US20220273595A1 - Compositions and methods for treating eczema - Google Patents
Compositions and methods for treating eczema Download PDFInfo
- Publication number
- US20220273595A1 US20220273595A1 US17/746,796 US202217746796A US2022273595A1 US 20220273595 A1 US20220273595 A1 US 20220273595A1 US 202217746796 A US202217746796 A US 202217746796A US 2022273595 A1 US2022273595 A1 US 2022273595A1
- Authority
- US
- United States
- Prior art keywords
- aureus
- propionic acid
- composition
- skin
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 112
- 238000000034 method Methods 0.000 title claims abstract description 44
- 201000004624 Dermatitis Diseases 0.000 title abstract description 35
- 208000010668 atopic eczema Diseases 0.000 title abstract description 35
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims abstract description 228
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims abstract description 161
- 235000019260 propionic acid Nutrition 0.000 claims abstract description 114
- 239000003246 corticosteroid Substances 0.000 claims abstract description 28
- 230000003637 steroidlike Effects 0.000 claims abstract description 26
- 239000003636 conditioned culture medium Substances 0.000 claims abstract description 25
- 239000003974 emollient agent Substances 0.000 claims abstract description 24
- 229940052366 colloidal oatmeal Drugs 0.000 claims abstract description 23
- 239000002955 immunomodulating agent Substances 0.000 claims abstract description 22
- 229940121354 immunomodulator Drugs 0.000 claims abstract description 22
- 230000003115 biocidal effect Effects 0.000 claims abstract description 20
- 230000002584 immunomodulator Effects 0.000 claims abstract description 18
- 150000002148 esters Chemical class 0.000 claims abstract description 15
- 238000000855 fermentation Methods 0.000 claims abstract description 15
- 230000004151 fermentation Effects 0.000 claims abstract description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 35
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 34
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 32
- 230000000699 topical effect Effects 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 27
- 239000001384 succinic acid Substances 0.000 claims description 15
- 239000003242 anti bacterial agent Substances 0.000 claims description 12
- 239000004615 ingredient Substances 0.000 claims description 11
- YZWRNSARCRTXDS-UHFFFAOYSA-N tripropionin Chemical compound CCC(=O)OCC(OC(=O)CC)COC(=O)CC YZWRNSARCRTXDS-UHFFFAOYSA-N 0.000 claims description 11
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 5
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 5
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 4
- 239000004599 antimicrobial Substances 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
- UFAHZIUFPNSHSL-MRVPVSSYSA-N O-propanoyl-L-carnitine Chemical compound CCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C UFAHZIUFPNSHSL-MRVPVSSYSA-N 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- PELLUIPPBKHUAB-GRYCIOLGSA-N [(1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl] propanoate Chemical compound CCC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C PELLUIPPBKHUAB-GRYCIOLGSA-N 0.000 claims description 2
- 230000000813 microbial effect Effects 0.000 claims 2
- YMMVCTFOVNOGFQ-UHFFFAOYSA-N 2-(2-propanoyloxyethoxy)ethyl propanoate Chemical compound CCC(=O)OCCOCCOC(=O)CC YMMVCTFOVNOGFQ-UHFFFAOYSA-N 0.000 claims 1
- ZMFGAUXLTPASPR-UHFFFAOYSA-M trimethyl(2-propanoyloxyethyl)azanium;iodide Chemical compound [I-].CCC(=O)OCC[N+](C)(C)C ZMFGAUXLTPASPR-UHFFFAOYSA-M 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 51
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 abstract description 26
- 150000004666 short chain fatty acids Chemical class 0.000 abstract description 19
- 244000005714 skin microbiome Species 0.000 abstract description 16
- 229940081066 picolinic acid Drugs 0.000 abstract description 13
- 235000021391 short chain fatty acids Nutrition 0.000 abstract description 8
- 230000001580 bacterial effect Effects 0.000 abstract description 7
- 238000004458 analytical method Methods 0.000 abstract description 6
- 210000003491 skin Anatomy 0.000 description 44
- 241000186427 Cutibacterium acnes Species 0.000 description 39
- 210000002510 keratinocyte Anatomy 0.000 description 21
- 239000008186 active pharmaceutical agent Substances 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 230000012010 growth Effects 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- -1 dipropionate Chemical compound 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 230000003110 anti-inflammatory effect Effects 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 15
- 238000009472 formulation Methods 0.000 description 15
- 230000000845 anti-microbial effect Effects 0.000 description 14
- 244000005700 microbiome Species 0.000 description 14
- 108010088160 Staphylococcal Protein A Proteins 0.000 description 13
- 108090000371 Esterases Proteins 0.000 description 12
- 229960001334 corticosteroids Drugs 0.000 description 12
- 230000000844 anti-bacterial effect Effects 0.000 description 11
- 235000011187 glycerol Nutrition 0.000 description 11
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 10
- 239000006071 cream Substances 0.000 description 10
- 241000186216 Corynebacterium Species 0.000 description 9
- 208000012868 Overgrowth Diseases 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000013066 combination product Substances 0.000 description 9
- 229940127555 combination product Drugs 0.000 description 9
- KASDHRXLYQOAKZ-XDSKOBMDSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-XDSKOBMDSA-N 0.000 description 9
- 229960001967 tacrolimus Drugs 0.000 description 9
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 9
- 229940088710 antibiotic agent Drugs 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 230000006872 improvement Effects 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- 239000002953 phosphate buffered saline Substances 0.000 description 8
- 229960005330 pimecrolimus Drugs 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 208000003251 Pruritus Diseases 0.000 description 7
- 241000191940 Staphylococcus Species 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 230000007803 itching Effects 0.000 description 7
- 238000010610 time kill assay Methods 0.000 description 7
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 6
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 238000011866 long-term treatment Methods 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 230000002195 synergetic effect Effects 0.000 description 6
- 231100000765 toxin Toxicity 0.000 description 6
- 239000003053 toxin Substances 0.000 description 6
- 108700012359 toxins Proteins 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 241000186429 Propionibacterium Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 101710101607 Toxic shock syndrome toxin-1 Proteins 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 230000028709 inflammatory response Effects 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 239000006166 lysate Substances 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 230000008439 repair process Effects 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 208000027244 Dysbiosis Diseases 0.000 description 4
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000003240 coconut oil Substances 0.000 description 4
- 235000019864 coconut oil Nutrition 0.000 description 4
- 229960002593 desoximetasone Drugs 0.000 description 4
- VWVSBHGCDBMOOT-IIEHVVJPSA-N desoximetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@H](C(=O)CO)[C@@]1(C)C[C@@H]2O VWVSBHGCDBMOOT-IIEHVVJPSA-N 0.000 description 4
- 229960002124 diflorasone diacetate Drugs 0.000 description 4
- BOBLHFUVNSFZPJ-JOYXJVLSSA-N diflorasone diacetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)COC(C)=O)(OC(C)=O)[C@@]2(C)C[C@@H]1O BOBLHFUVNSFZPJ-JOYXJVLSSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000007140 dysbiosis Effects 0.000 description 4
- 229960001347 fluocinolone acetonide Drugs 0.000 description 4
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 4
- 239000003862 glucocorticoid Substances 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 239000002054 inoculum Substances 0.000 description 4
- 229960002744 mometasone furoate Drugs 0.000 description 4
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 235000019271 petrolatum Nutrition 0.000 description 4
- 238000013207 serial dilution Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 231100000617 superantigen Toxicity 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 229940037128 systemic glucocorticoids Drugs 0.000 description 4
- 229940100611 topical cream Drugs 0.000 description 4
- 229960002117 triamcinolone acetonide Drugs 0.000 description 4
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 229940122739 Calcineurin inhibitor Drugs 0.000 description 3
- 101710192106 Calcineurin-binding protein cabin-1 Proteins 0.000 description 3
- 102100024123 Calcineurin-binding protein cabin-1 Human genes 0.000 description 3
- 206010061819 Disease recurrence Diseases 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 230000000941 anti-staphylcoccal effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229950003468 dupilumab Drugs 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 229960003085 meticillin Drugs 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 229940055019 propionibacterium acne Drugs 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 208000017520 skin disease Diseases 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 230000006433 tumor necrosis factor production Effects 0.000 description 3
- 239000003871 white petrolatum Substances 0.000 description 3
- KEJGAYKWRDILTF-DEMCRKGTSA-N (3ar,5s,6s,6ar)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol Chemical compound O1C(C)(C)OCC1[C@@H]1[C@H](O)[C@H]2OC(C)(C)O[C@H]2O1 KEJGAYKWRDILTF-DEMCRKGTSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 101000867232 Escherichia coli Heat-stable enterotoxin II Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 description 2
- POPFMWWJOGLOIF-XWCQMRHXSA-N Flurandrenolide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O POPFMWWJOGLOIF-XWCQMRHXSA-N 0.000 description 2
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 description 2
- FOGXJPFPZOHSQS-AYVLZSQQSA-N Hydrocortisone butyrate propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O FOGXJPFPZOHSQS-AYVLZSQQSA-N 0.000 description 2
- 102000010787 Interleukin-4 Receptors Human genes 0.000 description 2
- 108010038486 Interleukin-4 Receptors Proteins 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 239000004909 Moisturizer Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 235000018936 Vitellaria paradoxa Nutrition 0.000 description 2
- 241001135917 Vitellaria paradoxa Species 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229960002227 clindamycin Drugs 0.000 description 2
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 2
- 229960004703 clobetasol propionate Drugs 0.000 description 2
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 description 2
- 229960001357 clocortolone pivalate Drugs 0.000 description 2
- SXYZQZLHAIHKKY-GSTUPEFVSA-N clocortolone pivalate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(=O)C(C)(C)C)[C@@]2(C)C[C@@H]1O SXYZQZLHAIHKKY-GSTUPEFVSA-N 0.000 description 2
- FZCHYNWYXKICIO-FZNHGJLXSA-N cortisol 17-valerate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O FZCHYNWYXKICIO-FZNHGJLXSA-N 0.000 description 2
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 229960003662 desonide Drugs 0.000 description 2
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 2
- 229960003722 doxycycline Drugs 0.000 description 2
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 231100000655 enterotoxin Toxicity 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229960004511 fludroxycortide Drugs 0.000 description 2
- 229960000785 fluocinonide Drugs 0.000 description 2
- 229960000289 fluticasone propionate Drugs 0.000 description 2
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 2
- 229960002383 halcinonide Drugs 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 229960001067 hydrocortisone acetate Drugs 0.000 description 2
- 229960002846 hydrocortisone probutate Drugs 0.000 description 2
- 229960000631 hydrocortisone valerate Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000001333 moisturizer Effects 0.000 description 2
- 235000019645 odor Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229960000470 omalizumab Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229960002794 prednicarbate Drugs 0.000 description 2
- FNPXMHRZILFCKX-KAJVQRHHSA-N prednicarbate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O FNPXMHRZILFCKX-KAJVQRHHSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000006041 probiotic Substances 0.000 description 2
- 235000018291 probiotics Nutrition 0.000 description 2
- WAQWPHRYXZNOBX-UHFFFAOYSA-N propanoic acid 2-(2-propanoyloxyethoxy)ethyl propanoate Chemical class CCC(O)=O.CCC(=O)OCCOCCOC(=O)CC WAQWPHRYXZNOBX-UHFFFAOYSA-N 0.000 description 2
- SWJBKFPUULGRJE-UHFFFAOYSA-M propanoic acid trimethyl(2-propanoyloxyethyl)azanium iodide Chemical class [I-].CCC(O)=O.CCC(=O)OCC[N+](C)(C)C SWJBKFPUULGRJE-UHFFFAOYSA-M 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 2
- 229960001225 rifampicin Drugs 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 229940057910 shea butter Drugs 0.000 description 2
- 230000036559 skin health Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- 229950008396 ulobetasol propionate Drugs 0.000 description 2
- BDSYKGHYMJNPAB-LICBFIPMSA-N ulobetasol propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]2(C)C[C@@H]1O BDSYKGHYMJNPAB-LICBFIPMSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 description 1
- QPMJJFBKWXQIDV-SGNQUONSSA-N *.B.C.C1CCC2C(C1)CCC1C3CCCC3CCC21.[2HH] Chemical compound *.B.C.C1CCC2C(C1)CCC1C3CCCC3CCC21.[2HH] QPMJJFBKWXQIDV-SGNQUONSSA-N 0.000 description 1
- UEBUKTNBFTWMNA-SGNQUONSSA-N *.B.C.CCC(CCC(C)C1CCC2(C)C3CCC4C(C)(C)CCCC4(C)C3CCC12C)C(C)C.[2HH] Chemical compound *.B.C.CCC(CCC(C)C1CCC2(C)C3CCC4C(C)(C)CCCC4(C)C3CCC12C)C(C)C.[2HH] UEBUKTNBFTWMNA-SGNQUONSSA-N 0.000 description 1
- 108020004465 16S ribosomal RNA Proteins 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 description 1
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical class CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 description 1
- 101710092462 Alpha-hemolysin Proteins 0.000 description 1
- 101710197219 Alpha-toxin Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical class [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000589562 Brucella Species 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical class [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241001112695 Clostridiales Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 101710146739 Enterotoxin Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 206010033733 Papule Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 101710124951 Phospholipase C Proteins 0.000 description 1
- 238000003559 RNA-seq method Methods 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010048222 Xerosis Diseases 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 229960000458 allantoin Drugs 0.000 description 1
- 239000002776 alpha toxin Substances 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940003587 aquaphor Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 230000037365 barrier function of the epidermis Effects 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- 150000001783 ceramides Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 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
- 230000009429 distress Effects 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- QQQMUBLXDAFBRH-UHFFFAOYSA-N dodecyl 2-hydroxypropanoate Chemical compound CCCCCCCCCCCCOC(=O)C(C)O QQQMUBLXDAFBRH-UHFFFAOYSA-N 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 229940021013 electrolyte solution Drugs 0.000 description 1
- 229940020485 elidel Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000147 enterotoxin Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000036566 epidermal hyperplasia Effects 0.000 description 1
- 210000005175 epidermal keratinocyte Anatomy 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229940107702 grapefruit seed extract Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 230000036074 healthy skin Effects 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical class [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000008088 immune pathway Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 239000002395 mineralocorticoid Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229940127249 oral antibiotic Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003209 petroleum derivative Substances 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical class [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229940037129 plain mineralocorticoids for systemic use Drugs 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 150000005599 propionic acid derivatives Chemical class 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940112971 protopic Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000009094 second-line therapy Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 229940075560 sodium lauryl sulfoacetate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- UAJTZZNRJCKXJN-UHFFFAOYSA-M sodium;2-dodecoxy-2-oxoethanesulfonate Chemical compound [Na+].CCCCCCCCCCCCOC(=O)CS([O-])(=O)=O UAJTZZNRJCKXJN-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000036572 transepidermal water loss Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- MTZBBNMLMNBNJL-UHFFFAOYSA-N xipamide Chemical compound CC1=CC=CC(C)=C1NC(=O)C1=CC(S(N)(=O)=O)=C(Cl)C=C1O MTZBBNMLMNBNJL-UHFFFAOYSA-N 0.000 description 1
- 239000002888 zwitterionic surfactant Substances 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39566—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against immunoglobulins, e.g. anti-idiotypic antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
- C07K16/4283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
- C07K16/4291—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig against IgE
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
Definitions
- the present invention is related to compositions and methods for the treatment of eczema, and, in particular, to topical compositions and methods based upon pharmaceutically and cosmetically acceptable preparations of propionic acid and derivatives thereof.
