ITRM20120339A1 - USE OF MY (MELANOMA INHIBITOR ACTIVITY) FOR THE TREATMENT OF SKIN IPERPIGMENTATION AND FOR THE COSMETIC WHITENING OF THE SKIN - Google Patents
USE OF MY (MELANOMA INHIBITOR ACTIVITY) FOR THE TREATMENT OF SKIN IPERPIGMENTATION AND FOR THE COSMETIC WHITENING OF THE SKIN Download PDFInfo
- Publication number
- ITRM20120339A1 ITRM20120339A1 IT000339A ITRM20120339A ITRM20120339A1 IT RM20120339 A1 ITRM20120339 A1 IT RM20120339A1 IT 000339 A IT000339 A IT 000339A IT RM20120339 A ITRM20120339 A IT RM20120339A IT RM20120339 A1 ITRM20120339 A1 IT RM20120339A1
- Authority
- IT
- Italy
- Prior art keywords
- skin
- mia
- fragments
- cosmetic
- melanocytes
- Prior art date
Links
- 239000002537 cosmetic Substances 0.000 title claims description 20
- 230000002087 whitening effect Effects 0.000 title claims description 15
- 238000011282 treatment Methods 0.000 title claims description 14
- 230000000694 effects Effects 0.000 title description 20
- 201000001441 melanoma Diseases 0.000 title description 12
- 239000003112 inhibitor Substances 0.000 title 1
- 230000000699 topical effect Effects 0.000 claims description 20
- 239000012634 fragment Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- 206010040865 Skin hyperpigmentation Diseases 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 102100022185 Melanoma-derived growth regulatory protein Human genes 0.000 description 60
- 101710195116 Melanoma-derived growth regulatory protein Proteins 0.000 description 60
- 210000003491 skin Anatomy 0.000 description 48
- 210000002752 melanocyte Anatomy 0.000 description 23
- 239000000047 product Substances 0.000 description 16
- 208000000069 hyperpigmentation Diseases 0.000 description 13
- 230000003810 hyperpigmentation Effects 0.000 description 13
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 8
- 206010047642 Vitiligo Diseases 0.000 description 8
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 7
- 108010044426 integrins Proteins 0.000 description 7
- 102000006495 integrins Human genes 0.000 description 7
- 208000003351 Melanosis Diseases 0.000 description 6
- 102000003425 Tyrosinase Human genes 0.000 description 6
- 108060008724 Tyrosinase Proteins 0.000 description 6
- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-RMPHRYRLSA-N 0.000 description 6
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 230000009471 action Effects 0.000 description 5
- 210000002469 basement membrane Anatomy 0.000 description 5
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000010534 mechanism of action Effects 0.000 description 5
- 206010008570 Chloasma Diseases 0.000 description 4
- 229960000271 arbutin Drugs 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000000215 hyperchromic effect Effects 0.000 description 4
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 description 4
- 229960004705 kojic acid Drugs 0.000 description 4
- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241001340526 Chrysoclista linneella Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 206010064127 Solar lentigo Diseases 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- -1 hydroquinone glycoside Chemical class 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 230000003061 melanogenesis Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-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
- 208000023268 Becker naevus Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 206010014970 Ephelides Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 101000620359 Homo sapiens Melanocyte protein PMEL Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000021710 Hyperpigmentation disease Diseases 0.000 description 2
- 102100022430 Melanocyte protein PMEL Human genes 0.000 description 2
- 206010027145 Melanocytic naevus Diseases 0.000 description 2
- 208000007256 Nevus Diseases 0.000 description 2
- 208000012641 Pigmentation disease Diseases 0.000 description 2
- 206010040829 Skin discolouration Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000007712 Tinea Versicolor Diseases 0.000 description 2
- 206010056131 Tinea versicolour Diseases 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229940061720 alpha hydroxy acid Drugs 0.000 description 2
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 238000004061 bleaching Methods 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 108010032337 diaminobenzidine peroxidase Proteins 0.000 description 2
- 238000002845 discoloration Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 230000036074 healthy skin Effects 0.000 description 2
- SUSRLLXAXAIZPH-OBPIAQAESA-N hydroquinone beta-D-glucopyranoside Natural products OC[C@H]1O[C@@H](Cc2ccc(O)cc2)[C@H](O)[C@@H](O)[C@@H]1O SUSRLLXAXAIZPH-OBPIAQAESA-N 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 208000022742 linear and whorled nevoid hypermelanosis Diseases 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 210000000434 stratum corneum Anatomy 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- 235000012871 Arctostaphylos uva ursi Nutrition 0.000 description 1
- 240000006439 Aspergillus oryzae Species 0.000 description 1
- 235000002247 Aspergillus oryzae Nutrition 0.000 description 1
- 241000195940 Bryophyta Species 0.000 description 1
- 235000007575 Calluna vulgaris Nutrition 0.000 description 1
- 206010007191 Capillary fragility Diseases 0.000 description 1
- 206010072036 Congenital melanocytic naevus Diseases 0.000 description 1
- 206010067248 Congenital naevus Diseases 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- 206010053695 Diabetic dermopathy Diseases 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 241000208421 Ericaceae Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 108010042918 Integrin alpha5beta1 Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 206010025421 Macule Diseases 0.000 description 1
- 201000009139 Mongolian Spot Diseases 0.000 description 1
- 101100422515 Mus musculus Stk32c gene Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 208000009077 Pigmented Nevus Diseases 0.000 description 1
- 206010057041 Poikiloderma Diseases 0.000 description 1
- 206010036229 Post inflammatory pigmentation change Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010040799 Skin atrophy Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 206010070835 Skin sensitisation Diseases 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- QHNORJFCVHUPNH-UHFFFAOYSA-L To-Pro-3 Chemical compound [I-].[I-].S1C2=CC=CC=C2[N+](C)=C1C=CC=C1C2=CC=CC=C2N(CCC[N+](C)(C)C)C=C1 QHNORJFCVHUPNH-UHFFFAOYSA-L 0.000 description 1
- 244000003892 Vaccinium erythrocarpum Species 0.000 description 1
- SXEHKFHPFVVDIR-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=C(NN)C=C1 SXEHKFHPFVVDIR-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 201000010272 acanthosis nigricans Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003127 anti-melanomic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000011138 biotechnological process Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000007854 depigmenting agent Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 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 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 229940114123 ferulate Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 238000007489 histopathology method Methods 0.000 description 1
- 150000001261 hydroxy acids Chemical class 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 208000012929 large congenital melanocytic nevus Diseases 0.000 description 1
- 238000013532 laser treatment Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000002780 melanosome Anatomy 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 108091005601 modified peptides Proteins 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 235000011929 mousse Nutrition 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008756 pathogenetic mechanism Effects 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 231100000760 phototoxic Toxicity 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 210000004694 pigment cell Anatomy 0.000 description 1
- 201000000508 pityriasis versicolor Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 201000003385 seborrheic keratosis Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007390 skin biopsy Methods 0.000 description 1
- 230000004215 skin function Effects 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 231100000370 skin sensitisation Toxicity 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000036561 sun exposure Effects 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical class OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
Description
Descrizione dell’Invenzione: “Uso di MIA (Attività inibitoria melanoma) per il trattamento della iper-pigmentazione cutanea e per lo sbiancamento cosmetico della pelle†Description of the Invention: â € œUse of MIA (Melanoma inhibitory activity) for the treatment of skin hyper-pigmentation and for cosmetic skin whiteningâ €
DESCRIZIONE DESCRIPTION
Sfondo dell’Invenzione Background of the Invention
La presente invenzione si riferisce sia al campo farmaceutico che a quello cosmetico in quanto si riferisce all’uso di MIA (Attività Inibitoria Melanoma) o frammenti della stessa per il trattamento dell’iper-pigmentazione cutanea e alle relative composizioni farmaceutiche che la comprendono, nonché l’uso cosmetico di MIA o frammenti della stessa per lo sbiancamento della pelle e le relative composizioni cosmetiche che la comprendono. The present invention refers to both the pharmaceutical and cosmetic fields as it refers to the use of MIA (Melanoma Inhibitory Activity) or fragments thereof for the treatment of skin hyper-pigmentation and to the related pharmaceutical compositions which include it , as well as the cosmetic use of MIA or fragments thereof for the whitening of the skin and the related cosmetic compositions that include it.
