to regenerate and regenerate capillaries and capillaries to mature.
- a rat tail lymphedema model was prepared, and a regenerative medical intradermal administration formulation to which the present invention was applied was administered intradermally, in a comparison group administered subcutaneously, and in a control group that was not administered, in the peripheral region of tail skin resection. It is a photograph showing the state. It is a photograph which shows the result of having produced the skin damage model of a rat back
- a skin damage model of the rat spine was prepared, and the intradermal administration preparation for regenerative medicine to which the present invention was applied was administered subcutaneously or intradermally to PRP, or administered intradermally to bFGF, and then histopathological examination was conducted to regenerate epidermis. It is the scored graph.
- a preferred form of the intradermal preparation for regenerative medicine according to the present invention contains a growth factor released from platelet-rich plasma.
- Platelet-rich plasma can regenerate capillaries and capillaries by stimulation, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor (eg TGF- ⁇ ), stromal cell-derived It releases growth factors such as factors (eg, SDF-1a), epidermal growth factor (EGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF).
- PDGF platelet-derived growth factor
- VEGF vascular endothelial growth factor
- TGF- ⁇ transforming growth factor
- stromal cell-derived It releases growth factors such as factors (eg, SDF-1a), epidermal growth factor (EGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF).
- the intradermal preparation for regenerative medicine contains a plurality of physiologically active substances such as growth factors as active ingredients. Since these physiologically active substances such as growth factors are stable unlike cells, the intradermal preparation for regenerative medicine can be used by dissolving
- platelet rich plasma is preferably collected from the patient to be treated.
- platelet rich plasma of the same species as the animal to be treated.
- This intradermal preparation for regenerative medicine is manufactured as follows.
- Blood is collected from patients and target animals, and 1000-5000 rpm. For 1 to 60 minutes at room temperature, eg 20 to 30 ° C. to obtain platelet rich plasma. For example, about 4 ml of platelet-rich plasma is obtained from 10-20 ml of human blood.
- thrombin was added to a concentration of 50 to 1000 U / ml at 20 to 30 ° C. and calcium chloride was further added to a concentration of 1 to 100 mM
- platelets were synergistically influenced by both effects. As a result of being stimulated and activated to release a physiologically active substance such as a growth factor, an intradermal preparation for regenerative medicine is obtained. In addition, you may activate only with thrombin and may activate only with calcium chloride.
- the platelet-rich plasma collected in this way is activated by stimulation of platelets at room temperature, for example, 20-30 ° C., preferably 20 ° C., and releases physiologically active substances such as growth factors. May be used as an intradermal preparation for regenerative medicine. It may be activated in combination with the addition of thrombin and / or calcium chloride to form an intradermal preparation for regenerative medicine.
- low-temperature treatment PRP in which platelet-rich plasma is stimulated by standing at a low temperature, for example, 0 to 10 ° C., preferably 3 to 5 ° C., more preferably 4 ° C. for a certain time or more, preferably 30 minutes or more, is also used for platelets. When activated, it releases physiologically active substances such as growth factors.
- a physiologically active substance such as a released growth factor is more important as an active ingredient than activated platelets, for example, as a preparation for intradermal administration for regenerative medicine while leaving platelets remaining or filtering off platelets, It may be administered to a patient.
- Intradermal preparations for regenerative medicine are prepared by freeze-dried platelet-rich plasma containing growth factors, etc. that has been stimulated and dissolved or suspended in saturated saline or the like when administered to patients. May be.
- This intradermal preparation for regenerative medicine is preferably prepared so that the platelet count of the platelet-rich plasma is 1 ⁇ 10 ⁇ 5 to 1 ⁇ 10 ⁇ 7 / ⁇ l. If it is thinner than this concentration range, it is too dilute and sufficient growth factors and the like are not calculated. If this concentration range is exceeded, the effect reaches its peak and valuable preparations are wasted. It is preferably 0.5 ⁇ 10 ⁇ 6 to 5 ⁇ 10 ⁇ 6 pieces / ⁇ l, and more preferably 1 ⁇ 10 ⁇ 6 pieces / ⁇ l.
- an intradermal administration device for regenerative medicine is used.