- Eczema also referred to as atopic dermatitis or AD
- AD atopic dermatitis
- the disease is also seen in many adults and follows a relapsing course.
- AD patients show signs of psychological and psychosocial distress to discomfort and embarrassment or anger regarding their appearance, and patients over 16 years of age showed significantly lower scores on social functioning and mental health than the general population.
- Up to 60% of children with AD report sleep disturbance due to itching, increasing to 83% during exacerbation, which typically affects the sleep of other household members.
- AD The disease pathogenesis of AD is believed to be due to a combination of environmental and genetic factors resulting in compromised skin barrier function, inflammation and the appearance of erythema and papules.
- Up to 80-100% of patients suffering from AD are colonized with S. aureus compared to only about 5-30% of control patients.
- S. aureus strains isolated from AD lesions have been shown to produce a variety of toxins and enzymes with aggressive cell-damaging and inflammation-inducing properties.
- aureus directly damages keratinocytes by adhering to cells and forming transmembrane pores through the secretion of staphylococcal toxin ultimately leading to the breakdown of cellular ATP metabolism.
- S. aureus superantigens elicit the production of IgE antibodies, which levels correlate with disease severity.
- Treatments for AD which reduce the bacterial load, include the administration of oral antibiotics, topical corticosteroids, toxin neutralizing agents and dilute bleach bath, although, studies have shown that S. aureus colonization can rapidly reoccur following termination of treatment, and it is recommended that long-term treatments are used to reduce the occurrence of AD associated flare-ups.
- Treatment with anti-staphylococcal antibiotics in conjunction with topical corticosteroids demonstrated better clinical improvement than treatment with topical corticosteroids alone suggesting treatments aimed at reducing the bacterial load are effective. Long-term treatments with antibiotics, however, are not advised due to the propensity of S. aureus strains to form antibiotic resistance. Methicillin-resistant S.
- aureus strains have developed an elaborate set of defenses against commonly used antibiotics and resistant S. aureus strains have been isolated from AD lesions.
- the prolonged use of topical corticosteroids is also not recommended due to side-effects, and a survey of 200 dermatology outpatients with AD showed that 72.5% of parents concerned about applying topical corticosteroids onto their children and 24% of them admitted non-compliance due to these concerns.
- the present invention includes a topical composition for the treatment of AD.
- the composition includes propionic acid or a non-steroidal ester of propionic acid in a pharmaceutically acceptable topical preparation.
- propionic acid is prepared by fermentation of P. acnes .
- the fermentation product of P. acnes called conditioned media, is used in the formulation of a topical treatment for atopic dermatitis.
- propionic acid or a non-steroidal ester of propionic acid is prepared by chemical synthesis.
- the present invention includes a method of treating AD.
- the method includes administering to a subject in need thereof, a topical composition comprising propionic acid or a non-steroidal ester of propionic acid in a pharmaceutically acceptable topical preparation.
- the present invention includes a method of preparing a topical formulation for treating AD, the method comprising combining propionic acid or a non-steroidal ester of propionic acid with a carrier substance in a pharmaceutically acceptable topical preparation.
- the composition may include propionic acid in a pharmaceutically acceptable topical preparation.
- the propionic acid may be present in the composition in an amount suitable for delivering to the skin at least 1 mM propionic acid.
- the composition may include the non-steroidal derivative of propionic acid, 2-(2-propionyloxyethoxy)ethylester (PA-DEG-PA) in a pharmaceutically acceptable topical preparation.
- PA-DEG-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM-DEG-PA.
- the composition may include the non-steroidal derivative of propionic acid. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl propionate (M-PA) in a pharmaceutically acceptable topical preparation.
- M-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM M-PA.
- the composition may include the non-steroidal derivative of propionic acid C 12 H 20 O 6 , glyceryl tripropionate—tripropionin (tri-PA) in a pharmaceutically acceptable topical preparation.
- the tri-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM tri-PA.
- the composition may include the non-steroidal derivative of propionic acid 2-[2-(propionyloxy)ethoxy]ethyl propionate (di-PA) in a pharmaceutically acceptable topical preparation.
- the di-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM di-PA.
- the composition may include the non-steroidal derivative of propionic acid propionylcholineiodide (ch-PA) in a pharmaceutically acceptable topical preparation.
- the ch-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM ch-PA.
- the composition may include the non-steroidal derivative of propionic acid propionyl-L-carnitine (ca-PA) in a pharmaceutically acceptable topical preparation.
- the ca-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM ca-PA.
- the composition may include the non-steroidal derivative of propionic acid that is an ester of glycerol and propionic acid (PA-glycerol-PA) in a pharmaceutically acceptable topical preparation.
- PA-glycerol-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM PA-glycerol-PA.
- the composition may further include a corticosteroid.
- the corticosteroid may be any one or more of clobetasol propionate, diflorasone diacetate, halobetasol propionate, betamethasone, dipropionate, desoximetasone, diflorasone diacetate, fluocinonide, halcinonide, mometasone furoate, triamcinolone acetonide, clocortolone pivalate, desoximetasone, fluocinolone acetonide, flurandrenolide, fluticasone propionate, mometasone furoate, triamcinolone acetonide, hydrocortisone, hydrocortisone acetate, fluocinolone acetonide, hydrocortisone probutate, hydrocortisone valerate, prednicarbate and desonide.
- the composition may further include an antibiotic.
- the antibiotic may be anti-staphylococcal antibiotic such as muciprocin, clindamycin, rifampin, doxycycline, or a quinolone.
- the composition may further include an immunomodulator.
- the immunomodulator may be a calcineurin inhibitor such as tacrolimus or pimecrolimus.
- the composition may further include an antibody.
- the antibody may be a monoclonal antibody that blocks IgE function such as Omalizumab or Dupilumab that blocks the IL-4 receptor alpha subunit.
- the composition may further include colloidal oatmeal.
- the composition may further include other short chain fatty acids or their derivatives.
- the short chain fatty acid may be succinic acid or butyric acid.
- Short chain fatty acids or their derivatives should be in a concentration that will deliver a dose to the skin that is below MIC for P. acnes.
- the composition may further include picolinic acid or its derivatives.
- the composition may further include succinic acid.
- the succinic acid should be in concentrations that is below MIC for P. acnes.
- composition may further include conditioned media prepared by fermentation of P. acnes.
- the composition may further include an emollient.
- the emollient may be white petrolatum, coconut oil, and other moisture-retaining compounds.
- FIG. 1 shows MIC assay of P. acnes conditioned media against S. aureus.
- FIG. 2 shows evaluation of the bactericidal properties of PA against S. aureus using the time-kill assay.
- FIG. 3 shows MIC values for the growth inhibition of S. aureus by tripropionin with or without the addition of an esterase.
- FIG. 4 shows PA and TPA time kill assay in the presence of an esterase.
- the present invention is directed to new compositions, methods of treatment and methods of formulation based upon compositions for AD.
- the compositions are based upon pharmaceutically acceptable preparations of propionic acid and derivatives thereof.
- combination products of propionic acid and derivatives thereof with other APIs active pharmaceutical ingredients
- other APIs active pharmaceutical ingredients
- combination products of propionic acid and derivatives thereof with other APIs that are currently used for the treatment of eczema and eczema-like diseases were identified and used for the treatment of eczema that provide synergistic effects and significantly improved unexpected properties compared to the API alone including being significantly faster-acting, having less side effects, controlling S. aureus overgrowth as well as inflammation and resulting in less frequent disease recurrence thus managing the symptoms of eczema significantly more efficiently.
- Combination products were also identified that are suitable for use in children due to reduced side effects that are suitable for long term use.
- the term “about” is intended to refer to a range of values above and below a stated value such as for example, values encompassing 10% below up to 10% above a stated value.
- API Active pharmaceutical ingredient
- the term “combination” with respect to active agents refers to a composition of two or more active agents, in particular, antimicrobial and anti-inflammatory agents.
- a combination of active agents may include propionic acid derivative of propionic acid.
- the compositions may further include P. acne -derived conditioned media, a corticosteroid, immunomodulator, antibiotic, antibody, short chain fatty acid (succinic acid or butyric acid), picolinic acid, colloidal oatmeal, and/or emollient.
- a steroid refers to an organic compound with four rings, A, B. C and D arranged in the specific configuration as shown below:
- a non-steroidal compound refers to a compound that lacks the typical steroid four ring system above.
- a corticosteroid refers to any of a group of steroid hormones produced in the adrenal cortex or made synthetically. There are two kinds: glucocorticoids and mineralocorticoids of which glucocorticoids have been used in treating various skin diseases involving inflammation. Unless otherwise indicated herein, the term corticosteroid is intended to refer to glucocorticoids when used in connection with compositions and methods for treating various skin diseases.
- corticosteroids that are glucocorticoids include, but are not limited to clobetasol propionate, diflorasone diacetate, halobetasol propionate, betamethasone, dipropionate, desoximetasone, diflorasone diacetate, fluocinonide, halcinonide, mometasone furoate, triamcinolone acetonide, clocortolone pivalate, desoximetasone, fluocinolone acetonide, flurandrenolide, fluticasone propionate, mometasone furoate, triamcinolone acetonide, hydrocortisone, hydrocortisone acetate, fluocinolone acetonide, hydrocortisone probutate, hydrocortisone valerate, prednicarbate, desonide and combinations thereof.
- An antibiotic refers to antibiotic creams and ointments such as anti-staphylococcal antibiotic including muciprocin, clindamycin, rifampin, doxycycline, or a quinolone.
- An immunomodulator refers to Tacrolimus which is an immunomodulator that acts as a calcineurin inhibitor.
- Tacrolimus is available in 2 strengths, 0.1% for adults and 0.03% for children, although 0.1% preparation is routinely used in children.
- Tacrolimus is an ointment and is indicated for moderate-to-severe AD. It is indicated for children older than 2 years.
- Pimecrolimus 1% is also an immunomodulator and calcineurin inhibitor.
- Pimecrolimus is produced in a cream base for use twice a day; it is indicated for mild AD in persons older than 2 years and is particularly useful on the face.
- a 2006 black box warning has been issued in the United States based on research that has shown an increase in malignancy in association with the calcineurin inhibitors. These agents are also much more expensive than corticosteroids and should only be used as second-line therapy.
- Pimecrolimus cream has been marketed as Elidel and tacrolimus ointment and Pro
- An antibody refers to Omalizumab which is a monoclonal antibody that blocks IgE function, Dupilumab which is another monoclonal antibody that blocks the IL-4 receptor alpha subunit, which is required for both IL-4 and IL-13 signaling, and other monoclonal antibodies that are involved with IgE function blocking.