Iper-pigmentazione cutanea (o ipercromia) Skin hyper-pigmentation (or hyperchromia)
Si definisce iper-pigmentazione cutanea (o ipercromia) un alterato e circoscritto aumento del colore della pelle rispetto alla cute circostante normo-pigmentata. Esempi di iper-pigmentazioni cutanee sono rappresentati da: melasma, lentigo solari, lentigo senili, nevi (nevo melanocitico congenito, nevo melanocitico acquisito, nevo di Becker, nevus spilus, macchia mongolica), poichilodermia di Civatte, lentiggini, efelidi, chiazze caffe-latte, ipercromie post-infiammatorie o posttraumatiche o indotte da farmaci o indotte da malattie sistemiche o indotte da gravidanza. Skin hyper-pigmentation (or hyperchromia) is defined as an altered and limited increase in skin color compared to the surrounding normal-pigmented skin. Examples of skin hyper-pigmentations are represented by: melasma, solar lentigo, senile lentigo, nevi (congenital melanocytic nevus, acquired melanocytic nevus, Becker's nevus, nevus spilus, Mongolian spot), Civatte poikiloderma, freckles, freckles, coffee spots milk, post-inflammatory or post-traumatic or drug-induced hyperchromias or induced by systemic or pregnancy-induced diseases.
Tali manifestazioni pigmentarie sono dovute ad un aumento della deposizione cheratinocitaria di melanina da parte dei melanociti presenti nella zona iperpigmentata (iper-pigmentazioni superficiali) o ad un loro aumento numerico in seguito ad uno o più stimoli, non ancora ben definiti (iper-pigmentazioni profonde) (Stulberg DL, Clark N, Tovey D. Common hyperpigmentation disorders in adults: Part I. Diagnostic approach, café au lait macules, diffuse hyperpigmentation, sun exposure, and phototoxic reactions. Am Fam Physician.2003; 68: 1955-60. Stulberg These pigmentary manifestations are due to an increase in the keratinocyte deposition of melanin by the melanocytes present in the hyperpigmented area (superficial hyper-pigmentations) or to their numerical increase following one or more stimuli, not yet well defined (deep hyper-pigmentation ) (Stulberg DL, Clark N, Tovey D. Common hyperpigmentation disorders in adults: Part I. Diagnostic approach, cafà © au lait macules, diffuse hyperpigmentation, sun exposure, and phototoxic reactions. Am Fam Physician. 2003; 68: 1955-60 Stulberg
DL, Clark N, Tovey D. Common hyperpigmentation disorders in adults: Part II. Melanoma, seborrheic keratoses, acanthosis nigricans, melasma, diabetic dermopathy, tinea versicolor, and postinflammatory hyperpigmentation. Am Fam Physician.2003; 68: 1963-8). DL, Clark N, Tovey D. Common hyperpigmentation disorders in adults: Part II. Melanoma, seborrheic keratoses, acanthosis nigricans, melasma, diabetic dermopathy, tinea versicolor, and postinflammatory hyperpigmentation. Am Fam Physician. 2003; 68: 1963-8).
Terapie per la iper-pigmentazione cutanea Skin hyper-pigmentation therapies
Ad oggi per la terapia delle ipercromie cutanee sono disponibili prodotti topici, quali quelli contenenti idrochinone, il quale agisce sia bloccando la melanogenesi come substrato alternativo della tirosinasi, sia agendo come agente citotossico selettivo per i melanociti. L'impiego dell'idrochinone a dosi elevate dà spesso fenomeni irritativi e presenta il rischio di tossicità correlato all'uso prolungato (Tse TW. Hydroquinone for skin lightening: safety profile, duration of use and when should we stop? J Dermatolog Treat. 2010; 21 :272-5). Altri prodotti topici contengono arbutina, che à ̈ un glucoside idrochinonico, che si trova in natura nelle foglie dell'uva ursina e nelle sommità fiorite dell'erica e di altre Ericaceae; l’azione dell’arbutina à ̈ dovuta alla sua capacità di competere per il legame con i recettori della tirosinasi, la sua efficacia à ̈ scarsa (Masse MO, Duvallet V, Borremans M, Goeyens L. Identification and quantitative analysis of kojic acid and arbutine in skin-whitening cosmetics. Int J Cosmet Sci.2001; 23: 219-32). To date, topical products are available for the therapy of skin hyperchromias, such as those containing hydroquinone, which acts both by blocking melanogenesis as an alternative substrate for tyrosinase, and by acting as a selective cytotoxic agent for melanocytes. The use of hydroquinone at high doses often causes irritation and presents the risk of toxicity related to prolonged use (Tse TW. Hydroquinone for skin lightening: safety profile, duration of use and when should we stop? J Dermatolog Treat. 2010 ; 21: 272-5). Other topical products contain arbutin, which is a hydroquinone glycoside, which occurs naturally in the leaves of bearberry and in the flowering tops of heather and other Ericaceae; the action of arbutin is due to its ability to compete for binding with tyrosinase receptors, its efficacy is poor (Masse MO, Duvallet V, Borremans M, Goeyens L. Identification and quantitative analysis of kojic acid and arbutine in skin-whitening cosmetics. Int J Cosmet Sci. 2001; 23: 219-32).
Ulteriori prodotti topici contengono alfa-idrossiacidi, come per esempio acido citrico, lattico, glicolico, tricloroacetico, i quali intervengono nei processi di rinnovamento dello strato corneo, consentendo di rallentare, se non di evitare, la ipercheratinizzazione. Alte concentrazioni di alfa-idrossiacidi hanno un'azione prevalentemente esfoliante, con una conseguente riduzione dello spessore dello strato corneo con un effetto schiarente generalizzato. Detti prodotti hanno scarsa efficacia sulle iper-pigmentazioni profonde e possibili fenomeni di sensibilizzazione cutanea e irritazione prolungata (Kornhauser A, Coelho SG, Hearing VJ. Applications of hydroxy acids: classification, mechanisms, and photoactivity. Clin Cosmet Investig Dermatol.2010; 3: 135-42). Additional topical products contain alpha-hydroxy acids, such as citric, lactic, glycolic, trichloroacetic acids, which intervene in the renewal processes of the stratum corneum, allowing to slow down, if not avoid, hyperkeratinization. High concentrations of alpha-hydroxy acids have a predominantly exfoliating action, with a consequent reduction in the thickness of the stratum corneum with a generalized lightening effect. These products have little effect on deep hyper-pigmentation and possible phenomena of skin sensitization and prolonged irritation (Kornhauser A, Coelho SG, Hearing VJ. Applications of hydroxy acids: classification, mechanisms, and photoactivity. Clin Cosmet Investig Dermatol. 2010; 3: 135-42).