- the intradermal administration device 1 for regenerative medicine is composed of a syringe body 10 and a needle assembly 20 as described with reference to FIG. 1 which is an exploded front view thereof.
- the syringe body 10 includes a syringe outer cylinder 12 of a regenerative medical intradermal administration device, a pusher 11 in which a gasket 13 is screwed into the distal end and the gasket 13 is inserted into the syringe outer cylinder 12 and the proximal end side is exposed, A cylinder tip 17 that extends from the syringe outer cylinder 12 and has an inner space that communicates from the inside of the syringe outer cylinder 12 to the outside, and an intradermal dosage form 15 for regenerative medicine that is sandwiched between the cylinder tip 17 and the gasket 13 and becomes a drug solution in the syringe outer cylinder 12.
- a lock mechanism 16 which is a female screw attached to the syringe outer cylinder 12 on the outer periphery of the cylinder tip 17.
- a tube tip 17 having a tube hole that can discharge the intradermal administration preparation 15 for regenerative medicine is sealed with a cap 18 and / or hermetically sealed together with the syringe body 10.
- the injection needle assembly 20 has a needle hole that communicates from the needle tip to the needle proximal end in the fitting tube 22 provided on the outer periphery with a male screw that engages with the lock mechanism 16, and has a blade surface at the needle tip.
- An injection needle 27 composed of a needle tube, a needle hub 24 that holds the injection needle 27 at the tip, and an elastic body 23 that fills the gap between the tube tip 17 and the needle hub 24 by screwing of the lock mechanism 16 are fitted ( (See FIG. 2).
- the injection needle 27 protrudes from the adjustment portion 25 at the center of the needle hub 24 and protrudes from the end surface on the needle tip side of the adjustment portion 25 of the needle hub 24 to reach the needle tip so that the needle can be administered into the skin 32.
- a length L 1 and 2mm at the longest, and 1mm for a minimum of Haridocho L 2 is of 26-35 gauge (corresponding to the diameter 0.45 ⁇ 0.15 mm).
- the needle hub 24 surrounds the adjusting portion 25 and a cylindrical stabilizing portion 26 protrudes.
- the injection needle assembly 20 is sealed in a packaging container 21b covered with a packaging lid 21a until just before use, and the packaging lid 21a is peeled off during use.
- the intradermal administration preparation 15 for regenerative medicine is administered as follows using the intradermal administration device 1 for regenerative medicine.
- the intradermal preparation 15 for regenerative medicine which is platelet-rich plasma
- the amount of one shot that can administer the intradermal preparation 15 for regenerative medicine to one place in the skin 32 is 500 ⁇ l (0.5 ml), preferably 300 ⁇ l at most, so the inhalation amount is 500 ⁇ l (0.5 ml). Preferably, it is 300 ⁇ l or less.
- the maximum dose for a single dose is 500 ⁇ l (0.5 ml), preferably 300 ⁇ l for the patient, and the total continuous dose is 500 ⁇ l (maximum for the patient in 2 to 3 consecutive doses at the same site ( 0.5 ml) preferably 300 ⁇ l.
- the packaging lid 21a is peeled off, and the needle base with the needle is replaced with the injection needle assembly 20 while sandwiching the packaging container 21b.
- FIG. 2 which is a partially enlarged cross-sectional view of the intradermal administration device 1 for regenerative medicine
- the tube tip 17 of the syringe body 10 is lightly pushed into the insertion tube 22 of the injection needle assembly 20, and then the tube tip
- the locking mechanism 16 of the female screw surrounding 17 is screwed into the male screw on the outer periphery of the insertion tube 22 of the injection needle assembly 20 and tightened.
- the tube tip 17 is further inserted into the inner portion of the fitting tube 22, and the elastic body 23 is compressed, so that there is no gap with the tube tip 17, thereby becoming liquid-tight.
- the lock mechanism 16 is sufficiently tightened, the packaging container 21b is removed.
- the needle tip side of the injection needle 27 of the regenerative medical intradermal administration device 1 is directed to the skin 30 as a treatment target site for a disease of lymphedema, skin ulcer, skin acne, or skin damage.
- a disease of lymphedema skin ulcer, skin acne, or skin damage.
- the skin 30 is affected skin for lymphedema, and for other diseases, the skin 30 is skin around the diseased area.