- Short chain fatty acids refers to succinic acid, butyric acid or their derivatives. These short chain fatty acids should be used in concentrations to deliver dose to the skin that is below P. acnes MIC. These short chain fatty acids should provide anti-inflammatory effects and not antimicrobial effect (because they are present in a concentration below MIC).
- Colloidal oatmeal refers to substance produced by finely grinding the oat and boiling it to extract the colloidal material. Colloidal oatmeal is used as a skin protectant. Its use as a skin protectant is regulated by the U.S. Food and Drug Administration (FDA) according to the Over-The-Counter Final Monograph for Skin Protectant Drug Products issued in June 2003.
- FDA U.S. Food and Drug Administration
- An emollient refers to substances that soften and moisturize the skin. Emollients/moisturizers work by forming an oily layer on the top of the skin that traps water in the skin. Petrolatum, lanolin, mineral oil, coconut oil and dimethicone are common emollients. Emollients can also contain humectants, including glycerin, lecithin, and propylene glycol that draw water into the outer layer of skin. Many products also have ingredients that soften skin (allantoin). Other moisturizers include white petrolatum, Aquaphor, Atopiclair, Mimyx, and other emollients composed of ceramides, cholesterol and lipids naturally found in the top layer of the skin. The active ingredient should be applied before or together with the emollient.
- Conditioned media refers to fermentation products produced during Propionibacterium acnes ( P. acnes ) fermentation and secreted into the media.
- references herein to an API including, but not limited to propionic acid, a derivative of propionic acid and/or a corticosteroid, antibiotic, immunomodulator, antibody, conditioned media, succinic acid, propionic acid, picolinic acid, colloidal oatmeal, emollient is intended to include pharmaceutically acceptable solvates, salts, hydrates or hydrated salts, their optical isomers, racemates, diastereomers, enantiomers or the polymorphic crystalline structures of the compounds.
- composition refers to a composition that combines one or more API's with a pharmaceutically acceptable carrier such that the composition is suitable for therapeutic use in vitro, in vivo or ex vivo.
- the term “pharmaceutically acceptable carrier” encompasses any suitable pharmaceutical carriers, such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, various types of wetting agents and the like.
- suitable pharmaceutical carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, various types of wetting agents and the like.
- the compositions also can include stabilizers and preservatives. Examples of carriers, stabilizers and adjuvants, can be found in Remington: The Science and Practice of Pharmacy. Lippincott Williams & Wilkins. Twenty-First edition ( May 19, 2005).
- cosmetically acceptable encompasses any formulation that is acceptable for topical use free of offensive odors, unnatural colors or unacceptable side effects.
- mass % a mass( a ) ⁇ (mass( a )+mass( b )+mass( c )+ . . . ) ⁇ 100 (w/w %).
- compositions, treatment methods and formulation methods based upon compositions that may include propionic acid and a derivative of propionic acid.
- the compositions may also include P. acnes conditioned media, a corticosteroid, and/or antibiotic, immunomodulator, antibody, colloidal oatmeal, emollient, short chain fatty acids, succinic acid, butyric acid, and/or picolinic acid.
- the composition may include propionic acid in an amount that delivers from about 1 to about 1,000 mM propionic acid to the skin.
- Such compositions may include propionic acid in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %.
- the amount of propionic acid in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %.
- the propionic acid may further be combined with one or more API's and a carrier system.
- the composition may include a derivative of propionic acid that is a non-steroidal ester of propionic acid.
- the non-steroidal ester may be 2-(2-propionyloxyethoxy)ethylester (PA-DEG-PA) in a pharmaceutically acceptable topical preparation.
- PA-DEG-PA may be present in the composition in an amount that delivers from about 1 to about 1,000 mM PA-DEG-PA to the skin.
- compositions may include PA-DEG-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %.
- the amount of PA-DEG-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %.
- the PA-DEG-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient. P. acnes conditioned media and a carrier system.
- the composition may include the non-steroidal ester (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl propionate (M-PA) in a pharmaceutically acceptable topical preparation.
- the M-PA may be present in the composition in an amount that delivers from about 1 to about 1,000 mM M-PA to the skin.
- Such compositions may include M-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %.
- the amount of M-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %.
- the M-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient, P. acnes conditioned media and a carrier system.
- the composition may include the non-steroidal ester of glycerol and propionic acid (PA-glycerol-PA) in a pharmaceutically acceptable topical preparation.
- the PA-glycerol-PA may be present in the composition in an amount that delivers from about 1 to about 1,000 mM PA-glycerol-PA to the skin.
- compositions may include PA-glycerol-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %.
- the amount of PA-glycerol-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %.
- the PA-glycerol-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient, P. acnes conditioned media and a carrier system.
- API's may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient, P. acnes conditioned media and a carrier system.
- the composition may include the non-steroidal derivative of propionic acid C 12 H 20 O 6 , glyceryl tripropionate—tripropionin (tri-PA) in a pharmaceutically acceptable topical preparation.
- the tri-PA may be present in the composition in an amount that delivers from about 1 to about 1,000 mM tri-PA to the skin.
- Such compositions may include tri-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %.
- the amount of tri-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %.
- the tri-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient. P. acnes conditioned media and a carrier system.
- the composition may include the non-steroidal derivative of propionic acid 2-[2-(propionyloxy)ethoxy]ethyl propionate (di-PA) in a pharmaceutically acceptable topical preparation.
- the di-PA may be present in the composition in an amount that delivers from about 1 to about 1,000 mM di-PA to the skin.
- Such compositions may include di-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %.
- the amount of di-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %.
- the di-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient. P. acnes conditioned media and a carrier system.
- the composition may include the non-steroidal derivative of propionic acid propionylcholineiodide (ch-PA) in a pharmaceutically acceptable topical preparation.
- ch-PA propionic acid propionylcholineiodide
- the ch-PA may be present in the composition in an amount that delivers from about 1 to about 1.000 mM ch-PA to the skin.
- Such compositions may include ch-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %.
- the amount of ch-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %.
- the ch-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient, P. acnes conditioned media and a carrier system.
- the composition may include the non-steroidal derivative of propionic acid propionyl-L-carnitine (ca-PA) in a pharmaceutically acceptable topical preparation.
- the ca-PA may be present in the composition in an amount that delivers from about 1 to about 1.000 mM ca-PA to the skin.
- Such compositions may include ca-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %.
- the amount of ca-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %.
- the ca-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient, P. acnes conditioned media and a carrier system.
- compositions of the present invention may be incorporated into a pharmaceutically acceptable carrier system which may include creams, ointments, gels, lotions, solutions, cleansing solutions, and the like.
- Pharmaceutically acceptable carriers may include a surfactant such as an anionic surfactant, a cationic surfactant, a zwitterionic surfactant or a nonionic surfactant.
- Pharmaceutically acceptable carrier systems may also contain ingredients that include, but are not limited to, saline, aqueous electrolyte solutions, ethanol, dimethyl sulfoxide, dimethyl isosorbide, isopropyl myristate, lauryl lactate, diisopropyl adipate, sodium lauryl sulfoacetate; ionic and nonionic osmotic agents such as sodium chloride, potassium chloride, glycerol, propylene glycol and dextrose; pH adjusters and buffers such as salts of hydroxide, phosphate, citrate, acetate, borate; and trolamine; antioxidants such as salts, acids and/or bases of bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetyl cysteine, cystein, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherols, and as
- Such pharmaceutically acceptable carriers may be preserved against bacterial contamination using preservatives, including, but are not limited to, benzalkonium chloride, ethylene diamine tetra-acetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, natural preservatives such as grapefruit seed extract, or may be formulated as a non-preserved formulation for either single or multiple use.
- preservatives including, but are not limited to, benzalkonium chloride, ethylene diamine tetra-acetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, natural preservatives such as grapefruit seed extract, or may be formulated as a non-preserved formulation for either single or multiple use.
- the methods of treatment of the present invention are useful for the treatment of skin diseases including AD flare-ups that are associated with a skin microbiome dysbiosis, including an overgrowth of S. aureus, Corynebacterium and/or other microbes in the skin microbiome and a decrease of P. acnes and/or other microbes in the skin microbiome.
- Treatment of AD may include determining the skin microbiome profile of a subject, administering to a subject a composition that includes a one or more API's, and monitoring the response and disease state including prevention of flare-ups by monitoring the skin microbiome profile of a subject.
- compositions of the present invention can be administered at a variety of intervals. In some instances, administration may be once a day. In other instances, administration can be less or more frequently, such as 1, 2, 3, or 4 times a day, 1 time every 2 days, or once a week.
- the treatment methods may be monitored by following any of the pathogenic aspects of AD including skin microbiome profiling including determining the levels and ratios of S. aureus, Corynebacterium and P. acnes in the skin microbiome, genomic and histologic profiling of lesional biomarkers including markers of epidermal hyperplasia, markers of cellular infiltrates and terminal differentiation as well as the measuring of immune markers of inflammatory mediators (See, for example, Mansouri. Y. et al., Immune Pathways in Eczema, and Definition of Biomarkers through Broad and Targeted Therapeutics. J. Clin Med. 2015 May; 4(5): 858-873).
- Formulation methods known in the art may be used to prepare the compositions of the present invention.
- a one-batch formulation method may be used in which the components of the pharmaceutical formulation are combined in a single container and the components may be added to the container simultaneously or consecutively.
- S. aureus A 10 ml culture of S. aureus was prepared in cation-adjusted Mueller Hinton II Broth (CA-MHB) and grown at 37° C. 215 RPM overnight. The overnight culture was subcultured in fresh CA-MHB and grown at 37° C. 215 RPM until an optical density at 600 nm (OD600 nm) of 1.0 was reached. This inoculum preparation was used for all experiments.
- CA-MHB cation-adjusted Mueller Hinton II Broth
- P. acnes (ATCC 6919) conditioned media: A P. acnes inoculum (5 ml) was prepared in Reinforced Clostridial Media (RCM) and grown anaerobically at 37° C. in a Gas-Pak (BD) for 48 hours. This culture was subcultured into 5 ml aliquots of fresh RCM and anaerobically grown at 37° C. for 15 days with or without 1% glycerol. P. acnes in RCM without glycerol. RCM with glycerol only, and RCM only were used as controls.
- RCM Reinforced Clostridial Media
- BD Gas-Pak
- the cells were pelleted by centrifugation (12.000 ⁇ g, 2 mins) and the supernatants were removed and filtered through a 0.22 m filter for sterilization. The filtered supernatants were aliquoted and stored at ⁇ 80° C. until use.
- MIC minimal inhibitory concentration
- P. acnes fermentation extracts, propionic acid (PA), and tripropionin (tri-PA) against S. aureus were determined according to the microbroth dilution method from the Clinical Laboratory Standards Institute (CLSI) document M100-S22.
- S. aureus was cultured as described above, pelleted by centrifugation, washed with PBS and resuspended in PBS to a concentration of 10 7 CFU/ml.
- Two-fold serial dilutions of the P. acnes glycerol fermentation extract (90 ⁇ l) or propionic acid (0-100 mM) were added to wells in a 96-well plate followed by 10 ⁇ l of the prepared S.
- aureus inoculum The MIC of tripropionin was evaluated with and without the presence of 0.2 mg/ml porcine liver esterase (Sigma #E3019-20KU) and the assay was prepared as described for PA. All assays with PA and tri-PA were performed in the presence of 10% DMSO. P. acnes glycerol fermentation extract. PA or tri-PA without S. aureus and TSB broth with S. aureus only were used for negative and positive controls, respectively. Plates were incubated under aerobic conditions for 16 hours at 37° C. Following incubation, each well was resuspended by pipetting and the optical density at 600 nm (OD600) was determined on a plate reader. The MIC value was defined as the first well showing ⁇ 90% reduction in growth compared to controls.
- Time-kill assay A time-kill assay was performed to monitor the bactericidal activity of propionic acid (PA). An inoculum of S. aureus was prepared as described above and combined with PA at concentrations corresponding to 1 ⁇ , 2 ⁇ and 4 ⁇ the MIC of PA (15 mM) in TSB broth. A final concentration of 10′ CFU/ml of S. aureus was used. Assays were performed in 100 ⁇ l volumes in 96-well plates and incubated at 37° C. in a sealed bag to prevent evaporation.
- PA propionic acid
- FIG. 1 shows the decrease in growth of S. aureus with higher concentrations of the P. acnes conditioned media.
- the P. acnes conditioned media blue and red
- the P. acnes conditioned media without glycerol inhibited S. aureus growth at a 1:2 dilution which suggested that the RCM broth contained a substrate for P. acnes fermentation (red).
- the bactericidal properties of PA against S. aureus were evaluated using the time-kill assay. Concentrations of PA at 1 ⁇ , 2 ⁇ and 4 ⁇ the MIC (15 mM) were tested against S. aureus and samples were measured after 0, 1, 7, and 24 hours. FIG. 2 shows that at 4 ⁇ the MIC. PA is bactericidal against S. aureus after 7 hours. After 7 hours, PA is shown to be bactericidal against S. aureus at 4 ⁇ the MIC.