Altri prodotti ad uso topico contengono acido retinoico, il cui meccanismo d'azione à ̈ strettamente collegato alla attività esfoliante; sono coinvolti anche l'allontanamento e la dispersione dei granuli di melanina dai cheratinociti. Anche questi prodotti mostrano un’efficacia scarsa nelle iper-pigmentazioni profonde e possono causare fototossicità in caso di esposizione ai raggi UV (Ortonne JP. Retinoid therapy of pigmentary disorders. Dermatol Ther.2006; 19: 280-8). Other topical products contain retinoic acid, whose mechanism of action is closely linked to exfoliating activity; the removal and dispersion of melanin granules from keratinocytes are also involved. These products also show poor efficacy in deep hyper-pigmentation and can cause phototoxicity in case of UV exposure (Ortonne JP. Retinoid therapy of pigmentary disorders. Dermatol Ther.2006; 19: 280-8).
Esistono anche prodotti ad uso topico contenenti alfa-tocoferolo, il quale blocca l'attacco dei radicali liberi sugli acidi grassi insaturi ed inibisce l'attività della tirosinasi svolgendo la funzione di schiarente cutaneo, ma con scarsa efficacia sulle iper-pigmentazioni sia superficiali che profonde (Funasaka Y, Komoto M, Ichihashi M. Depigmenting effect of alpha-tocopheryl ferulate on normal human melanocytes. Pigment Cell Res.2000; 8: 170-4). There are also products for topical use containing alpha-tocopherol, which blocks the attack of free radicals on unsaturated fatty acids and inhibits the activity of tyrosinase performing the function of skin lightening, but with little effect on both superficial and deep hyper-pigmentation. (Funasaka Y, Komoto M, Ichihashi M. Depigmenting effect of alpha-tocopheryl ferulate on normal human melanocytes. Pigment Cell Res. 2000; 8: 170-4).
Sono disponibili anche prodotti a base di acido azelaico, che à ̈ prodotto in natura dal lievito Pityrosporum ovalis responsabile nell'uomo della pityriasis versicolor una patologia cutanea caratterizzata dalla comparsa di chiazze bianche dovuta all'azione depigmentante dell'acido azelaico. Il meccanismo d'azione si basa sull'inibizione competitiva dell'attività della tirosinasi. E’ noto che detti prodotti Impiegano molto tempo prima di mostrare un certo grado di efficacia e sono poco efficaci sulle iper-pigmentazioni profonde (Nazzaro-Porro M, Passi S, Zina G, Breathnach AS. The depigmenting effect of azelaic acid. Arch Dermatol.1990; 126: 1649-51). There are also products based on azelaic acid, which is naturally produced by the yeast Pityrosporum ovalis responsible for pityriasis versicolor in humans, a skin disease characterized by the appearance of white patches due to the depigmenting action of azelaic acid. The mechanism of action is based on the competitive inhibition of tyrosinase activity. It is known that these products take a long time to show a certain degree of efficacy and are not very effective on deep hyper-pigmentation (Nazzaro-Porro M, Passi S, Zina G, Breathnach AS. The depigmenting effect of azelaic acid. Arch Dermatol. 1990; 126: 1649-51).
Altri prodotti ad uso topico contengono acido ascorbico e/o suoi derivati, i quali non inibiscono direttamente la tirosinasi, bensì agiscono come riducenti sugli intermedi della melanina, bloccando a vari livelli le reazioni ossidative della melanogenesi. Detti prodotti mostrano scarsa efficacia sulle iper-pigmentazioni profonde (Marini A, Farwick M, Grether-Beck S, Brenden H, Felsner I, Jaenicke T, Weber M, Schild J, Maczkiewitz U, Köhler T, Bonfigli A, Pagani V, Krutmann J. Modulation of skin pigmentation by the tetrapeptide PKEK: in vitro and in vivo evidence for skin whitening effects. Exp Dermatol.2012; 21: 140-6) Other topical products contain ascorbic acid and / or its derivatives, which do not directly inhibit tyrosinase, but act as reducing agents on melanin intermediates, blocking the oxidative reactions of melanogenesis at various levels. These products show poor efficacy on deep hyper-pigmentations (Marini A, Farwick M, Grether-Beck S, Brenden H, Felsner I, Jaenicke T, Weber M, Schild J, Maczkiewitz U, Köhler T, Bonfigli A, Pagani V , Krutmann J. Modulation of skin pigmentation by the tetrapeptide PKEK: in vitro and in vivo evidence for skin whitening effects. Exp Dermatol. 2012; 21: 140-6)
Esitono anche prodotti per uso topico contenenti acido kojico, il quale inattiva la tirosinasi chelando gli ioni rame. L’acido kojico à ̈ prodotto attraverso processi biotecnologici da Aspergillus Oryzae, ha scarsa efficacia nelle iper-pigmentazioni sia superficiali che profonde e presenta frequenti fenomeni di irritazione cutanea (Masse MO, Duvallet V, Borremans M, Goeyens L. Identification and quantitative analysis of kojic acid and arbutine in skin-whitening cosmetics. Int J Cosmet Sci. There are also topical products containing kojic acid, which inactivates tyrosinase by chelating copper ions. Kojic acid is produced through biotechnological processes by Aspergillus Oryzae, has poor efficacy in both superficial and deep hyper-pigmentations and presents frequent skin irritation phenomena (Masse MO, Duvallet V, Borremans M, Goeyens L. Identification and quantitative analysis of kojic acid and arbutine in skin-whitening cosmetics. Int J Cosmet Sci.
2001; 23: 219-32). 2001; 23: 219-32).
Infine i corticosteroidi topici quando applicati a lungo possono dare uno sbiancamento per inibizione della melanogenesi. Essi sono gravati da moltissimi effetti collaterali locali come la atrofia cutanea e la fragilità capillare e sistemici come l’osteoporosi, la sindrome di Cushing iatrogena, l’ipertensione ed il ritardo di crescita Finally, topical corticosteroids, when applied for a long time, can give a whitening by inhibiting melanogenesis. They are burdened by many local side effects such as skin atrophy and capillary fragility and systemic such as osteoporosis, iatrogenic Cushing's syndrome, hypertension and growth retardation.
(Nnoruka E, Okoye O.Topical steroid abuse: its use as a depigmenting agent. J Natl Med Assoc.2006; 98: 934-9). (Nnoruka E, Okoye O.Topical steroid abuse: its use as a depigmenting agent. J Natl Med Assoc. 2006; 98: 934-9).
In alternativa ai prodotti per uso topico la terapia delle ipercromie cutanee può essere fatta con peeling chimici e/o trattamenti laser, entrambi gravati da effetti collaterali come gli esiti cicatriziali, le discromie in senso ipo- o ipercromico e gli arrossamenti persistenti (Kar HK, Gupta L, Chauhan A. A comparative study on efficacy of high and low fluence Q-switched Nd:YAG laser and glycolic acid peel in melasma. Indian J Dermatol Venereol Leprol.2012; 78: 165-71). As an alternative to topical products, skin hyperchromia therapy can be done with chemical peels and / or laser treatments, both burdened by side effects such as scarring, hypo- or hyperchromic discoloration and persistent redness (Kar HK, Gupta L, Chauhan A. A comparative study on efficacy of high and low fluence Q-switched Nd: YAG laser and glycolic acid peel in melasma. Indian J Dermatol Venereol Leprol. 2012; 78: 165-71).