- the intradermal administration device 1 for regenerative medicine is pressed so that the injection needle 27 is perpendicular to the skin 30. Then, the needle tip of the injection needle 27 is first punctured into the skin 30.
- the stabilizing portion 26 presses the skin epidermis 33 of the skin 30 and the adjusting portion 25 contacts the skin epidermis 33.
- the regenerative medical intradermal administration device 1 is stabilized so as not to shift.
- the injection needle 27 penetrates the skin epidermis 33 by the sharp blade surface of the needle tip, and the opening of the needle hole on the blade surface is exactly 1 to 5 from the surface of the skin epidermis 33 in the intradermal (dermis layer) 32 of the upper skin layer.
- the 4 mm relatively shallow intradermal target site 32 a to be injected is reached, but the subcutaneous tissue 31 is not reached.
- the pusher 11 is pushed out, and the intradermal administration preparation 15 for regenerative medicine is injected.
- the intradermal preparation 15 for regenerative medicine reaches the intradermal 32 having a depth of 1 to 4 mm from the surface of the skin epidermis 33.
- the intradermal preparation 15 for regenerative medicine is preferably administered over a wide range, for example, 100 to 500 ⁇ l (0.1 to 0.5 ml) per shot at 1 to 10 mm intervals in the range of the upper arm and lower limb to be treated. ) And 1 to 40 shots, preferably a plurality of times. Administration is preferably performed at 7-28 day intervals.
- the intradermal administration device 1 for regenerative medicine is sealed again with the packaging lid 21a (see FIG. 1) and then discarded as medical waste.
- lymphatic endothelial cells migrate by vascular endothelial cell growth factor (VEGF) contained in the intradermal preparation 15 for regenerative medicine, and further by platelet-derived growth factor (PDGF), smooth muscle and It is inferred that tight junctions migrated and capillary lymphatic vessels regenerated, resulting in the formation of mature lymphatic vessels. Actually, regeneration of neolymphatic vessels and the effect of improving edema have been confirmed in a tail lymphedema model using rats. Therefore, the intradermal preparation 15 for regenerative medicine is effective in improving lymphedema in the clinic.
- VEGF vascular endothelial cell growth factor
- PDGF platelet-derived growth factor
- lymphatic vessels it is considered that regeneration and neoplasia are promoted in a complex manner by the interaction of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), among others. It is thought that another factor also promotes regeneration / neogenesis by some interaction.
- PDGF platelet-derived growth factor
- VEGF vascular endothelial growth factor
- VEGF vascular endothelial growth factor
- PDGF platelet-derived growth factor
- granulation cells migrate by transforming growth factors (eg TGF- ⁇ ), resulting in lymphangiogenesis and granulation.
- TGF- ⁇ transforming growth factors
- lymphangiogenesis and granulation have been confirmed in a rat skin defect model. Accordingly, the intradermal preparation 15 for regenerative medicine is effective in improving clinical skin ulcers, skin acne and skin damage diseases.
- the intradermal preparation 15 for regenerative medicine When the intradermal preparation 15 for regenerative medicine is administered to a site having a depth of 1 to 4 mm from the surface of the skin epidermis 33, the regeneration and renewal of capillary lymph vessels, capillaries and granulations, and their maturation effects are high. . If it is this depth, the growth factor in the intradermal preparation 15 for regenerative medicine is locally administered, and it stays distributed in the skin for a long time without being diffused unnecessarily. Capillary lymphatic vessels, capillaries and other vessels and granulation cells can be regenerated and regenerated to mature.
- the corner growth factor does not form lymph vessels and granulations to be born, but also leaks from the skin epidermis.
- the growth factor at the corner is diffused, and lymphatic vessels, blood vessels and granulations to be regenerated / neoplastic cannot be formed.
- the adipose stem cell, the myeloid stem cell, the blood A physiologically active substance such as a growth factor can also be released using at least one stem cell selected from stem cells and the above-mentioned induced pluripotent stem cells.
- these stem cells and suspensions thereof can be used.
- collagenase is used for recovery of adipose stem cells among these stem cells.
- blood stem cells are identified after being cultivated and increased to the required number. Thereby, the intradermal preparation 15 for regenerative medicine which released the growth factor can be obtained.