- tripropionin (tri-PA, T-PA) against S. aureus were evaluated in the presence of an esterase.
- FIG. 3 shows that the MIC value of tri-PA against S. aureus was 30 mM when an esterase was not added (green). However, when an esterase was added to the reaction (purple), the MIC value decreased to 7.5 mM. This shows that tri-PA inhibited the growth of S. aureus and its growth inhibitory properties were increased in the presence of an esterase.
- FIG. 4 shows PA and tri-PA time kill assay in the presence of an esterase. PA showed complete killing of S. aureus after 5 hours and tri-PA was able to completely kill S. aureus after 24 hours.
- Example 7 Formulation of Tripropionin into a Topical Cream and Testing
- a 5% tripropionin topical cream was formulated using a 50/50 shea butter and coconut oil base with or without 1% colloidal oatmeal.
- the Shea butter and coconut oil were slowly heated at a low temperature until melted.
- the mixture was cooled to about 30° C. and triproionin and colloidal oatmeal were added.
- the mixture was then whipped with a mixer until a homogenous, light solid formed.
- the topical cream containing 5% tripropionin with or without 1% colloidal oatmeal and prepared in the Example 7 was tested in human subjects with eczema.
- This example compares PA. PA-DEG-PA. M-PA, tri-PA, di-PA, ch-PA, ca-PA, PA-glycerol-PA and other derivatives for antimicrobial properties.
- the anti- S. aureus activity of PA and PA-derivatives are compared by determining the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of each compound in the presence/absence of keratinocyte lysates. Briefly. 2-fold serial dilutions of each compound (0-100 mM) are made in 96-well plates and incubated with equal volumes of keratinocyte lysates and S. aureus . Toxin producing S. aureus strain 8325-4 and 5 clinical isolates of S. aureus strains obtained from the skin of AD patients are used in this experiment.
- MIC minimal inhibitory concentration
- MMC minimal bactericidal concentration
- the samples are resuspended by pipetting and the optical density at 600 nm (OD600 nm) are analyzed.
- the MIC value are defined as the concentration of drug in the first well displaying ⁇ 90% reduction in growth.
- the MBC values are determined as follows. Briefly, the samples from the MIC assay are diluted 1:10 to 1:10 6 and each dilution are spread on a TSB agar plate for CFU counting. The MBC value are defined as the first concentration displaying ⁇ 3 log 10 drop in CFU/ml. Appropriate negative controls are included, including PBS and appropriate vehicles used to resuspend PA or PA derivatives (+/ ⁇ keratinocyte lysates).
- PA and PA derivatives show antimicrobial properties against S. aureus including bactericidal effects both in the presence and absence of keratinocyte lysates.
- the anti- S. aureus activity is higher in the presence of keratinocyte lysates.
- Tri-PA was selected for formulation into a cream and further testing in humans.
- This example compares PA, PA-DEG-PA. M-PA, tri-PA, di-PA, ch-PA, ca-PA. PA-glycerol-PA and other derivatives for anti-inflammatory properties and determines if the compounds can protect keratinocytes from the S. aureus induced toxicity in vitro.
- S. aureus colonized on AD lesions exacerbate AD symptoms through the secretion of proteins, toxins and super-antigens.
- S. aureus superantigens S. aureus enterotoxin B (SEB), S. aureus enterotoxin A (SEA) and toxic shock syndrome toxin-1 (TSST-1) are produced by 57%-65% of S. aureus strains isolated from AD lesions and induce an inflammatory response in keratinocytes through the synthesis and release of TNF- ⁇ .
- Certain S. aureus strains also produce Staphylococcal protein A (SpA), which induces a TNF- ⁇ mediated immune response as well.
- S. aureus directly damages keratinocytes by adhering to the cells and the releasing the lysis-inducing toxin. ⁇ -toxin.
- Attenuation of inflammatory responses induced by Staphylococcal protein A, SpA by PA and PA derivatives is measured as follows:
- the spontaneously immortalized human keratinocyte cell line. HaCaT (Addexbio Technologies), is used to measure the reduction of TNF- ⁇ release following stimulation with SpA (Sigma) by PA and PA derivatives. Briefly, 5 ⁇ 105 cells/ml are plated in 24-well plates and incubated for 24 hours. The cells are treated with SpA (10 ⁇ g/mL) for 0-24 hours at 37° C. PA or PA derivatives are added to the cells in varying concentrations (0-100 mM) 10 min. 1, 6, 12 and 24 hours prior to the addition of SpA.
- PA or derivatives can prevent SpA-induced TNF- ⁇ production.
- Varying concentrations of PA or PA derivative are also added concurrently with SpA or 10 min. 1, 6, 12 and 24 hours after the addition of SpA. This measures if PA or derivatives can assuage the SpA-induced inflammatory response.
- Controls including incubating HaCaT cells with PBS (negative control), and incubating HaCaT cells with PA or PA derivative alone are included in testing.
- LPS a known stimulator of keratinocytes, is used to induce an inflammatory response in HaCaT cells. Culture supernatants are removed at various time points (0-24 hours) to monitor release of TNF- ⁇ using a commercially available ELISA kit.
- the anti-inflammatory properties of PA or PA derivatives are determined. PA and PA derivatives cause reduction in inflammatory responses when applied prior and/or post stimulation.
- Varying concentrations of PA or PA derivatives (0-100 mM) are added to the NHEK cells prior to, concurrently or following incubation with S. aureus and the ability of each drug to protect keratinocytes from the cytotoxic effects of S. aureus is determined.
- PBS and appropriate vehicles (used to resuspend PA or PA derivative) are used as negative control.
- Cell viability is determined by MTT/ESTA (3-[4,5-dimethylthiazol-2-yl]-2.5-diphenyl-tet-razolium bromide/eluted stain assay) after 1, 3, 6, 12 and 24 hours of incubation. To determine if PA and PA derivatives protect keratinocytes by inhibiting the growth of S.
- S. aureus in cell culture the viability of S. aureus is measured. Briefly. S. aureus (100 ⁇ l. 10 6 cells/ml) is added to confluent NHEK cells in the presence or absence of PA or PA derivative. In separate experiments, the supernatant is removed after 2, 4, 8, 16, and 24 hours and centrifuged to pellet the free bacteria. Since S. aureus adheres to keratinocytes, the NHEK cells are also trypsinized and incubated in 0.25% triton x-100 in PBS to lyse the cells.
- the lysed keratinocytes are combined with the pelleted supernatant and serial dilutions (1:10 to 1:10 6 ) are plated on supplemented Brucella broth agar to count the total number of viable S. aureus cells.
- PA and PA derivatives show protective properties towards keratinocytes and reduce cytotoxis effects of S. aureus on keratinocytes.
- PA or PA derivative exhibit concentration-dependent attenuation in TNF- ⁇ release following keratinocyte stimulation by SpA. In addition to SpA, other S.
- aureus superantigens such as staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin-1 (TSST-1), that elicit TNF- ⁇ production in keratinocytes, can be used for TNF- ⁇ induction and PA and PA derivatives evaluation.
- SEB staphylococcal enterotoxin B
- TSST-1 toxic shock syndrome toxin-1
- PA or PA derivatives are added prior to, during, or post incubation with SEB or TSST-1 to monitor changes in TNF- ⁇ production.
- PA derivative with a smaller MW ( ⁇ 500 Da) will be preferentially used to increase cell membrane penetration properties.
- the tri-PA candidate displaying both the anti- S. aureus and anti-inflammatory properties was used for formulation development and cream containing tri-PA with or without colloidal oatmeal was used for the treatment of eczema.
- PA derivatives that exhibit antimicrobial properties but do not exhibit sufficient anti-inflammatory properties are used for the treatment of eczema in combination with corticosteroids.
- the rationale for combining PA or PA derivative with corticosteroids is to decrease the concentration of corticosteroids needed to treat AD lesions resulting in a treatment with fewer side effects, restoring a healthier, more diverse microbiome, restoring P. acnes in the microbiome, preventing S. aureus overgrowth. Products with lower concentration of corticosteroids are suitable for a long-term treatment approach.
- the combination product provide significant improvement of efficacy due to synergistic effects of anti-inflammatory, antimicrobial (provided by PA and/or PA derivatives) and skin repair properties of the product that is critical for eczema treatment.
- PA and PA derivatives are also formulated in combination with antibiotics.
- the rationale for combining PA or PA derivatives with antibiotics is to decrease the concentration of antibiotics needed to treat S. aureus overgrowth and S. aureus -associated infections in AD subjects resulting in treatment with fewer side effects and less risk of developing resistance. Resistance prevention is a significant benefit that is provided by PA or PA derivative component in the formulation. Avoidance and/or lower doses of antibiotics restores a healthier, more diverse microbiome while increasing P. acnes in the microbiome and preventing S. aureus overgrowth. This makes the product suitable for a long-term treatment approach.
- the combination product provide synergies and significant improvement of efficacy due to anti-inflammatory, skin healing and antimicrobial properties of the product.
- PA and PA derivatives are also formulated in combination with immunomodulators including tacrolimus or pimecrolimus.
- the rationale for combining PA or PA derivatives with immunomodulators is to decrease the concentration of immunomodulators needed to treat AD resulting in treatment with fewer side effects that restores a healthier, more diverse microbiome, increases P. acnes in the microbiome and prevents S. aureus overgrowth, and is suitable for a long-term treatment approach.
- PA or PA derivatives improve the efficacy of tacrolimus or pimecrolimus when tacrolimus or pimecrolimus is used in recommended strength of 0.1% tacrolimus for adults and 0.03% tactrolimus for children or 1% pimecrolimus.
- the combination product provide significant improvement of efficacy due to synergistic effects of anti-inflammatory, antimicrobial (provided by PA and/or PA derivatives) and skin repair properties of the product that is critical for eczema treatment.
- PA and PA derivatives are also formulated in combination with antibodies, such as monoclonal antibodies Omalizuma. Dupilumab and other monoclonal antibodies that block IgE function.
- the rationale for combining PA or PA derivatives with antibodies is to decrease the concentration of antibodies needed to treat AD resulting in a treatment with fewer side effects, less cost, and restoring a healthier, more diverse microbiome, increasing P. acnes in the microbiome and preventing S. aureus overgrowth, and a treatment suitable for a long-term use.
- the combination product provide significant improvement of efficacy due to synergistic effects of anti-inflammatory, antimicrobial and skin repair properties of the combination product that is critical for eczema treatment.
- PA and PA derivatives are also formulated in combination with short chain fatty acids including succinic acid and butyric acid and their derivatives.
- short chain fatty acids including succinic acid and butyric acid and their derivatives.
- the rationale for combining PA-based compounds with short chain fatty acid (succinic acid or butyric acid) is to significantly increase anti-inflammatory effects of the composition.
- the combination product provide significant improvement of efficacy due to synergistic effects of anti-inflammatory, antimicrobial and skin repair properties of the combination product that is critical for eczema treatment.
- PA and PA derivatives are also formulated in combination with emollients such as white petrolate.
- emollients such as white petrolate.
- the rationale for combining PA or PA derivatives with emollients is to restore dysfunctional epidermal barrier, combat xerosis and transepidermal water loss.
- the PA or PA derivative are applied before or at the same time as the emollient.
- the rationale for combing PA-based compounds with corticosteroids, antibiotics, immunomodulators, antibodies, colloidal oatmeal or other APIs is to improve the efficacy of the treatment and potentially decrease the concentration of APIs needed to treat AD resulting in a treatment with fewer side effects that may be better suited for a long-term treatment.
- the combination product provide significant improvement of efficacy due to synergistic effects of anti-inflammatory, antimicrobial and skin repair properties of the combination product that is critical for eczema treatment.
- the rationale for combining PA-based compounds with P. acnes conditioned media is to increase anti-inflammatory and anti- S. aureus effects of the composition.
- the PA-based combination candidate are formulated into a suitable format (lotion, cream, gel, or ointment) and used for the treatment of eczema.
- This example describes methods for treating and monitoring eczema that incorporate skin microbiome analysis. It has been shown that AD subjects have skin microbiome dysbiosis which includes increase in Staphylococcus and Corynebacterium bacteria on their skin. At the same time, inflammation increases and the quality of the skin's protective barrier deteriorates. Proliferation of Staphylococcus and Corynebacterium bacteria is associated with reduction of Propionibacterium and other beneficial bacteria. AD flare-ups are also associated with Staphylococcus and Corynebacterium bacteria increase. The correlation between the bacterial overgrowth and eczema including inflammation and the condition of the skin's protective barrier.
- a method of treatment of eczema includes the following steps:
- Microbiome sampling may include skin swabs.
- Microbiome analysis may include 16S RNA sequencing. PCR, or ELISA-based approaches. Microbiome analysis may be performed by specialized clinics, laboratories or by subjects themselves.
Abstract
Disclosed are compositions, methods of treatment using the compositions and methods of preparing the compositions for the treatment of eczema. The compositions may include propionic acid and/or non-steroidal esters of propionic acid. The compositions may further include a corticosteroid, immunomodulator, antibiotic, antibody, colloidal oatmeal, conditioned media prepared by bacterial fermentation, short chain fatty acids, picolinic acid, or emollient. The method of treatment may include analysis of the skin microbiome.