Sbiancamento della pelle Skin whitening
I prodotti utilizzati nello sbiancamento cutaneo sono gli stessi prodotti topici utilizzati per le ipercromie. Agendo su una superficie cutanea più ampia, sono gravati da maggiori effetti collaterali dovuti al loro maggiore assorbimento sistemico. The products used in skin whitening are the same topical products used for hyperchromias. By acting on a larger skin surface, they are burdened by greater side effects due to their greater systemic absorption.
MIA (Melanoma Inhibitory Activity) MIA (Melanoma Inhibitory Activity)
E’ noto che la disseminazione metastatica del melanoma maligno (un tumore di derivazione melanocitaria) può essere determinata da un distacco attivo di cellule tumorali e che tale distacco può essere causato da una piccola proteina secreta dalle cellule melanomatose chiamata MIA – Attività Inibitoria Melanoma (Melanoma Inhibitory Activity) (Bosserhoff AK, Stoll R, Sleeman JP, Bataille F, Buettner R, Holak TA. Active detachment involves inhibition of cell-matrix contacts of malignant melanoma cells by secretion of melanoma inhibitory activity. Lab Invest 2003; 83: 1583-94). E’ stato dimostrato che MIA interagisce con l’integrina alpha5beta1 (Bauer R, Humphries M, Fassler R, Winklmeier A, Craig SE, Bosserhoff AK. Regulation of integrin activity by MIA. J Biol Chem 2006; 281: 11669-77). L’interazione tra una proteina autoprodotta dai melanociti maligni (MIA) e una molecola di adesione dei melanociti stessi (l’integrina alpha5beta1) à ̈ quindi responsabile di un distacco attivo dei melanociti neoplastici nel melanoma maligno. It is known that the metastatic dissemination of malignant melanoma (a tumor of melanocyte origin) can be caused by an active detachment of tumor cells and that this detachment can be caused by a small protein secreted by melanoma cells called MIA - Inhibitory activity Melanoma (Melanoma Inhibitory Activity) (Bosserhoff AK, Stoll R, Sleeman JP, Bataille F, Buettner R, Holak TA. Active detachment involves inhibition of cell-matrix contacts of malignant melanoma cells by secretion of melanoma inhibitory activity. Lab Invest 2003; 83 : 1583-94). MIA has been shown to interact with integrin alpha5beta1 (Bauer R, Humphries M, Fassler R, Winklmeier A, Craig SE, Bosserhoff AK. Regulation of integrin activity by MIA. J Biol Chem 2006; 281: 11669-77 ). The interaction between a protein self-produced by malignant melanocytes (MIA) and an adhesion molecule of the melanocytes themselves (integrin alpha5beta1) is therefore responsible for an active detachment of neoplastic melanocytes in malignant melanoma.
Nella domanda italiana N. RM2011A000134 a nome dello stesso richiedente, à ̈ stato descritto l’uso di peptidi, peptidi modificati e anticorpi o frammenti di anticorpi che inibiscono l’attività di MIA per il trattamento della vitiligine, nonché il loro uso come marcatori dello sviluppo della vitiligine e come strumenti per il controllo di pazienti con vitiligine e anche per la prevenire l’insorgenza di chiazze vitiligoidee e per rendere efficaci le terapie già note. Infatti lo stesso richiedente ha mostrato che la proteina MIA à ̈ presente in pazienti affetti da vitiligine e non nelle persone sane e che à ̈ coinvolta nel reale meccanismo patogenetico che porta alla formazione delle In the Italian application No. RM2011A000134 in the name of the same applicant, the use of peptides, modified peptides and antibodies or antibody fragments that inhibit the activity of MIA for the treatment of vitiligo, as well as their use, has been described as markers of the development of vitiligo and as tools for the control of patients with vitiligo and also to prevent the onset of vitiligoid patches and to make known therapies effective. In fact, the same applicant showed that the MIA protein is present in patients suffering from vitiligo and not in healthy people and that it is involved in the real pathogenetic mechanism that leads to the formation of
chiazze di vitiligine. In particolare, il richiedente ha dimostrato che MIA à ̈ presente nelle macchie ipo-pigmentate della vitiligine di soggetti affetti da questa patologia, e questa molecola à ̈ responsabile del meccanismo patogenico della malattia. patches of vitiligo. In particular, the applicant demonstrated that MIA is present in the hypo-pigmented spots of vitiligo of subjects affected by this pathology, and this molecule is responsible for the pathogenic mechanism of the disease.
La presenza di MIA à ̈ stata esclusa in cute di soggetti sani mentre à ̈ stato accertato che MIA viene prodotto fisiologicamente in corso di accrescimento delle cartilagini o in corso di gravidanza. Non si conoscono ancora le funzioni di MIA in tali ambiti. E’ stato inoltre riscontrata la presenza di MIA a livello sanguigno (alla concentrazione compresa tra 1.8 e 7.6 ng/ml) anche in soggetti sani, segno che MIA à ̈ comunemente presente nel sangue umano ma assente a livello cutaneo (Bosserhoff AK, Kaufmann M, Kaluza B, Bartke I, Zirngibl H, Hein R, Stolz W, Buettner R. Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma. Cancer Res.1997; 57: 3149-53). The presence of MIA has been excluded in the skin of healthy subjects while it has been ascertained that MIA is produced physiologically during cartilage growth or during pregnancy. The functions of MIA in these areas are not yet known. The presence of MIA was also found in the blood (at a concentration between 1.8 and 7.6 ng / ml) even in healthy subjects, a sign that MIA is commonly present in human blood but absent in the skin (Bosserhoff AK, Kaufmann M, Kaluza B, Bartke I, Zirngibl H, Hein R, Stolz W, Buettner R. Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma. Cancer Res. 1997; 57: 3149-53).
Il meccanismo di azione di MIA che prevede l’interazione di tale molecola con le integrine alpha5beta1 melanocitarie à ̈ stato verificato solo in corso di patologie cutanee come la vitiligine (Domanda di Brevetto in Italia N. RM2011A000134) ed il melanoma (Bauer R, Humphries M, Fassler R, Winklmeier A, Craig SE, Bosserhoff AK. Regulation of integrin activity by MIA. J Biol Chem 2006; 281: 11669-77). The mechanism of action of MIA which involves the interaction of this molecule with the melanocytic alpha5beta1 integrins has been verified only in the course of skin diseases such as vitiligo (Patent Application in Italy No. RM2011A000134) and melanoma (Bauer R, Humphries M, Fassler R, Winklmeier A, Craig SE, Bosserhoff AK. Regulation of integrin activity by MIA. J Biol Chem 2006; 281: 11669-77).
Sebbene la letteratura scientifica non abbia assegnato a MIA alcuna funzione a livello cutaneo in soggetti sani (Bosserhoff AK, Kaufmann M, Kaluza B, Bartke I, Zirngibl H, Hein R, Stolz W, Buettner R. Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma. Cancer Res. 1997; 57: 3149-53) lo stesso inventore ha investigato se nella cute affetta da ipercromia o normopigmentata di soggetti sani MIA, o frammenti della stessa, poteva essere impiegata per il trattamento di tali iper-pigmentazioni cutanee o per ottenere uno sbiancamento cosmetico della cute. Although the scientific literature has not assigned any skin function to MIA in healthy subjects (Bosserhoff AK, Kaufmann M, Kaluza B, Bartke I, Zirngibl H, Hein R, Stolz W, Buettner R. Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma. Cancer Res. 1997; 57: 3149-53) the same inventor investigated whether in hyperchromic or normopigmented skin of healthy subjects MIA, or fragments thereof, could be used for the treatment of such hyperchromic - skin pigmentation or to obtain a cosmetic whitening of the skin.