- the myeloid stem cells may be used as they are without being degraded.
- platelets such as platelets, adipose stem cells, myeloid stem cells, blood stem cells, and induced pluripotent stem cells all possess pluripotency and proliferative ability and are useful for treatments such as tissue regeneration.
- These cells release many physiologically active substances such as growth factors (for example, proteins that are growth-inducing factors) and regenerate lymphatic vessels and blood vessels by subcutaneous administration.
- growth factors for example, proteins that are growth-inducing factors
- platelets contained in platelet-rich plasma contain ⁇ granules and ⁇ granules.
- granules include platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor (eg TGF- ⁇ ), stromal cell derived factor (eg SDF-1a), epithelial cell factor (EGF) And physiologically active substances such as growth factors such as fibroblast growth factor (FGF) and hepatocyte growth factor (HGF).
- PDGF platelet derived growth factor
- VEGF vascular endothelial growth factor
- TGF- ⁇ transforming growth factor
- stromal cell derived factor eg SDF-1a
- epithelial cell factor EGF
- physiologically active substances such as growth factors such as fibroblast growth factor (FGF) and hepatocyte growth factor (HGF).
- FGF fibroblast growth factor
- HGF hepatocyte growth factor
- the platelet-rich plasma has already been used in a treatment method for regenerating skin tissue by injecting subcutaneously for anti-aging and cosmetics, and has been found to be highly safe.
- the therapeutic method of administering the intradermal preparation 15 for regenerative medicine into the skin, particularly into the dermis layer, is due to a synergistic effect with physiologically active substances such as a plurality of growth factors, and capillary lymphatic vessels, capillaries and granulations of broken skin. It can be a treatment for lymphedema that efficiently regenerates and regenerates, matures to induce regeneration of thick lymphatic vessels and blood vessels, and drains the accumulated skin lymph.
- a plurality of physiologically active substances such as growth factors are distributed and staying in the skin of the target site to be treated, thereby causing lymphedema.
- diseases such as skin ulcers, skin pressure ulcers, and skin damage caused by lower limb ischemia can be safely treated in a short time.
- the papillary dermis is a tissue in which the capillary lymph network and the capillary network are dense
- the reticular dermis is a tissue that becomes the passage of the capillary lymph vessels and the capillary vessels.
- the pathology of diseases such as lymphedema, skin ulcers, skin pressure sores, and skin damage develops due to the accumulation of lymph in the skin due to the destruction of these vascular networks, and the accumulation of lymph in the subcutaneous tissue.
- It is desirable to administer the intradermal preparation 15 for regenerative medicine intradermally because growth factors and cells necessary for regeneration of capillary lymphatic vessels and capillaries in the skin are locally distributed and dispersed and retained.
- an intradermal administration device for regenerative medicine as shown in FIG. 1 may be used, or a syringe equipped with a needle base with a needle for general-purpose Manto method may be used.
- injecting intradermally with the Manto method requires very skilled skills, and the regenerative medicine shown in FIG. 1 is more suitable than a syringe for the Manto method suitable for administering 0.5 to several ml to the target site.
- the intradermal administration device 1 is more suitable for clinical use.
- Platelet rich plasma was prepared from whole mammalian blood by multiple centrifugations. A kit for preparing PRP and a centrifuge may be used. The platelet-rich plasma was adjusted to a concentration of 1 ⁇ 10 6 cells / ⁇ l by using a blood cell counter, and then the platelet-rich plasma was allowed to stand at 4 ° C. for 30 minutes or more for stimulation at 4 ° C.
- the test method of this model is a follow-up observation in which the diameter of the tail skin resection peripheral portion is measured over time, and further, the healing of the tail skin resection peripheral portion is observed over time.
- the surgical group positive control
- spontaneous healing is observed without administering the intradermal preparation for regenerative medicine after excision surgery
- healthy untreated An untreated group (negative control) that was followed up without administration of an intradermal preparation for regenerative medicine was used.