Description
- This application is a divisional of US patent Application 16/302,639, filed Nov. 17, 2018, which is a National Stage of International Application No. PCT/US2017/033347, filed May 18, 2017, which claims the benefit of U.S. Provisional Application Ser. No. 62/338,344 filed May 18, 2016, all of which are incorporated herein by reference in its entirety.
- Not Applicable.
- The present invention is related to compositions and methods for the treatment of eczema, and, in particular, to topical compositions and methods based upon pharmaceutically and cosmetically acceptable preparations of propionic acid and derivatives thereof.
- Eczema (also referred to as atopic dermatitis or AD) predominantly occurs in children in developed countries and is continuing to increase in prevalence among children of low-income nations. The disease is also seen in many adults and follows a relapsing course. AD patients show signs of psychological and psychosocial distress to discomfort and embarrassment or anger regarding their appearance, and patients over 16 years of age showed significantly lower scores on social functioning and mental health than the general population. Up to 60% of children with AD report sleep disturbance due to itching, increasing to 83% during exacerbation, which typically affects the sleep of other household members.
- Disease onset also comes with a significant financial burden for patients and families with an economic impact of almost 1 billion US dollars each year in the USA. The market opportunity is significant with therapeutic sales in the nine major markets—the US, France Germany. Italy. Spain, UK, Japan, China and India—are expected to reach $5.6 billion by 2022 at a Compounded Annual Growth Rate (CAGR) of 3.8%.
- The disease pathogenesis of AD is believed to be due to a combination of environmental and genetic factors resulting in compromised skin barrier function, inflammation and the appearance of erythema and papules. Up to 80-100% of patients suffering from AD are colonized with S. aureus compared to only about 5-30% of control patients. During AD flare-ups, the loss of microbiome diversity towards an overgrowth of S. aureus correlates with disease severity. S. aureus strains isolated from AD lesions have been shown to produce a variety of toxins and enzymes with aggressive cell-damaging and inflammation-inducing properties. S. aureus directly damages keratinocytes by adhering to cells and forming transmembrane pores through the secretion of staphylococcal toxin ultimately leading to the breakdown of cellular ATP metabolism. S. aureus superantigens elicit the production of IgE antibodies, which levels correlate with disease severity.
- Treatments for AD, which reduce the bacterial load, include the administration of oral antibiotics, topical corticosteroids, toxin neutralizing agents and dilute bleach bath, although, studies have shown that S. aureus colonization can rapidly reoccur following termination of treatment, and it is recommended that long-term treatments are used to reduce the occurrence of AD associated flare-ups. Treatment with anti-staphylococcal antibiotics in conjunction with topical corticosteroids demonstrated better clinical improvement than treatment with topical corticosteroids alone suggesting treatments aimed at reducing the bacterial load are effective. Long-term treatments with antibiotics, however, are not advised due to the propensity of S. aureus strains to form antibiotic resistance. Methicillin-resistant S. aureus strains have developed an elaborate set of defenses against commonly used antibiotics and resistant S. aureus strains have been isolated from AD lesions. The prolonged use of topical corticosteroids is also not recommended due to side-effects, and a survey of 200 dermatology outpatients with AD showed that 72.5% of parents worried about applying topical corticosteroids onto their children and 24% of them admitted non-compliance due to these concerns.
- Thus there is a need for new treatments for AD that can decrease the toxic and inflammatory effects induced by S. aureus colonization with minimal side effects and a low propensity for developing resistance, reduced level of disease recurrence and longer disease-free periods.
- Accordingly, the inventors herein have succeeded in devising new compositions and methods of treatment for AD based upon based upon pharmaceutically and cosmetically acceptable preparations of propionic acid and derivatives thereof.
- Thus, in various embodiments, the present invention includes a topical composition for the treatment of AD. The composition includes propionic acid or a non-steroidal ester of propionic acid in a pharmaceutically acceptable topical preparation.
- In various other embodiments, propionic acid is prepared by fermentation of P. acnes. The fermentation product of P. acnes, called conditioned media, is used in the formulation of a topical treatment for atopic dermatitis.
- In various other embodiments, propionic acid or a non-steroidal ester of propionic acid is prepared by chemical synthesis.
- In various other embodiments, the present invention includes a method of treating AD. The method includes administering to a subject in need thereof, a topical composition comprising propionic acid or a non-steroidal ester of propionic acid in a pharmaceutically acceptable topical preparation.
- In still other embodiments, the present invention includes a method of preparing a topical formulation for treating AD, the method comprising combining propionic acid or a non-steroidal ester of propionic acid with a carrier substance in a pharmaceutically acceptable topical preparation.
- In various of the embodiments above, the composition may include propionic acid in a pharmaceutically acceptable topical preparation. The propionic acid may be present in the composition in an amount suitable for delivering to the skin at least 1 mM propionic acid.
- In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid, 2-(2-propionyloxyethoxy)ethylester (PA-DEG-PA) in a pharmaceutically acceptable topical preparation. The PA-DEG-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM-DEG-PA.
- In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl propionate (M-PA) in a pharmaceutically acceptable topical preparation. The M-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM M-PA.
- In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid C12H20O6, glyceryl tripropionate—tripropionin (tri-PA) in a pharmaceutically acceptable topical preparation. The tri-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM tri-PA.
- In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid 2-[2-(propionyloxy)ethoxy]ethyl propionate (di-PA) in a pharmaceutically acceptable topical preparation. The di-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM di-PA. In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid propionylcholineiodide (ch-PA) in a pharmaceutically acceptable topical preparation. The ch-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM ch-PA. In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid propionyl-L-carnitine (ca-PA) in a pharmaceutically acceptable topical preparation. The ca-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM ca-PA.
- In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid that is an ester of glycerol and propionic acid (PA-glycerol-PA) in a pharmaceutically acceptable topical preparation. The PA-glycerol-PA may be present in the composition in an amount suitable for delivering to the skin at least 1 mM PA-glycerol-PA.
- In various embodiments, the composition may further include a corticosteroid. The corticosteroid may be any one or more of clobetasol propionate, diflorasone diacetate, halobetasol propionate, betamethasone, dipropionate, desoximetasone, diflorasone diacetate, fluocinonide, halcinonide, mometasone furoate, triamcinolone acetonide, clocortolone pivalate, desoximetasone, fluocinolone acetonide, flurandrenolide, fluticasone propionate, mometasone furoate, triamcinolone acetonide, hydrocortisone, hydrocortisone acetate, fluocinolone acetonide, hydrocortisone probutate, hydrocortisone valerate, prednicarbate and desonide.
- In various embodiments, the composition may further include an antibiotic. The antibiotic may be anti-staphylococcal antibiotic such as muciprocin, clindamycin, rifampin, doxycycline, or a quinolone.
- In various embodiments, the composition may further include an immunomodulator. The immunomodulator may be a calcineurin inhibitor such as tacrolimus or pimecrolimus.
- In various embodiments, the composition may further include an antibody. The antibody may be a monoclonal antibody that blocks IgE function such as Omalizumab or Dupilumab that blocks the IL-4 receptor alpha subunit.
- In various embodiments, the composition may further include colloidal oatmeal.
- In various embodiments, the composition may further include other short chain fatty acids or their derivatives. The short chain fatty acid may be succinic acid or butyric acid. Short chain fatty acids or their derivatives should be in a concentration that will deliver a dose to the skin that is below MIC for P. acnes.
- In various embodiments, the composition may further include picolinic acid or its derivatives.
- In various embodiments, the composition may further include succinic acid. The succinic acid should be in concentrations that is below MIC for P. acnes.
- In various embodiments the composition may further include conditioned media prepared by fermentation of P. acnes.
- In various embodiments, the composition may further include an emollient. The emollient may be white petrolatum, coconut oil, and other moisture-retaining compounds.
- These and other features, aspects and advantages of the present teachings will become better understood with reference to the following description, examples and appended claims.
- Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.
-
FIG. 1 shows MIC assay of P. acnes conditioned media against S. aureus. -
FIG. 2 shows evaluation of the bactericidal properties of PA against S. aureus using the time-kill assay. -
FIG. 3 shows MIC values for the growth inhibition of S. aureus by tripropionin with or without the addition of an esterase. -
FIG. 4 shows PA and TPA time kill assay in the presence of an esterase. - The present invention is directed to new compositions, methods of treatment and methods of formulation based upon compositions for AD. The compositions are based upon pharmaceutically acceptable preparations of propionic acid and derivatives thereof.
- It has been shown previously by Shu et al. (Shu, M. et al. Fermentation of Propionibacterium acnes, a Commensal Bacterium in the Human Skin Microbiome, as Skin Probiotics against Methicillin-Resistant Staphylococcus aureus. PLoS One. 2013; 8(2):e55380, pp. 1-11) and Wang et al. (Wang, Y. et al., Propionic acid and its esterified derivative suppress the growth of methicillin resistant Staphylococcus aureus USA300. Beneficial Microbes, 2014: 5(2): 161-168) that propionic acid and fermentation products of P. acnes inhibit growth of S. aureus. However, it has not been known that these compounds can be used for the treatment of eczema, reduce itching associated with eczema and eczema symptoms in skin patches and disease recurrence. Additionally, propionic acid can be cosmetically unacceptable due to a strong odor and therefore not suitable for continuous use. Formulations containing odor-free derivatives of propionic acid were identified that showed properties suitable for skincare applications for the treatment of eczema. Additionally, combination products of propionic acid and derivatives thereof with other APIs (active pharmaceutical ingredients) that are currently used for the treatment of eczema and eczema-like diseases were identified and used for the treatment of eczema that provide synergistic effects and significantly improved unexpected properties compared to the API alone including being significantly faster-acting, having less side effects, controlling S. aureus overgrowth as well as inflammation and resulting in less frequent disease recurrence thus managing the symptoms of eczema significantly more efficiently. Combination products were also identified that are suitable for use in children due to reduced side effects that are suitable for long term use.
- As used herein, the singular forms “a”. “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a formulation” includes a plurality of such formulations and reference to “the method” includes reference to one or more methods and equivalents thereof known to those skilled in the art, and so forth.
- As used herein, the term “about” is intended to refer to a range of values above and below a stated value such as for example, values encompassing 10% below up to 10% above a stated value.
- The term “and/or” is intended to mean either or both of two recited elements.
- “Active pharmaceutical ingredient” (“API”) refers to a substance, in particular an antimicrobial or anti-inflammatory agent, in a pharmaceutical composition that is delivered for a desired effect.
- As used herein, the term “combination” with respect to active agents refers to a composition of two or more active agents, in particular, antimicrobial and anti-inflammatory agents. In the present invention, a combination of active agents may include propionic acid derivative of propionic acid. The compositions may further include P. acne-derived conditioned media, a corticosteroid, immunomodulator, antibiotic, antibody, short chain fatty acid (succinic acid or butyric acid), picolinic acid, colloidal oatmeal, and/or emollient. A steroid refers to an organic compound with four rings, A, B. C and D arranged in the specific configuration as shown below:
- An example of a steroid compound having the four rings, A, B, C and D is shown below with IUPAC-α roved ring lettering and atom numbering:
- A non-steroidal compound refers to a compound that lacks the typical steroid four ring system above.
- A corticosteroid refers to any of a group of steroid hormones produced in the adrenal cortex or made synthetically. There are two kinds: glucocorticoids and mineralocorticoids of which glucocorticoids have been used in treating various skin diseases involving inflammation. Unless otherwise indicated herein, the term corticosteroid is intended to refer to glucocorticoids when used in connection with compositions and methods for treating various skin diseases.
- Such corticosteroids that are glucocorticoids include, but are not limited to clobetasol propionate, diflorasone diacetate, halobetasol propionate, betamethasone, dipropionate, desoximetasone, diflorasone diacetate, fluocinonide, halcinonide, mometasone furoate, triamcinolone acetonide, clocortolone pivalate, desoximetasone, fluocinolone acetonide, flurandrenolide, fluticasone propionate, mometasone furoate, triamcinolone acetonide, hydrocortisone, hydrocortisone acetate, fluocinolone acetonide, hydrocortisone probutate, hydrocortisone valerate, prednicarbate, desonide and combinations thereof.
- An antibiotic refers to antibiotic creams and ointments such as anti-staphylococcal antibiotic including muciprocin, clindamycin, rifampin, doxycycline, or a quinolone.
- An immunomodulator refers to Tacrolimus which is an immunomodulator that acts as a calcineurin inhibitor. Tacrolimus is available in 2 strengths, 0.1% for adults and 0.03% for children, although 0.1% preparation is routinely used in children. Tacrolimus is an ointment and is indicated for moderate-to-severe AD. It is indicated for children older than 2 years. Pimecrolimus 1% is also an immunomodulator and calcineurin inhibitor. Pimecrolimus is produced in a cream base for use twice a day; it is indicated for mild AD in persons older than 2 years and is particularly useful on the face. A 2006 black box warning has been issued in the United States based on research that has shown an increase in malignancy in association with the calcineurin inhibitors. These agents are also much more expensive than corticosteroids and should only be used as second-line therapy. Pimecrolimus cream has been marketed as Elidel and tacrolimus ointment and Protopic.