Problema tecnico Technical problem
Lo stesso inventore, sorprendentemente ed in modo inatteso ha trovato che la proteina MIA, o frammenti della stessa, à ̈ capace di eliminare i melanociti di cute sana o iper-pigmentata in quanto à ̈ in grado di rompere i legami tra la membrana basale e tali melanociti alterati favorendo il loro rimpiazzo da parte dei melanociti sani circostanti. The same inventor, surprisingly and unexpectedly, found that the MIA protein, or fragments thereof, is capable of eliminating the melanocytes of healthy or hyper-pigmented skin as it is able to break the bonds between the basement membrane and these altered melanocytes favoring their replacement by the surrounding healthy melanocytes.
A tutt’oggi, non sono disponibili delle terapie mirate diverse dai trattamenti topici, il laser e i peeling chimici, come precedentemente descritto. To date, there are no targeted therapies available other than topical treatments, lasers and chemical peels, as previously described.
Il problema tecnico della presente invenzione à ̈ di fornire un trattamento delle ipercromie cutanee che non mostri gli effetti collaterali delle terapie già note sopra descritte, come la sovente inefficacia del trattamento, la tossicità , la teratogenicità , la formazione di cicatrici, l’indizione di discromie ipocromiche o ipercromiche della zona trattata e gli arrossamenti persistenti. The technical problem of the present invention is to provide a treatment of skin hyperchromias that does not show the side effects of the already known therapies described above, such as the often ineffectiveness of the treatment, toxicity, teratogenicity, scar formation, induction of hypochromic or hyperchromic discolorations of the treated area and persistent redness.
Vi à ̈ inoltre una forte esigenza di fornire trattamenti cosmetici adeguati in alternativa ai trattamenti medici, in particolare nell’uso per lo sbiancamento (bleaching), metodica utilizzata da soggetti a fototipo scuro per rendere più bianca la cute e anche nelle vitiligini per decolorare le isole di cute normo-pigmentata in maniera da rendere omogeneo il colorito cutaneo. There is also a strong need to provide adequate cosmetic treatments as an alternative to medical treatments, in particular in the use for whitening (bleaching), a method used by subjects with a dark phototype to make the skin whiter and also in vitiligo to bleach. the islands of normo-pigmented skin in order to make the skin complexion homogeneous.
Oggetto dell’invenzione Object of the invention
È pertanto oggetto della presente invenzione l’uso di MIA o frammenti della stessa per il trattamento delle dell’iper-pigmentazioni cutanee. MIA à ̈ la sequenza di 131 amminoacidi con accession number CAG46449.1 (GenBank). Therefore, the object of the present invention is the use of MIA or fragments thereof for the treatment of skin hyper-pigmentations. MIA is the 131 amino acid sequence with accession number CAG46449.1 (GenBank).
Costituiscono un ulteriore oggetto della presente invenzione composizioni farmaceutiche comprendenti MIA o frammenti della stessa e opportuni eccipienti farmaceuticamente accettabili. Dette composizioni sono preferibilmente adatte all’uso iniettivo, preferibilmente sub-cutaneo e topico. A further object of the present invention are pharmaceutical compositions comprising MIA or fragments thereof and suitable pharmaceutically acceptable excipients. Said compositions are preferably suitable for injective use, preferably subcutaneous and topical.
Costituisce un ulteriore oggetto della presente invenzione l’uso cosmetico, per lo sbiancamento della pelle. A further object of the present invention is the cosmetic use, for skin whitening.
Costituiscono un ulteriore oggetto della presente invenzione composizioni cosmetiche, preferibilmente ad uso topico, che comprendono MIA o frammenti della stessa. A further object of the present invention is cosmetic compositions, preferably for topical use, which comprise MIA or fragments thereof.
Ulteriori caratteristiche della presente invenzione saranno chiare dalla seguente descrizione dettagliata con riferimento agli esempi sperimentali e alle tavole dei disegni allegate. Further characteristics of the present invention will become clear from the following detailed description with reference to the experimental examples and to the accompanying drawings.
Breve descrizione delle figure Brief description of the figures
La Figura 1 mostra il meccanismo d’azione di MIA sull’iperpigmentazione, in cui il quadro (A) rappresenta l’area di iperpigmentazione cutanea dovuta a melanociti alterati; il quadro (B) mostra l’applicazione di una composizione comprendente MIA, il quadro (C) distacco dei melanociti alterati, il quadro (D) mostra ricolonizzazione della membrana basale da parte dei melanociti normali ed il quadro (E) mostra la normalizzazione del colorito cutaneo. Figure 1 shows the mechanism of action of MIA on hyperpigmentation, in which picture (A) represents the area of skin hyperpigmentation due to altered melanocytes; picture (B) shows the application of a composition including MIA, picture (C) detachment of altered melanocytes, picture (D) shows recolonization of the basement membrane by normal melanocytes and picture (E) shows normalization of the skin complexion.
La Figura 2 mostra il meccanismo d’azione di MIA per lo sbiancamento della cute, in cui il quadro (A) rappresenta la cute normopigmentata; il quadro (B) mostra l’applicazione di una composizione comprendente MIA, il quadro (C) distacco dei melanociti su cui à ̈ stata applicata la formulazione a base di MIA e il quadro (D) mostra il conseguente sbiancamento cutaneo. Figure 2 shows the mechanism of action of MIA for skin whitening, in which frame (A) represents normal pigmented skin; picture (B) shows the application of a composition including MIA, picture (C) detachment of melanocytes on which the MIA-based formulation has been applied and picture (D) shows the consequent skin whitening.
Descrizione dettagliata dell’Invenzione Detailed description of the Invention
Definizioni Definitions
Ai sensi della presente invenzione, per ipercromia o iper-pigmentazione cutanea si intende un alterato e circoscritto aumento del colore della pelle rispetto alla cute circostante normo-pigmentata. According to the present invention, by skin hyperchromia or hyper-pigmentation is meant an altered and limited increase in the color of the skin with respect to the surrounding normal-pigmented skin.
Ai sensi della presente invenzione, per sbiancamento (bleaching) si intende l’uso di sostanze chimiche applicate topicamente al fine di indurre uno schiarimento del colorito cutaneo o fornire un colorito uniforme della pelle diminuendo la concentrazione di melanina. According to the present invention, bleaching refers to the use of chemicals applied topically in order to induce a lightening of the skin color or to provide a uniform color of the skin by decreasing the concentration of melanin.
Ai sensi della presente invenzione si intende per frammenti di MIA frammenti funzionali di MIA in grado di produrre l’effetto desiderato, cioà ̈ il trattamento dell’iperpigmentazione o ipercromia cutanea e lo sbiancamento della pelle. According to the present invention, fragments of MIA are meant functional fragments of MIA capable of producing the desired effect, ie the treatment of skin hyperpigmentation or hyperchromia and skin whitening.
È pertanto oggetto della presente invenzione l’uso di MIA, o frammenti della stessa, per il trattamento dell’iper-pigmentazione o ipercromia cutanea. Therefore, the object of the present invention is the use of MIA, or fragments thereof, for the treatment of skin hyper-pigmentation or hyperchromia.