- FIG. 3 shows the results of measuring the diameter of the peripheral portion of the tail skin resection over time until the fourth week after the rat tail edema lymph model was prepared. Moreover, the healing progress state of the peripheral part of the tail skin resection in the surgical group and the PRP-administered group (4 ° C. cooling treatment PRP group) after one week has elapsed since the preparation of the rat tail edema lymph model is shown in FIG. As apparent from FIGS. 3 and 4, the PRP-administered group had both edematous lymphs suppressed and tail swelling less than the surgical group in which the edema lymphs were produced and the tails were swollen. Was clearly observed, and granulation tissue regeneration and wound healing were confirmed rapidly and remarkably.
- Test Example 2 PRP intradermal / subcutaneous administration effectiveness comparison
- the 4 ° C. cooled PRP prepared in Example 1 was used as an intradermal administration preparation for regenerative medicine. 500 ⁇ l each was intradermally administered with a syringe using a certain 27G needle, and 100 ⁇ l ⁇ 5 sites (total amount 500 ⁇ l) were subcutaneously administered.
- the test method of this model is a follow-up observation in which the diameter of the tail skin resection peripheral portion is measured over time, and further, the healing of the tail skin resection peripheral portion is observed over time.
- control group after the preparation of the rat tail edema lymph model, the surgical group (positive control) in which spontaneous healing is observed without administering the intradermal preparation for regenerative medicine after excision surgery, and healthy untreated An untreated group (negative control) that was followed up without administration of an intradermal preparation for regenerative medicine was used.
- FIG. 5 shows the results of measuring the diameter of the tail skin resection portion over time until 4 weeks after the rat tail edema lymph model was prepared. Moreover, the healing progress state of the peripheral part of the tail skin resection in the PRP intradermal administration group and the PRP subcutaneous administration group after 3 weeks from preparation of the rat tail edema lymph model is shown in FIG. As is clear from FIG. 5 and FIG. 6, the PRP intradermal administration group has suppressed edema lymph and the edema lymph is suppressed compared to the surgical group in which edema lymph is produced and the tail is swollen and the PRP subcutaneous administration group in which improvement of edema lymph is not observed. Swelling was small, new granulation was clearly observed in the peripheral part of the tail skin resection, and granulation tissue regeneration and wound healing were confirmed rapidly and remarkably.
- Epidermal regeneration was compared by different skin injury models. Using a rat (SD, male, 8 weeks old), shaving the back, using a scalpel with a 20mm diameter circular skin at the center and left and right of the midline, and excising the skin at 2 sites per animal I did it. PRP (adjusted to 10 6 / ⁇ l) was cooled at 4 ° C. for 30 minutes or more, and further administered 100 ⁇ l ⁇ 5 sites intradermally and subcutaneously (administration was performed twice every 5 days).
- bFGF Fiblast spray 250 ⁇ g: Trafermin / Kaken Pharmaceutical Co., Ltd.
- administration was performed once a day for a total of 5 times.
- autopsy was performed, the skin was collected, and histopathological examination was performed after HE staining.
- the pathological evaluation was performed by scoring epidermal regeneration. The scoring is evaluated in 4 stages of ⁇ : slight, +: regeneration is observed, ++: sufficient regeneration, and +++: complete (excision of the entire excision).
- FIG. 7 shows a photograph of the pathological tissue after HE staining of PRP intradermal administration.
- FIG. 8 shows the results of scoring after PRP subcutaneous / intradermal administration or bFGF intradermal administration.
- epidermal tissue was significantly regenerated by intradermal administration of PRP as compared to subcutaneous administration of PRP or intradermal administration of bFGF.
- PDGF platelet-derived growth factor
- VEGF vascular endothelial growth factor
- TGF- ⁇ stromal cell-derived factor
- EGF epidermal growth factor
- FGF fibroblast growth factor
- HGF hepatocyte growth factor
- the preparation for intradermal use for regenerative medicine of the present invention is a skin ulcer / cutaneous pressure ulcer / skin caused by lymphedema after the dissection of the primary cancer and lymph nodes, lymphedema caused by anticancer drug treatment or X-ray radiation treatment, and lower limb ischemia It can be used to treat diseases such as injury.
- the method for producing an intradermal preparation for regenerative medicine of the present invention is used when preparing an intradermal preparation for regenerative medicine and efficiently administering it to the skin at the time of treatment or in advance.