- An antibody refers to Omalizumab which is a monoclonal antibody that blocks IgE function, Dupilumab which is another monoclonal antibody that blocks the IL-4 receptor alpha subunit, which is required for both IL-4 and IL-13 signaling, and other monoclonal antibodies that are involved with IgE function blocking.
- Short chain fatty acids refers to succinic acid, butyric acid or their derivatives. These short chain fatty acids should be used in concentrations to deliver dose to the skin that is below P. acnes MIC. These short chain fatty acids should provide anti-inflammatory effects and not antimicrobial effect (because they are present in a concentration below MIC).
- Colloidal oatmeal refers to substance produced by finely grinding the oat and boiling it to extract the colloidal material. Colloidal oatmeal is used as a skin protectant. Its use as a skin protectant is regulated by the U.S. Food and Drug Administration (FDA) according to the Over-The-Counter Final Monograph for Skin Protectant Drug Products issued in June 2003.
- An emollient refers to substances that soften and moisturize the skin. Emollients/moisturizers work by forming an oily layer on the top of the skin that traps water in the skin. Petrolatum, lanolin, mineral oil, coconut oil and dimethicone are common emollients. Emollients can also contain humectants, including glycerin, lecithin, and propylene glycol that draw water into the outer layer of skin. Many products also have ingredients that soften skin (allantoin). Other moisturizers include white petrolatum, Aquaphor, Atopiclair, Mimyx, and other emollients composed of ceramides, cholesterol and lipids naturally found in the top layer of the skin. The active ingredient should be applied before or together with the emollient.
- Conditioned media refers to fermentation products produced during Propionibacterium acnes (P. acnes) fermentation and secreted into the media.
- Reference herein to an API including, but not limited to propionic acid, a derivative of propionic acid and/or a corticosteroid, antibiotic, immunomodulator, antibody, conditioned media, succinic acid, propionic acid, picolinic acid, colloidal oatmeal, emollient is intended to include pharmaceutically acceptable solvates, salts, hydrates or hydrated salts, their optical isomers, racemates, diastereomers, enantiomers or the polymorphic crystalline structures of the compounds.
- The term “pharmaceutical composition” or ‘pharmaceutical preparation” refers to a composition that combines one or more API's with a pharmaceutically acceptable carrier such that the composition is suitable for therapeutic use in vitro, in vivo or ex vivo.
- As used herein, the term “pharmaceutically acceptable carrier” encompasses any suitable pharmaceutical carriers, such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, various types of wetting agents and the like. The compositions also can include stabilizers and preservatives. Examples of carriers, stabilizers and adjuvants, can be found in Remington: The Science and Practice of Pharmacy. Lippincott Williams & Wilkins. Twenty-First edition (May 19, 2005).
- As used herein, the term “cosmetically acceptable” encompasses any formulation that is acceptable for topical use free of offensive odors, unnatural colors or unacceptable side effects.
- Unless otherwise indicated, concentrations are given as mass weight percentages. i.e. w/w %. Mass weight percentages (w/w %) for combination formulations are calculated as follows:
-
mass % a=mass(a)÷(mass(a)+mass(b)+mass(c)+ . . . )×100 (w/w %). - Compositions
- The present invention includes compositions, treatment methods and formulation methods based upon compositions that may include propionic acid and a derivative of propionic acid. The compositions may also include P. acnes conditioned media, a corticosteroid, and/or antibiotic, immunomodulator, antibody, colloidal oatmeal, emollient, short chain fatty acids, succinic acid, butyric acid, and/or picolinic acid.
- In various embodiments, the composition may include propionic acid in an amount that delivers from about 1 to about 1,000 mM propionic acid to the skin. Such compositions may include propionic acid in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %. In various embodiments, the amount of propionic acid in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %. The propionic acid may further be combined with one or more API's and a carrier system.
- In various embodiments, the composition may include a derivative of propionic acid that is a non-steroidal ester of propionic acid. In various embodiments, the non-steroidal ester may be 2-(2-propionyloxyethoxy)ethylester (PA-DEG-PA) in a pharmaceutically acceptable topical preparation. The PA-DEG-PA may be present in the composition in an amount that delivers from about 1 to about 1,000 mM PA-DEG-PA to the skin. Such compositions may include PA-DEG-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %. In various embodiments, the amount of PA-DEG-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %. The PA-DEG-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient. P. acnes conditioned media and a carrier system. In various embodiments, the composition may include the non-steroidal ester (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl propionate (M-PA) in a pharmaceutically acceptable topical preparation. The M-PA may be present in the composition in an amount that delivers from about 1 to about 1,000 mM M-PA to the skin. Such compositions may include M-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %. In various embodiments, the amount of M-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %. The M-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient, P. acnes conditioned media and a carrier system. In various embodiments, the composition may include the non-steroidal ester of glycerol and propionic acid (PA-glycerol-PA) in a pharmaceutically acceptable topical preparation. The PA-glycerol-PA may be present in the composition in an amount that delivers from about 1 to about 1,000 mM PA-glycerol-PA to the skin. Such compositions may include PA-glycerol-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %. In various embodiments, the amount of PA-glycerol-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %. The PA-glycerol-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient, P. acnes conditioned media and a carrier system.
- In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid C12H20O6, glyceryl tripropionate—tripropionin (tri-PA) in a pharmaceutically acceptable topical preparation. The tri-PA may be present in the composition in an amount that delivers from about 1 to about 1,000 mM tri-PA to the skin. Such compositions may include tri-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %. In various embodiments, the amount of tri-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %. The tri-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient. P. acnes conditioned media and a carrier system.
- In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid 2-[2-(propionyloxy)ethoxy]ethyl propionate (di-PA) in a pharmaceutically acceptable topical preparation. The di-PA may be present in the composition in an amount that delivers from about 1 to about 1,000 mM di-PA to the skin. Such compositions may include di-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %. In various embodiments, the amount of di-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %. The di-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient. P. acnes conditioned media and a carrier system.
- In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid propionylcholineiodide (ch-PA) in a pharmaceutically acceptable topical preparation. The ch-PA may be present in the composition in an amount that delivers from about 1 to about 1.000 mM ch-PA to the skin. Such compositions may include ch-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %. In various embodiments, the amount of ch-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %. The ch-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient, P. acnes conditioned media and a carrier system.
- In various of the embodiments above, the composition may include the non-steroidal derivative of propionic acid propionyl-L-carnitine (ca-PA) in a pharmaceutically acceptable topical preparation. The ca-PA may be present in the composition in an amount that delivers from about 1 to about 1.000 mM ca-PA to the skin. Such compositions may include ca-PA in an amount of from about 0.01 to about 10 w/w % and in particular, from about 0.1, about 0.2, about 0.5 or about 0.75, about 1 w/w % to about 2, about 3, about 4, about 5, about 7.5 or about 10 w/w %. In various embodiments, the amount of ca-PA in the composition may be about 0.1, about 0.2, about 0.5, about 0.75, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 w/w %. The ca-PA may further be combined with one or more API's which may include a corticosteroid, antibiotic, immunomodulator, antibody, colloidal oatmeal, short chain fatty acid (succinic acid or butyric acid), picolinic acid, emollient, P. acnes conditioned media and a carrier system.
- The compositions of the present invention may be incorporated into a pharmaceutically acceptable carrier system which may include creams, ointments, gels, lotions, solutions, cleansing solutions, and the like. Pharmaceutically acceptable carriers may include a surfactant such as an anionic surfactant, a cationic surfactant, a zwitterionic surfactant or a nonionic surfactant. Pharmaceutically acceptable carrier systems may also contain ingredients that include, but are not limited to, saline, aqueous electrolyte solutions, ethanol, dimethyl sulfoxide, dimethyl isosorbide, isopropyl myristate, lauryl lactate, diisopropyl adipate, sodium lauryl sulfoacetate; ionic and nonionic osmotic agents such as sodium chloride, potassium chloride, glycerol, propylene glycol and dextrose; pH adjusters and buffers such as salts of hydroxide, phosphate, citrate, acetate, borate; and trolamine; antioxidants such as salts, acids and/or bases of bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetyl cysteine, cystein, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherols, and ascorbyl palmitate; compounds such as lecithin, phospholipids; petroleum derivatives such as mineral oil and white petrolatum; fats such as lanolin, peanut oil, palm oil, soybean oil; mono-, di-, and triglycerides; polymers of acrylic acid such as carboxypolymethylene gel, and hydrophobically modified cross-linked acrylate copolymer; polysaccharides such as dextrans and glycosaminoglycans such as sodium hyaluronate. Such pharmaceutically acceptable carriers may be preserved against bacterial contamination using preservatives, including, but are not limited to, benzalkonium chloride, ethylene diamine tetra-acetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, natural preservatives such as grapefruit seed extract, or may be formulated as a non-preserved formulation for either single or multiple use.
- Methods of Treatment
- The methods of treatment of the present invention are useful for the treatment of skin diseases including AD flare-ups that are associated with a skin microbiome dysbiosis, including an overgrowth of S. aureus, Corynebacterium and/or other microbes in the skin microbiome and a decrease of P. acnes and/or other microbes in the skin microbiome. Treatment of AD may include determining the skin microbiome profile of a subject, administering to a subject a composition that includes a one or more API's, and monitoring the response and disease state including prevention of flare-ups by monitoring the skin microbiome profile of a subject.
- The compositions of the present invention can be administered at a variety of intervals. In some instances, administration may be once a day. In other instances, administration can be less or more frequently, such as 1, 2, 3, or 4 times a day, 1 time every 2 days, or once a week.
- The treatment methods may be monitored by following any of the pathogenic aspects of AD including skin microbiome profiling including determining the levels and ratios of S. aureus, Corynebacterium and P. acnes in the skin microbiome, genomic and histologic profiling of lesional biomarkers including markers of epidermal hyperplasia, markers of cellular infiltrates and terminal differentiation as well as the measuring of immune markers of inflammatory mediators (See, for example, Mansouri. Y. et al., Immune Pathways in Eczema, and Definition of Biomarkers through Broad and Targeted Therapeutics. J. Clin Med. 2015 May; 4(5): 858-873).
- Formulation Methods
- Formulation methods known in the art may be used to prepare the compositions of the present invention. For example, a one-batch formulation method may be used in which the components of the pharmaceutical formulation are combined in a single container and the components may be added to the container simultaneously or consecutively.
- Preparation of S. aureus (ATCC 29213): A 10 ml culture of S. aureus was prepared in cation-adjusted Mueller Hinton II Broth (CA-MHB) and grown at 37° C. 215 RPM overnight. The overnight culture was subcultured in fresh CA-MHB and grown at 37° C. 215 RPM until an optical density at 600 nm (OD600 nm) of 1.0 was reached. This inoculum preparation was used for all experiments.
- Preparation of P. acnes (ATCC 6919) conditioned media: A P. acnes inoculum (5 ml) was prepared in Reinforced Clostridial Media (RCM) and grown anaerobically at 37° C. in a Gas-Pak (BD) for 48 hours. This culture was subcultured into 5 ml aliquots of fresh RCM and anaerobically grown at 37° C. for 15 days with or without 1% glycerol. P. acnes in RCM without glycerol. RCM with glycerol only, and RCM only were used as controls. The cells were pelleted by centrifugation (12.000×g, 2 mins) and the supernatants were removed and filtered through a 0.22 m filter for sterilization. The filtered supernatants were aliquoted and stored at −80° C. until use.
- The minimal inhibitory concentration (MIC): MIC of P. acnes fermentation extracts, propionic acid (PA), and tripropionin (tri-PA) against S. aureus were determined according to the microbroth dilution method from the Clinical Laboratory Standards Institute (CLSI) document M100-S22. S. aureus was cultured as described above, pelleted by centrifugation, washed with PBS and resuspended in PBS to a concentration of 107 CFU/ml. Two-fold serial dilutions of the P. acnes glycerol fermentation extract (90 μl) or propionic acid (0-100 mM) were added to wells in a 96-well plate followed by 10 μl of the prepared S. aureus inoculum. The MIC of tripropionin was evaluated with and without the presence of 0.2 mg/ml porcine liver esterase (Sigma #E3019-20KU) and the assay was prepared as described for PA. All assays with PA and tri-PA were performed in the presence of 10% DMSO. P. acnes glycerol fermentation extract. PA or tri-PA without S. aureus and TSB broth with S. aureus only were used for negative and positive controls, respectively. Plates were incubated under aerobic conditions for 16 hours at 37° C. Following incubation, each well was resuspended by pipetting and the optical density at 600 nm (OD600) was determined on a plate reader. The MIC value was defined as the first well showing ≥90% reduction in growth compared to controls.