Costituiscono un ulteriore oggetto della presente invenzione composizioni farmaceutiche comprendenti MIA, o frammenti della stessa, e opportuni eccipienti farmaceuticamente accettabili. A further object of the present invention are pharmaceutical compositions comprising MIA, or fragments thereof, and suitable pharmaceutically acceptable excipients.
Poiché à ̈ preferibile la veicolazione di MIA dall’epidermide fino alla giunzione dermoepidermica dove sono localizzati i melanociti che causano l’alterazione cutanea, à ̈ preferibile la formulazione delle composizioni farmaceutiche per somministrazione subcutanea o per l’uso topico. Since it is preferable to convey MIA from the epidermis to the dermal-epidermal junction where the melanocytes that cause skin alteration are located, the formulation of pharmaceutical compositions for subcutaneous administration or for topical use is preferable.
Per la veicolazione topica sono preferibili composizioni in cui sono presenti frammenti di MIA. For topical delivery, compositions in which MIA fragments are present are preferable.
La composizione per l’uso topico si presenta sotto una farmaceutica di impiego dermatologico, quale unguento, crema, emulsione, schiuma, mousse, lozione, gel o pasta atte ad essere applicate sulla pelle per ottenere l’azione suddetta. The composition for topical use is presented under a pharmaceutical for dermatological use, such as ointment, cream, emulsion, foam, mousse, lotion, gel or paste designed to be applied to the skin to obtain the aforementioned action.
L’esperto del ramo sarà in grado di scegliere gli opportuni eccipienti oleosi, idrofili ed emulsionanti da aggiungere al principio attivo nella preparazione delle suddette forme farmaceutiche. The skilled in the art will be able to choose the suitable oily, hydrophilic and emulsifying excipients to add to the active principle in the preparation of the aforesaid pharmaceutical forms.
La composizione per la somministrazione subcutanea si presenta sotto la forma di soluzione atta ad essere iniettata sottocute per ottenere l’azione suddetta. The composition for subcutaneous administration is presented in the form of a solution suitable to be injected under the skin to obtain the aforementioned action.
Nella formulazione iniettiva MIA o frammenti della stessa sono somministrati come soluzione o dispersione acquosa sterile, priva di pirogeni e come polvere sterile per la ricostituzione in una soluzione o dispersione sterile. In the MIA injection formulation or fragments thereof are administered as a sterile, pyrogen-free aqueous solution or dispersion and as a sterile powder for reconstitution into a sterile solution or dispersion.
Possono essere aggiunti agenti regolatori della tonicità , come cloruro di sodio, glicerolo e vari zuccheri. Possono essere inclusi anche stabilizzatori o idonei conservanti farmaceuticamente accettabili. Tonicity regulating agents such as sodium chloride, glycerol and various sugars can be added. Stabilizers or suitable pharmaceutically acceptable preservatives may also be included.
Possono essere fornite formulazioni in forma di dosaggio unitario, come soluzione sterile in una provetta o come provetta o sacchetto contenente una polvere liofilizzata per la ricostituzione con un veicolo idoneo come l’acqua per iniezione. Formulations can be provided in unit dosage form, as a sterile solution in a test tube or as a tube or pouch containing a lyophilized powder for reconstitution with a suitable vehicle such as water for injection.
L’esperto del ramo sarà in grado di scegliere gli opportuni diluenti ed eccipienti da aggiungere al principio attivo nella preparazione delle suddette forme farmaceutiche. The skilled in the art will be able to choose the suitable diluents and excipients to add to the active principle in the preparation of the aforesaid pharmaceutical forms.
Costituisce un ulteriore oggetto della presente invenzione l’uso cosmetico di MIA, o frammenti della stessa, per lo sbiancamento della pelle. A further object of the present invention is the cosmetic use of MIA, or fragments thereof, for skin whitening.
Costituiscono un ulteriore oggetto della presente invenzione composizioni cosmetiche, che comprendono MIA, o frammenti della stessa. Cosmetic compositions, which comprise MIA, or fragments thereof, constitute a further object of the present invention.
Le suddette composizioni cosmetiche sono preferibilmente per l’uso topico, e sono formulate in qualsiasi forma cosmetica normalmente usata per l’applicazione topica sulla pelle, come per esempio soluzione acquosa, acquosa-alcoolica od oleosa, un gel acquoso od oleoso, un liquido, una pasta o un prodotto solido anidro, una dispersione di olio in una fase acquosa in presenza di sferule, nanoparticelle polimeriche, nanosfere e nanocapsule, vescicole lipidiche di tipo ionico e/o non ionico, un’emulsione diretta (O/A), inversa (A/O) o multipla (O/A/O e A/O/A). The aforementioned cosmetic compositions are preferably for topical use, and are formulated in any cosmetic form normally used for topical application on the skin, such as for example aqueous, aqueous-alcoholic or oily solution, an aqueous or oily gel, a liquid, a paste or an anhydrous solid product, a dispersion of oil in an aqueous phase in the presence of spherules, polymeric nanoparticles, nanospheres and nanocapsules, ionic and / or non-ionic lipid vesicles, a direct emulsion (O / A ), reverse (A / O) or multiple (O / A / O and A / O / A).
La composizione può essere più o meno fluida ed avere l’aspetto di una crema bianca o colorata, un latte, una lozione, un siero, una pasta, una schiuma o essere applicata forma di un aerosol; può essere in forma solida, in forma di stick o di prodotto compatto. The composition can be more or less fluid and have the appearance of a white or colored cream, a milk, a lotion, a serum, a paste, a foam or be applied in the form of an aerosol; it can be in solid form, in stick form or as a compact product.
La composizione cosmetica può contenere adiuvanti noti all’esperto nel campo cosmetico, quali agenti gelificanti idrofili o lipofili, agenti attivi idrofili o lipofili, conservanti, antiossidanti, solventi, fragranze, cariche, schermi solari, pigmenti, assorbiodori e coloranti, in quantità usate convenzionalmente. The cosmetic composition may contain adjuvants known to the expert in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, fragrances, fillers, sunscreens, pigments, odor absorbers and dyes, in quantities used conventionally.
Questi adiuvanti e anche le loro concentrazioni sono tali da non alterare le proprietà di MIA. These adjuvants and also their concentrations are such that they do not alter the properties of MIA.
L’uso di MIA non induce effetti collaterali paragonabili a quelli delle tecniche note e non crea problemi di tossicità . Infatti à ̈ noto che MIA si trova comunemente nel sangue umano ma la concentrazione utilizzata non altera la concentrazione plasmatica, dove la normale una concentrazione plasmatica di MIA à ̈ compresa tra 1.8 e 7.6 ng/ml. The use of MIA does not induce side effects comparable to those of the known techniques and does not create toxicity problems. In fact it is known that MIA is commonly found in human blood but the concentration used does not alter the plasma concentration, where the normal plasma concentration of MIA is between 1.8 and 7.6 ng / ml.
L’invenzione verrà ora illustrata mediante riferimento ai seguenti esempi non limitanti. The invention will now be illustrated by reference to the following non-limiting examples.