- the intradermal administration device for regenerative medicine of the present invention is used to administer an intradermal administration preparation for regenerative medicine exclusively intradermally.
- 1 intradermal administration device for regenerative medicine
- 10 syringe body
- 11 pusher
- 12 syringe barrel
- 13 gasket
- 14 drug room
- 15 intradermal administration preparation for regenerative medicine
- 16 lock mechanism
- 17 cylinder tip
- 18 cap
- 20 injection needle assembly
- 21a packaging lid
- 21b packaging container
- 22 fitting cylinder
- 23 elastic body
- 24 needle hub
- 25 adjustment section
- 26 stabilization section
- 27 Injection needle
- 30 Skin
- 32 Intradermal
- 32a Intradermal target site
- 33 Skin epidermis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cell Biology (AREA)
- Developmental Biology & Embryology (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Virology (AREA)
- Biotechnology (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Infusion, Injection, And Reservoir Apparatuses (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
L'invention concerne : une formulation intradermique pour la médecine régénérative pour effectuer un traitement pour induire et assurer de manière sûre, simple et fiable la régénération ou la renaissance de vaisseaux lymphatiques, de vaisseaux sanguins, ou la granulation dans des conditions comme un lymphœdème, pour lequel il n'y a pas de méthode de traitement efficace, et les ulcères cutanés, les ulcères par pression de la peau et les dommages cutanés apparaissant lors de lésions ischémiques des jambes; et un dispositif d'administration intradermique pour la médecine régénérative. La formulation intradermique pour la médecine régénérative est une formulation à administrer par voie intradermique, la formulation intradermique contenant du plasma riche en plaquettes et un facteur de croissance libéré à partir d'au moins un type de cellules souches choisies parmi les cellules souches provenant de tissu adipeux, les cellules souches myéloïdes, les cellules souches sanguines et les cellules souches pluripotentes induites. Le dispositif d'administration intradermique (1) pour la médecine régénérative comprend une chambre à médicament (14) pour héberger une formulation intradermique (15) pour la médecine régénérative, et une aiguille (24) et/ou canule pour l'administration de la formulation intradermique (15) pour la médecine régénérative.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017509909A JPWO2016158756A1 (ja) | 2015-03-31 | 2016-03-25 | 再生医療用皮内投与製剤 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015072040 | 2015-03-31 | ||
JP2015-072040 | 2015-03-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016158756A1 true WO2016158756A1 (fr) | 2016-10-06 |
Family
ID=57004309
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2016/059633 WO2016158756A1 (fr) | 2015-03-31 | 2016-03-25 | Formulation intradermique pour la médecine régénérative |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPWO2016158756A1 (fr) |
WO (1) | WO2016158756A1 (fr) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013046868A1 (fr) * | 2011-09-29 | 2013-04-04 | テルモ株式会社 | Seringue |
WO2013046867A1 (fr) * | 2011-09-29 | 2013-04-04 | テルモ株式会社 | Seringue |
WO2013065017A2 (fr) * | 2011-11-03 | 2013-05-10 | Centre Hospitalier Universitaire Vaudois (C.H.U.V.) | Plasma riche en plaquettes (prp) et peptide issu de la prominine-1 stimulent la lymphangiogenèse |
-
2016
- 2016-03-25 JP JP2017509909A patent/JPWO2016158756A1/ja active Pending
- 2016-03-25 WO PCT/JP2016/059633 patent/WO2016158756A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013046868A1 (fr) * | 2011-09-29 | 2013-04-04 | テルモ株式会社 | Seringue |