- Time-kill assay: A time-kill assay was performed to monitor the bactericidal activity of propionic acid (PA). An inoculum of S. aureus was prepared as described above and combined with PA at concentrations corresponding to 1×, 2× and 4× the MIC of PA (15 mM) in TSB broth. A final concentration of 10′ CFU/ml of S. aureus was used. Assays were performed in 100 μl volumes in 96-well plates and incubated at 37° C. in a sealed bag to prevent evaporation. At various time points (0, 1, 7, and 24 hours) 10 μl of each sample was removed and diluted 1:10 to 1:104 in sterile PBS and 20 μl of each dilution was spotted in triplicate on a TSB agar plates. Bacterial growth was determined by counting CFUs. The bactericidal properties of PA and tri-PA against S. aureus were also evaluated in the presence of an esterase. Each drug was used at a concentration 4× the MIC value and 0.2 mg/ml porcine liver esterase. The assay was setup and evaluated as described above. Samples were analyzed after 0, 1, 5, and 24 hours.
- S. aureus was incubated with two-fold serial dilutions of P. acnes conditioned media to monitor the growth inhibitory properties.
FIG. 1 shows the decrease in growth of S. aureus with higher concentrations of the P. acnes conditioned media. The P. acnes conditioned media (blue and red) inhibited the growth of S. aureus when the broth is diluted 1:2 whereas the media with glycerol control (green) and media only control (purple) did not inhibit S. aureus growth. The P. acnes conditioned media without glycerol inhibited S. aureus growth at a 1:2 dilution which suggested that the RCM broth contained a substrate for P. acnes fermentation (red). - The bactericidal properties of PA against S. aureus were evaluated using the time-kill assay. Concentrations of PA at 1×, 2× and 4× the MIC (15 mM) were tested against S. aureus and samples were measured after 0, 1, 7, and 24 hours.
FIG. 2 shows that at 4× the MIC. PA is bactericidal against S. aureus after 7 hours. After 7 hours, PA is shown to be bactericidal against S. aureus at 4× the MIC. - The growth inhibitory properties of tripropionin (tri-PA, T-PA) against S. aureus were evaluated in the presence of an esterase.
FIG. 3 shows that the MIC value of tri-PA against S. aureus was 30 mM when an esterase was not added (green). However, when an esterase was added to the reaction (purple), the MIC value decreased to 7.5 mM. This shows that tri-PA inhibited the growth of S. aureus and its growth inhibitory properties were increased in the presence of an esterase. - The bactericidal properties of PA and tri-PA against S. aureus were compared in the presence of an esterase. Both compounds were tested at a concentration 4× the determined MIC and compared to a growth control.
FIG. 4 shows PA and tri-PA time kill assay in the presence of an esterase. PA showed complete killing of S. aureus after 5 hours and tri-PA was able to completely kill S. aureus after 24 hours. - A 5% tripropionin topical cream was formulated using a 50/50 shea butter and coconut oil base with or without 1% colloidal oatmeal. The Shea butter and coconut oil were slowly heated at a low temperature until melted. The mixture was cooled to about 30° C. and triproionin and colloidal oatmeal were added. The mixture was then whipped with a mixer until a homogenous, light solid formed.
- The topical cream containing 5% tripropionin with or without 1% colloidal oatmeal and prepared in the Example 7 was tested in human subjects with eczema. The subjects applied the cream two times per day or whenever needed to reduce itching. The following values were recorded prior and post application: general skin health, itching, appearance of eczema patches (presence of raised skin, oozing/weeping, bleeding, skin softness/smoothness), and side effects. Results showed that after application of the topical formulation containing 5% tripropionin with or without 1% colloidal oatmeal no negative side effects were observed. The subjects used using various topical products for eczema treatment but experienced constant itching in eczema patches that persisted despite prior to using other products. After application of the cream containing tripropionic (+/−colloidal oatmeal), the itching was reduced by at least 80% after application of the cream for 2 days. In 50% of patches, the itching stopped completely after use. There was significant improvement in the general skin health and the skin in eczema patches became much smoother and softer and the appearance of eczema patches became less visible. The oozing/weeping of the skin stopped and any previous bleeding stopped and the patches started healing. The cosmetic acceptability was scored as excellent.
- This example compares PA. PA-DEG-PA. M-PA, tri-PA, di-PA, ch-PA, ca-PA, PA-glycerol-PA and other derivatives for antimicrobial properties.
- The anti-S. aureus activity of PA and PA-derivatives are compared by determining the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of each compound in the presence/absence of keratinocyte lysates. Briefly. 2-fold serial dilutions of each compound (0-100 mM) are made in 96-well plates and incubated with equal volumes of keratinocyte lysates and S. aureus. Toxin producing S. aureus strain 8325-4 and 5 clinical isolates of S. aureus strains obtained from the skin of AD patients are used in this experiment. Following 48 hours of incubation at 37° C., the samples are resuspended by pipetting and the optical density at 600 nm (OD600 nm) are analyzed. The MIC value are defined as the concentration of drug in the first well displaying ≥90% reduction in growth. The MBC values are determined as follows. Briefly, the samples from the MIC assay are diluted 1:10 to 1:106 and each dilution are spread on a TSB agar plate for CFU counting. The MBC value are defined as the first concentration displaying ≥3 log10 drop in CFU/ml. Appropriate negative controls are included, including PBS and appropriate vehicles used to resuspend PA or PA derivatives (+/−keratinocyte lysates).
- The antimicrobial properties of PA and PA derivatives are compared. PA and PA derivatives show antimicrobial properties against S. aureus including bactericidal effects both in the presence and absence of keratinocyte lysates. The anti-S. aureus activity is higher in the presence of keratinocyte lysates. Tri-PA was selected for formulation into a cream and further testing in humans.
- This example compares PA, PA-DEG-PA. M-PA, tri-PA, di-PA, ch-PA, ca-PA. PA-glycerol-PA and other derivatives for anti-inflammatory properties and determines if the compounds can protect keratinocytes from the S. aureus induced toxicity in vitro.
- S. aureus colonized on AD lesions exacerbate AD symptoms through the secretion of proteins, toxins and super-antigens. S. aureus superantigens (S. aureus enterotoxin B (SEB), S. aureus enterotoxin A (SEA) and toxic shock syndrome toxin-1 (TSST-1)) are produced by 57%-65% of S. aureus strains isolated from AD lesions and induce an inflammatory response in keratinocytes through the synthesis and release of TNF-α. Certain S. aureus strains also produce Staphylococcal protein A (SpA), which induces a TNF-α mediated immune response as well. S. aureus directly damages keratinocytes by adhering to the cells and the releasing the lysis-inducing toxin. α-toxin.
- Attenuation of inflammatory responses induced by Staphylococcal protein A, SpA by PA and PA derivatives is measured as follows: The spontaneously immortalized human keratinocyte cell line. HaCaT (Addexbio Technologies), is used to measure the reduction of TNF-α release following stimulation with SpA (Sigma) by PA and PA derivatives. Briefly, 5×105 cells/ml are plated in 24-well plates and incubated for 24 hours. The cells are treated with SpA (10 μg/mL) for 0-24 hours at 37° C. PA or PA derivatives are added to the cells in varying concentrations (0-100 mM) 10 min. 1, 6, 12 and 24 hours prior to the addition of SpA. This measures if PA or derivatives can prevent SpA-induced TNF-α production. Varying concentrations of PA or PA derivative are also added concurrently with SpA or 10 min. 1, 6, 12 and 24 hours after the addition of SpA. This measures if PA or derivatives can assuage the SpA-induced inflammatory response. Controls, including incubating HaCaT cells with PBS (negative control), and incubating HaCaT cells with PA or PA derivative alone are included in testing. As a positive control, LPS, a known stimulator of keratinocytes, is used to induce an inflammatory response in HaCaT cells. Culture supernatants are removed at various time points (0-24 hours) to monitor release of TNF-α using a commercially available ELISA kit. The anti-inflammatory properties of PA or PA derivatives are determined. PA and PA derivatives cause reduction in inflammatory responses when applied prior and/or post stimulation.
- These experiments determine that PA or PA derivative decrease the cytotoxic effect of S. aureus on keratinocytes. The analysis is performed as follows: Primary epidermal keratinocyte cultures NHEK (ATCC@ PCS-200-011) are used in these experiments. Briefly, S. aureus strain 8325-4 (106 CFU/ml) are grown acrobically in nutrient broth, centrifuged and washed twice with 0.85% NaCl followed by resuspention in keratinocyte basal medium. The resuspended bacteria are then added to NHEK cells (5×103 cells/cm3) in 24-well plates. Varying concentrations of PA or PA derivatives (0-100 mM) are added to the NHEK cells prior to, concurrently or following incubation with S. aureus and the ability of each drug to protect keratinocytes from the cytotoxic effects of S. aureus is determined. PBS and appropriate vehicles (used to resuspend PA or PA derivative) are used as negative control. Cell viability is determined by MTT/ESTA (3-[4,5-dimethylthiazol-2-yl]-2.5-diphenyl-tet-razolium bromide/eluted stain assay) after 1, 3, 6, 12 and 24 hours of incubation. To determine if PA and PA derivatives protect keratinocytes by inhibiting the growth of S. aureus in cell culture, the viability of S. aureus is measured. Briefly. S. aureus (100 μl. 106 cells/ml) is added to confluent NHEK cells in the presence or absence of PA or PA derivative. In separate experiments, the supernatant is removed after 2, 4, 8, 16, and 24 hours and centrifuged to pellet the free bacteria. Since S. aureus adheres to keratinocytes, the NHEK cells are also trypsinized and incubated in 0.25% triton x-100 in PBS to lyse the cells. The lysed keratinocytes are combined with the pelleted supernatant and serial dilutions (1:10 to 1:106) are plated on supplemented Brucella broth agar to count the total number of viable S. aureus cells. PA and PA derivatives show protective properties towards keratinocytes and reduce cytotoxis effects of S. aureus on keratinocytes. PA or PA derivative exhibit concentration-dependent attenuation in TNF-α release following keratinocyte stimulation by SpA. In addition to SpA, other S. aureus superantigens, such as staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin-1 (TSST-1), that elicit TNF-α production in keratinocytes, can be used for TNF-α induction and PA and PA derivatives evaluation. PA or PA derivatives are added prior to, during, or post incubation with SEB or TSST-1 to monitor changes in TNF-α production. PA derivative with a smaller MW (<500 Da) will be preferentially used to increase cell membrane penetration properties.
- The tri-PA candidate displaying both the anti-S. aureus and anti-inflammatory properties was used for formulation development and cream containing tri-PA with or without colloidal oatmeal was used for the treatment of eczema.
- PA derivatives that exhibit antimicrobial properties but do not exhibit sufficient anti-inflammatory properties are used for the treatment of eczema in combination with corticosteroids. The rationale for combining PA or PA derivative with corticosteroids is to decrease the concentration of corticosteroids needed to treat AD lesions resulting in a treatment with fewer side effects, restoring a healthier, more diverse microbiome, restoring P. acnes in the microbiome, preventing S. aureus overgrowth. Products with lower concentration of corticosteroids are suitable for a long-term treatment approach. The combination product provide significant improvement of efficacy due to synergistic effects of anti-inflammatory, antimicrobial (provided by PA and/or PA derivatives) and skin repair properties of the product that is critical for eczema treatment.
- PA and PA derivatives are also formulated in combination with antibiotics. The rationale for combining PA or PA derivatives with antibiotics is to decrease the concentration of antibiotics needed to treat S. aureus overgrowth and S. aureus-associated infections in AD subjects resulting in treatment with fewer side effects and less risk of developing resistance. Resistance prevention is a significant benefit that is provided by PA or PA derivative component in the formulation. Avoidance and/or lower doses of antibiotics restores a healthier, more diverse microbiome while increasing P. acnes in the microbiome and preventing S. aureus overgrowth. This makes the product suitable for a long-term treatment approach. In addition, the combination product provide synergies and significant improvement of efficacy due to anti-inflammatory, skin healing and antimicrobial properties of the product.
- PA and PA derivatives are also formulated in combination with immunomodulators including tacrolimus or pimecrolimus. The rationale for combining PA or PA derivatives with immunomodulators is to decrease the concentration of immunomodulators needed to treat AD resulting in treatment with fewer side effects that restores a healthier, more diverse microbiome, increases P. acnes in the microbiome and prevents S. aureus overgrowth, and is suitable for a long-term treatment approach. In addition. PA or PA derivatives improve the efficacy of tacrolimus or pimecrolimus when tacrolimus or pimecrolimus is used in recommended strength of 0.1% tacrolimus for adults and 0.03% tactrolimus for children or 1% pimecrolimus. The combination product provide significant improvement of efficacy due to synergistic effects of anti-inflammatory, antimicrobial (provided by PA and/or PA derivatives) and skin repair properties of the product that is critical for eczema treatment.
- PA and PA derivatives are also formulated in combination with antibodies, such as monoclonal antibodies Omalizuma. Dupilumab and other monoclonal antibodies that block IgE function. The rationale for combining PA or PA derivatives with antibodies is to decrease the concentration of antibodies needed to treat AD resulting in a treatment with fewer side effects, less cost, and restoring a healthier, more diverse microbiome, increasing P. acnes in the microbiome and preventing S. aureus overgrowth, and a treatment suitable for a long-term use. The combination product provide significant improvement of efficacy due to synergistic effects of anti-inflammatory, antimicrobial and skin repair properties of the combination product that is critical for eczema treatment.