Esempio 1 Example 1
Campioni bioptici Biopsy samples
Sono stati raccolti 5 campioni bioptici da cute affetta da differenti tipi ipercromie (3 melasma, 1 lentigo solare, 1 nevo di Becker) mentre ulteriori 5 campioni bioptici sono stati raccolti da cute normopigmentata. Five biopsy samples were collected from skin affected by different types of hyperchromia (3 melasma, 1 solar lentigo, 1 Becker nevus) while a further 5 biopsy samples were collected from normal pigmented skin.
Inserimento di MIA Insertion of MIA
Su ciascun campione à ̈ stata iniettata una soluzione contenente MIA in soluzione fisiologica alla concentrazione di 100 microgr/ml. I campioni sono stati incubati per 48 ore in piastre Petri da 6 cm di diametro, in terreno di coltura DMEM (Dulbecco Modified Eagle’s Medium), arricchito con 10% FCS (Siero Bovino Fetale) e 1% di L-Glutamine 200 mM. Trascorse le 48 ore, tutti i campioni sono stati processati per analisi istopatologica ed immunoistochimica. A solution containing MIA in physiological solution at a concentration of 100 microgr / ml was injected on each sample. The samples were incubated for 48 hours in 6 cm diameter Petri dishes, in DMEM (Dulbecco Modified Eagle's Medium) culture medium, enriched with 10% FCS (Fetal Bovine Serum) and 1% L-Glutamine 200 mM. After 48 hours, all the samples were processed for histopathological and immunohistochemical analysis.
Istopatologia e immunoistochimica Histopathology and immunohistochemistry
Analisi microscopiche e macroscopiche sono state condotte sui campioni di cute con ipercromia e di cute normopigmentata. Tutti i campioni sono stati fissati in formalina al 10% in 0.1-mol/L (pH = 7.4) di buffer fosfatico disidratati in una serie di crescenti concentrazioni di alcol e poi imbevuti in paraffina per la microscopia. Sezioni spesse 4 micrometri sono state colorate con ematossilina e eosina, Azan-Mallory Heidenheim-modificata. Microscopic and macroscopic analyzes were performed on skin samples with hyperchromia and normopigmented skin. All samples were fixed in 10% formalin in 0.1-mol / L (pH = 7.4) of phosphate buffer dehydrated in a series of increasing alcohol concentrations and then soaked in paraffin for microscopy. Sections 4 micrometers thick were stained with hematoxylin and eosin, Azan-Mallory Heidenheim-modified.
Le sezioni ottenute da ogni biopsia cutanea sono state preparate, trattate e colorate per immunoistochimica secondo procedure standard. Sections obtained from each skin biopsy were prepared, processed and stained for immunohistochemistry according to standard procedures.
Per l’identificazione di premelanosomi e melanosomi maturi sono stati utilizzati anticorpi monoclonali di coniglio S100 e HMB45 (clone HMB45 dil 1/100 DAKO). Tramite tale marker à ̈ possibile identificare sia i melanociti di cute normo-pigmentata sia quelli di cute iper-pigmentata. Rabbit monoclonal antibodies S100 and HMB45 (clone HMB45 dil 1/100 DAKO) were used for the identification of premelanosomes and mature melanosomes. Through this marker it is possible to identify both the melanocytes of normo-pigmented skin and those of hyper-pigmented skin.
In breve, le sezioni sono state trattate con perossido d’idrogeno allo 0,3% in metanolo per bloccare l’attività della perossidasi endogena, successivamente sono state lavate con soluzione salina tamponata con fosfato e incubate in siero normale tamponato di cavallo per prevenire il legame con anticorpi aspecifici. Le sezioni sono state incubate con l’anticorpo primario per 1 ora a temperatura ambiente. Dopo il lavaggio, à ̈ stato aggiunto un anticorpo secondario marcato con biotina, seguito da uno coniugato con avidina-perossidasi. La diaminobenzidina à ̈ stata usato come cromogeno. Briefly, the sections were treated with 0.3% hydrogen peroxide in methanol to block the activity of endogenous peroxidase, then washed with phosphate buffered saline and incubated in normal buffered horse serum to prevent binding with non-specific antibodies. Sections were incubated with primary antibody for 1 hour at room temperature. After washing, a biotin-labeled secondary antibody was added, followed by one conjugated with avidin-peroxidase. Diaminobenzidine was used as a chromogen.
Sono stati testati e visualizzati con perossidasi diaminobenzidina (DAB) due anticorpi in due differenti sezioni sequenziali di cute normo-pigmentata e di cute iper-pigmentata con anti-integrina umana alpha5beta1 (Chemicon, by Millipore, MA, USA, Clone JB 1/50) e melanoma inhibitory activity (MIA, Santa Cruz Biotechnology, CA, USA, polyclonal antibody IgG dil:1/20). È stata eseguita simultaneamente una sulla stessa sezione una doppia immunofluorescenza per evidenziare colocalizzazione della proteina MIA e integrina alpha5beta1 mediante tecnica di immunomarcaggio sequenziale con anti-integrina alpha5beta1 umana e anti-melanoma inhibitory activity; i risultati sono stati visualizzati con anticorpi secondari anti-topo o anti-coniglio coniugati con fluorescina isocianato o rodamina (Chemicon, by Millipore, MA, USA). I nuclei sono stati marcati con TO-PRO 3 (Invitrogen, Molecular Probes; distribuito da Invitrogen, Milano, Italia). Mediante tale analisi à ̈ possibile verificare il corretto funzionamento di MIA ed il suo sito di legame a livello delle integrine alpha5beta1 espresse sui melanociti di cute normopigmentata e di cute iperpigmentata. Two antibodies in two different sequential sections of normo-pigmented skin and hyper-pigmented skin with human anti-integrin alpha5beta1 were tested and visualized with diaminobenzidine peroxidase (DAB) (Chemicon, by Millipore, MA, USA, Clone JB 1/50 ) and melanoma inhibitory activity (MIA, Santa Cruz Biotechnology, CA, USA, polyclonal antibody IgG dil: 1/20). A double immunofluorescence was performed simultaneously on the same section to highlight colocalization of the MIA protein and alpha5beta1 integrin by sequential immunolabeling technique with human anti-integrin alpha5beta1 and anti-melanoma inhibitory activity; the results were visualized with secondary anti-mouse or anti-rabbit antibodies conjugated with fluorescein isocyanate or rhodamine (Chemicon, by Millipore, MA, USA). Nuclei were labeled with TO-PRO 3 (Invitrogen, Molecular Probes; distributed by Invitrogen, Milan, Italy). By means of this analysis it is possible to verify the correct functioning of MIA and its binding site at the level of the alpha5beta1 integrins expressed on melanocytes of normopigmented skin and hyperpigmented skin.
Microfotografie sono state utilizzate mediante microscopio confocale a scanner laser TCS-SL (Leica, Wetzar, Germania). Photomicrographs were used by TCS-SL laser scanner confocal microscope (Leica, Wetzar, Germany).
Risultati Results
Tutti i campioni testati hanno visualizzato un legame di MIA con le integrine alpha5beta1 dei melanociti presenti con iniziale distacco dei melanociti dalla membrana basale. L’anticorpo anti-alpha5beta1 si co-localizza perfettamente con l’anticorpo anti-MIA e tale caratteristica era presente anche in melanociti già distaccati dalla membrana basale. All the tested samples showed a binding of MIA with the alpha5beta1 integrins of the melanocytes present with initial detachment of the melanocytes from the basement membrane. The anti-alpha5beta1 antibody co-localizes perfectly with the anti-MIA antibody and this feature was also present in melanocytes already detached from the basement membrane.