WO2013046867A1 (fr) * | 2011-09-29 | 2013-04-04 | テルモ株式会社 | Seringue |
WO2013065017A2 (fr) * | 2011-11-03 | 2013-05-10 | Centre Hospitalier Universitaire Vaudois (C.H.U.V.) | Plasma riche en plaquettes (prp) et peptide issu de la prominine-1 stimulent la lymphangiogenèse |
Non-Patent Citations (6)
Title |
---|
JIANG D ET AL.: "The effect of adipose tissue derived MSCs delivered by a chemically defined carrier on full-thickness cutaneous wound healing", BIOMATERIALS, vol. 34, no. 10, pages 2501 - 2515, XP055315716, ISSN: 0142-9612 * |
KENJI KUSUMOTO: "Treatment of chronic ulcers applying platelet-rich plasma (PRP", JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, vol. 237, no. 1, 2 April 2011 (2011-04-02), pages 141 - 145, ISSN: 0039-2359 * |
KUNIHISA TSUKADA: "Wakatta! Nichijo Shinryo no Kihon Koza Hitome de Wakaru! Saiketsu no Shikata·Chusha no Shikata no Kihon to Chuiten", RESIDENT NOTE, vol. 6, no. 2, May 2004 (2004-05-01), pages 139 - 149, ISSN: 1344-6746 * |
MAHARLOOEI MK ET AL.: "Adipose tissue derived mesenchymal stem cell (AD-MSC) promotes skin wound healing in diabetic rats", DIABETES RESEARCH AND CLINICAL PRACTICE, vol. 93, no. 2, 31 May 2011 (2011-05-31), pages 228 - 234, XP028260761, ISSN: 0168-8227 * |
TOYSERKANI MM ET AL.: "Stem cells snow promising results for lymphoedema treatment-a literature review", JOURNAL OF PLASTIC SURGERY AND HAND SURGERY, vol. 49, no. 2, pages 65 - 71, ISSN: 2000-6764 * |
YUDAI NISHINO: "Skin regenerative therapy to apply growth factors from stem cell", JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, vol. 239, no. 8, 19 November 2011 (2011-11-19), pages 851 - 854, ISSN: 0039-2359 * |
Also Published As
Publication number | Publication date |
---|---|
JPWO2016158756A1 (ja) | 2018-02-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Brans et al. | Histopathological evaluation of scalds and contact burns in the pig model | |
KR101738536B1 (ko) | 모발 성장 촉진용 염기성 섬유모세포 생장인자 조성물 및 그 제조 방법 | |
JP2009235004A (ja) | 細胞組織増加促進方法及び肌問題改善方法並びにこれらに用いるキット | |
CN105251011B (zh) | 一种用于浅度烧伤的喷膜剂及其制备方法 | |
CN111558128A (zh) | 一种载瘢痕修复药物的可溶性微针阵列及制备方法 | |
Leon-Villapalos et al. | Surgical repair of the acute burn wound: who, when, what techniques? What is the future? | |
US20230338296A1 (en) | Devices and methods for delivery of oxygen to a wound | |
JP2023534708A (ja) | 創傷治療薬の製造におけるポリペプチドの使用 | |
RU2562319C1 (ru) | Лимфотропный способ коррекции косметических проблем кожи доктора фаустовой | |
WO2016158756A1 (fr) | Formulation intradermique pour la médecine régénérative | |
RU2558995C1 (ru) | Способ лечения острой анальной трещины | |
CN103705910A (zh) | 一种齐考诺肽注射型皮下植入剂及其制备方法 | |
CN108815116A (zh) | 一种可治愈病理性瘢痕的白藜芦醇软膏、制备方法及应用 | |
RU2380121C1 (ru) | Инъекционная игла и способ ее использования для подкожных инъекций | |
CN101347535B (zh) | 一种烧、烫、灼伤再生膏 | |
Scarano et al. | Full-facial rejuvenation with autologous platelet-derived growth factors | |
RU2637086C1 (ru) | Способ снижения риска развития некроза конечностей при холодовой травме | |
Swaminathan et al. | Novel effective treatment for diabetic foot ulcers [DFU] by vacuum assisted wound closure therapy | |
CN114767786B (zh) | 一种防治液氮超低温冻伤的外用生肤油及其制备方法和应用 | |
RU2759478C1 (ru) | Способ лечения пациентов с хронической ишемией нижних конечностей | |
KR101080290B1 (ko) | 자가혈 필러 제조방법 | |
Bednarska et al. | The use of platelet-rich-plasma in aesthetic and regenerative medicine | |
Lee et al. | Various treatments of scar | |
CN116077565A (zh) | 一种促创面愈合制剂及其制备方法 | |
KR20170098676A (ko) | 피부 외상 치료용 중국 의약 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16772637 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2017509909 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 16772637 Country of ref document: EP Kind code of ref document: A1 |