Una possibile attività di MIA a livello di melanociti di cute iperpigmentata o normopigmentata era completamente inattesa. La presenza ematica di MIA (comunemente riscontrabile in qualsiasi soggetto sano) sembrava escludere la possibilità che MIA potesse avere un ruolo nel distacco dei melanociti da cute normopigmentata o iperpigmentata. Inoltre, la presenza di MIA a livello di cute sana era già stata esclusa. A possible activity of MIA at the level of melanocytes of hyperpigmented or normopigmented skin was completely unexpected. The blood presence of MIA (commonly found in any healthy subject) seemed to exclude the possibility that MIA could play a role in the detachment of melanocytes from normal or hyperpigmented skin. Furthermore, the presence of MIA in healthy skin had already been ruled out.
Questi dati dimostrano invece che se veicolato in opportuna sede dermoepidermica, MIA svolge la sua funzione di rottura dei legami tra integrine alpha5beta1 melanocitarie e membrana basale, causandone il loro distacco. These data instead show that if conveyed in an appropriate dermoepidermal site, MIA performs its function of breaking the bonds between melanocytic alpha5beta1 integrins and basement membrane, causing their detachment.
L’utilizzo di MIA nelle iperpigmentazioni cutanee e in cute sana à ̈ dunque in grado di causare il distacco dei melanociti responsabili delle iperpigmentazioni o del normale colorito cutaneo e di conseguenza risolvere tali iperpigmentazioni o ottenere uno sbiancamento cosmetico della cute. The use of MIA in skin hyperpigmentation and in healthy skin is therefore able to cause the detachment of the melanocytes responsible for hyperpigmentation or normal skin color and consequently resolve such hyperpigmentation or obtain a cosmetic whitening of the skin.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000339A ITRM20120339A1 (en) | 2012-07-16 | 2012-07-16 | USE OF MY (MELANOMA INHIBITOR ACTIVITY) FOR THE TREATMENT OF SKIN IPERPIGMENTATION AND FOR THE COSMETIC WHITENING OF THE SKIN |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000339A ITRM20120339A1 (en) | 2012-07-16 | 2012-07-16 | USE OF MY (MELANOMA INHIBITOR ACTIVITY) FOR THE TREATMENT OF SKIN IPERPIGMENTATION AND FOR THE COSMETIC WHITENING OF THE SKIN |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ITRM20120339A1 true ITRM20120339A1 (en) | 2014-01-17 |
Family
ID=46833058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT000339A ITRM20120339A1 (en) | 2012-07-16 | 2012-07-16 | USE OF MY (MELANOMA INHIBITOR ACTIVITY) FOR THE TREATMENT OF SKIN IPERPIGMENTATION AND FOR THE COSMETIC WHITENING OF THE SKIN |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | ITRM20120339A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001070253A1 (en) * | 2000-03-23 | 2001-09-27 | Akzo Nobel N.V. | Use of mia in immunotherapy |
| US20100212037A1 (en) * | 2002-10-16 | 2010-08-19 | Anja Katrin Bosserhoff | Mia-2 protein |
-
2012
- 2012-07-16 IT IT000339A patent/ITRM20120339A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001070253A1 (en) * | 2000-03-23 | 2001-09-27 | Akzo Nobel N.V. | Use of mia in immunotherapy |
| US20100212037A1 (en) * | 2002-10-16 | 2010-08-19 | Anja Katrin Bosserhoff | Mia-2 protein |
Non-Patent Citations (3)
| Title |
|---|
| BAUER RICHARD ET AL: "Regulation of integrin activity by MIA", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 281, no. 17, April 2006 (2006-04-01), pages 11669 - 11677, XP002693251, ISSN: 0021-9258 * |
| BORDIGNON MATTEO ET AL: "Expression of MIA (melanoma inhibitory activity) in vitiliginous melanocytes: a novel pathogenetic pathway?", JOURNAL OF INVESTIGATIVE DERMATOLOGY; 41ST ANNUAL MEETING OF THE EUROPEAN-SOCIETY-FOR-DERMATOLOGICAL-RESEARCH; BARCELONA, SPAIN; SEPTEMBER 07 -10, 2011, NATURE PUBLISHING GROUP, GB, vol. 131, no. Suppl. 2, 11 October 2011 (2011-10-11), pages S112, XP002660950, ISSN: 0022-202X * |
| JUTTA TATZEL ET AL: "Inhibition of melanoma inhibitory activity (MIA) expression in melanoma cells leads to molecular and phenotypic changes", PIGMENT CELL RESEARCH, vol. 18, no. 2, 1 April 2005 (2005-04-01), pages 92 - 101, XP055055349, ISSN: 0893-5785, DOI: 10.1111/j.1600-0749.2005.00212.x * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101687042B1 (en) | Calcium sequestration compositions and methods of treating skin pigmentation disorders and conditions | |
| ES2468368T3 (en) | 6-substituted 7-methoxy-2,2-dimethylchroman compounds and their use as pigment regulators | |
| JP6176893B2 (en) | Oleanoyl peptide composition and method for treating skin aging | |
| WO2008045272A2 (en) | Compositions and methods for skin lightening | |
| JP2002193738A (en) | Use of at least one extract from at least one azalea plant in composition for treating symptom of skin aging | |
| KR20120060205A (en) | Heparanase activity inhibitor | |
| KR101858095B1 (en) | Cosmetic composition comprising Curcumae Longae Rhizoma extract comprising curcumin as an active ingredient for skin lightening, reducing wrinkle formation, and alleviating pruritus | |
| MX2014007495A (en) | Compounds with anti-aging activities. | |
| US9126060B2 (en) | Cosmetic use of geranylgeranyl-2-propanol | |
| US20160175223A1 (en) | Anti-aging compositions comprising bile acid-fatty acid conjugates | |
| CN106061474B (en) | Method for treating alopecia using monoterpenoids | |
| KR20070001921A (en) | Use of idebenone for the preparation of a topically-applied depigmentation composition and corresponding composition | |
| Veiga et al. | Anti-aging peptides for advanced skincare: focus on nanodelivery systems | |
| JP2012240911A (en) | Anti-wrinkle agent, matrix metalloprotenase (mmp) inhibitor and/or laminin 5 production promoter, each comprising 1-piperidine propionate | |
| JP2004285050A (en) | Cosmetic use of ascorbic acid derivative as bleaching agent | |
| JP2003137714A (en) | Cosmetic composition or pharmaceutical composition | |
| ES2322198T3 (en) | DEPIGMENTING OR CLEARING COSMETIC COMPOSITION THAT UNDERSTANDS AT LEAST ONE OXAZOLINE AS A TITLE OF ACTIVE PRINCIPLE. | |
| ES2839503T3 (en) | Use of thiophosphate derivatives as skin depigmenting agents | |
| TW201622695A (en) | External dermatological agent for anti-ageing | |
| US20070154437A1 (en) | Peptide-tagged proteins and methods of making and using thereof | |
| ITRM20120339A1 (en) | USE OF MY (MELANOMA INHIBITOR ACTIVITY) FOR THE TREATMENT OF SKIN IPERPIGMENTATION AND FOR THE COSMETIC WHITENING OF THE SKIN | |
| KR102275267B1 (en) | Composition for improving skin | |
| KR20060023558A (en) | Topical agents containing phytanic acid or a derivative thereof | |
| KR20160114018A (en) | Composition for improving skin | |
| Khalid et al. | Anti-Aging Topical Peptides and Proteins |