- PA and PA derivatives are also formulated in combination with short chain fatty acids including succinic acid and butyric acid and their derivatives. The rationale for combining PA-based compounds with short chain fatty acid (succinic acid or butyric acid) is to significantly increase anti-inflammatory effects of the composition. The combination product provide significant improvement of efficacy due to synergistic effects of anti-inflammatory, antimicrobial and skin repair properties of the combination product that is critical for eczema treatment.
- PA and PA derivatives are also formulated in combination with emollients such as white petrolate. The rationale for combining PA or PA derivatives with emollients is to restore dysfunctional epidermal barrier, combat xerosis and transepidermal water loss. The PA or PA derivative are applied before or at the same time as the emollient.
- The rationale for combing PA-based compounds with corticosteroids, antibiotics, immunomodulators, antibodies, colloidal oatmeal or other APIs is to improve the efficacy of the treatment and potentially decrease the concentration of APIs needed to treat AD resulting in a treatment with fewer side effects that may be better suited for a long-term treatment. The combination product provide significant improvement of efficacy due to synergistic effects of anti-inflammatory, antimicrobial and skin repair properties of the combination product that is critical for eczema treatment.
- The rationale for combining PA-based compounds with short chain fatty acid (succinic acid or butyric acid) is to increase anti-inflammatory effects of the composition.
- The rationale for combining PA-based compounds with P. acnes conditioned media is to increase anti-inflammatory and anti-S. aureus effects of the composition.
- The rationale for combining PA-based compounds with picolinic acid is to increase anti-S. aureus effects of the composition.
- The PA-based combination candidate are formulated into a suitable format (lotion, cream, gel, or ointment) and used for the treatment of eczema.
- This example describes methods for treating and monitoring eczema that incorporate skin microbiome analysis. It has been shown that AD subjects have skin microbiome dysbiosis which includes increase in Staphylococcus and Corynebacterium bacteria on their skin. At the same time, inflammation increases and the quality of the skin's protective barrier deteriorates. Proliferation of Staphylococcus and Corynebacterium bacteria is associated with reduction of Propionibacterium and other beneficial bacteria. AD flare-ups are also associated with Staphylococcus and Corynebacterium bacteria increase. The correlation between the bacterial overgrowth and eczema including inflammation and the condition of the skin's protective barrier. A method of treatment of eczema includes the following steps:
-
- 1) Obtaining a sample of skin microbiome.
- 2) Analysis of skin microbiome
- 3) Determining the levels of microbiome dysbiosis by determining the levels of microbes such as Staphylococcus, Corynebacterium and Propionibacterium bacteria and comparing them to levels of Staphylococcus, Corynebacterium and Propionibacterium bacteria in healthy skin.
- 4) Deciding on the treatment regimen, which may include applying a treatment containing PA or PA derivatives.
- 5) Applying the treatment and monitoring symptoms.
- 6) Monitoring treatment effectiveness by monitoring the skin microbiome changes.
- 7) Changing the treatment if the levels of Staphylococcus, Corynebacterium and Propionibacterium remain unchanged.
- 8) Predicting AD flare-up timing by monitoring the skin microbiome dysbiosis.
- 9) Restarting treatment if levels Staphylococcus, Corynebacterium and Propionibacterium are becoming dysbiotic.
- 10) Incorporating microbiome history into the AD subject treatment record.
- Microbiome sampling may include skin swabs. Microbiome analysis may include 16S RNA sequencing. PCR, or ELISA-based approaches. Microbiome analysis may be performed by specialized clinics, laboratories or by subjects themselves.
- As various changes could be made in the above methods and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
- All references cited in this specification, including patents and patent applications, are hereby incorporated by reference. The discussion of references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art. Applicant reserves the right to challenge the accuracy and pertinency of the cited references.
- The detailed description set-forth above is provided to aid those skilled in the art in practicing the present invention. However, the invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.
- All publications, patents, patent applications and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention. Specifically intended to be within the scope of the present invention, and incorporated herein by reference in its entirety, is the following publications:
- Shu, M. et al. Fermentation of Propionibacterium acnes, a Commensal Bacterium in the Human Skin Microbiome, as Skin Probiotics against Methicillin-Resistant Staphylococcus aureus, PLoS One. 2013; 8(2):e55380, pp. 1-11.
- Wang. Y. et al., Propionic acid and its esterified derivative suppress the growth of methicillin resistant Staphylococcus aureus USA300. Beneficial Microbes, 2014; 5(2): 161-168.
Claims (15)
1. A method of treating atopic dermatitis (AD), the method comprising administering to a subject in need thereof, a composition consisting of
a non-steroidal ester of propionic acid, and
at least one ingredient selected from the group consisting of an antimicrobial agent, an anti-inflammatory agent, an immunomodulator, an antibiotic, colloidal oatmeal, succinic acid, butyric acid, conditioned media prepared by microbial fermentation, and an emollient, in a pharmaceutically acceptable topical preparation.
2. The method of claim 1 , wherein the non-steroidal ester of propionic acid is selected from the group consisting of tripropionin (Tri-PA), 2-(2-propionyloxyethoxy)ethylester (PA-DEG-PA), ester of glycerol and propionic acid (PA-glycerol-PA), (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl propionate (M-PA), 2-[2-(propionyloxy)ethoxy]ethyl propionate (di-PA), propionylcholineiodide (ch-PA), and propionyl-L-carnitine (ca-PA).
3. The method of claim 1 , wherein the non-steroidal ester of propionic acid is tripropionin (Tri-PA).
4. The method of claim 1 , wherein the non-steroidal ester of propionic acid is present in the composition in an amount from about 0.5 w/w % to about 10 w/w %.
5. The method of claim 1 , wherein the non-steroidal ester of propionic acid is Triporopionin (Tri-PA) present in the composition in an amount from about 0.5 w/w % to about 10 w/w %.
6. The method of claim 1 , wherein the at least one ingredient is colloidal oatmeal.
7. The method of claim 1 , wherein the at least one ingredient is an anti-inflammatory agent.
8. The method of claim 7 , wherein the anti-inflammatory agent is a corticosteroid.
9. The method of claim 1 , wherein the at least one ingredient is an antibiotic.
10. The method of claim 1 , wherein the at least one ingredient is an emollient.
11. The method of claim 1 , wherein the at least one ingredient is an immunomodulator.
12. The method of claim 1 , wherein the at least one ingredient is succinic acid or butyric acid.
13. The method of claim 1 , wherein the at least one ingredient is conditioned media prepared by microbial fermentation.
14. The method of claim 1 , wherein the at least one ingredient is an antimicrobial agent.
15. The method of claim 3 , wherein the Tri-PA is present in the composition in an amount from about 0.5 w/w % to about 10 w/w %.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/746,796 US20220273595A1 (en) | 2016-05-18 | 2022-05-17 | Compositions and methods for treating eczema |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662338344P | 2016-05-18 | 2016-05-18 | |
PCT/US2017/033347 WO2017201297A1 (en) | 2016-05-18 | 2017-05-18 | Compositions and methods for treating eczema |
US201816302639A | 2018-11-17 | 2018-11-17 | |
US17/746,796 US20220273595A1 (en) | 2016-05-18 | 2022-05-17 | Compositions and methods for treating eczema |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2017/033347 Division WO2017201297A1 (en) | 2016-05-18 | 2017-05-18 | Compositions and methods for treating eczema |
US16/302,639 Division US11364214B2 (en) | 2016-05-18 | 2017-05-18 | Compositions and methods for treating eczema |
Publications (1)
Publication Number | Publication Date |
---|---|
US20220273595A1 true US20220273595A1 (en) | 2022-09-01 |
Family
ID=60326595
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/302,639 Active US11364214B2 (en) | 2016-05-18 | 2017-05-18 | Compositions and methods for treating eczema |
US17/746,796 Abandoned US20220273595A1 (en) | 2016-05-18 | 2022-05-17 | Compositions and methods for treating eczema |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/302,639 Active US11364214B2 (en) | 2016-05-18 | 2017-05-18 | Compositions and methods for treating eczema |
Country Status (4)
Country | Link |
---|---|
US (2) | US11364214B2 (en) |
EP (1) | EP3458158A4 (en) |
CA (1) | CA3044544A1 (en) |
WO (1) | WO2017201297A1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11951140B2 (en) | 2011-02-04 | 2024-04-09 | Seed Health, Inc. | Modulation of an individual's gut microbiome to address osteoporosis and bone disease |
US11844720B2 (en) | 2011-02-04 | 2023-12-19 | Seed Health, Inc. | Method and system to reduce the likelihood of dental caries and halitosis |
US11951139B2 (en) | 2015-11-30 | 2024-04-09 | Seed Health, Inc. | Method and system for reducing the likelihood of osteoporosis |
US11839632B2 (en) | 2013-12-20 | 2023-12-12 | Seed Health, Inc. | Topical application of CRISPR-modified bacteria to treat acne vulgaris |
US11826388B2 (en) | 2013-12-20 | 2023-11-28 | Seed Health, Inc. | Topical application of Lactobacillus crispatus to ameliorate barrier damage and inflammation |
US11833177B2 (en) | 2013-12-20 | 2023-12-05 | Seed Health, Inc. | Probiotic to enhance an individual's skin microbiome |
CA3055930A1 (en) * | 2017-03-10 | 2018-09-13 | Prodermiq, Inc. | Customized skin care products and personal care products based on the analysis of skin flora |
WO2023215844A1 (en) * | 2022-05-04 | 2023-11-09 | Dermala, Inc. | Propionic acid ester compositions useful for treating eczema |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6080394A (en) * | 1999-11-08 | 2000-06-27 | Dow Corning Corporation | Polar solvent-in-oil emulsions and multiple emulsions |
DE10133200A1 (en) * | 2001-07-07 | 2003-01-23 | Beiersdorf Ag | Use of topical compositions containing carnitine and its precursors, derivatives or metabolites to, e.g. improve skin condition or to treat or prevent skin disorders, abnormal lipid peroxidation, reduced cell-cell communication or dandruff |
US20030064081A1 (en) * | 2001-10-01 | 2003-04-03 | Morgan William H. | Topical anti-pruritic composition |
KR100840391B1 (en) * | 2005-10-19 | 2008-06-23 | 변무원 | A pharmaceutical agent for ameliorating symptoms of atopic dermatitis containing refining wood vinegar |
BRPI0721698A2 (en) * | 2007-05-11 | 2013-01-22 | Sigma Tau Ind Famaceutiche Riunite S P A | Useful gel for the release of cosmetic active ingredients |
CA2728789A1 (en) * | 2008-06-24 | 2009-12-30 | Micropharma Limited | Nitric oxide compositions and devices and methods for cosmesis |
EP2468270A1 (en) * | 2010-12-21 | 2012-06-27 | GALENpharma GmbH | (R)-2-(3-fluoro-4-phenylphenyl)propionic acid for use in the treatment of skin diseases |
JP6031120B2 (en) * | 2011-12-06 | 2016-11-24 | ユニリーバー・ナームローゼ・ベンノートシヤープ | Disinfectant composition |
CN105050584A (en) * | 2013-02-28 | 2015-11-11 | 普雷西恩护肤公司 | Topical formulations of corticosteroids with enhanced bioavailability |
EP3903824A1 (en) | 2014-01-10 | 2021-11-03 | The Regents of The University of California | Skin probiotic |
US20150306230A1 (en) * | 2014-04-28 | 2015-10-29 | Celanese Acetate Llc | Drug delivery vehicles comprising cellulose derivatives, starch derivatives, and combinations thereof |
-
2017
- 2017-05-18 US US16/302,639 patent/US11364214B2/en active Active
- 2017-05-18 WO PCT/US2017/033347 patent/WO2017201297A1/en unknown
- 2017-05-18 EP EP17800174.9A patent/EP3458158A4/en not_active Withdrawn
- 2017-05-18 CA CA3044544A patent/CA3044544A1/en active Pending
-
2022
- 2022-05-17 US US17/746,796 patent/US20220273595A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US20190290605A1 (en) | 2019-09-26 |
US11364214B2 (en) | 2022-06-21 |
EP3458158A4 (en) | 2020-02-05 |
CA3044544A1 (en) | 2017-11-23 |
WO2017201297A1 (en) | 2017-11-23 |
EP3458158A1 (en) | 2019-03-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220273595A1 (en) | Compositions and methods for treating eczema | |
JP6944399B2 (en) | Probiotic bacteria | |
US11590149B2 (en) | Compositions and methods for treating acne vulgaris | |
Wu et al. | Daptomycin: evaluation of a high-dose treatment strategy | |
JP7313117B2 (en) | new usage | |
US20210030818A1 (en) | Compositions for use in balancing microbiome | |
Wang et al. | A new pharmacological effect of levornidazole: inhibition of NLRP3 inflammasome activation | |
Nakagawa et al. | Tacrolimus has antifungal activities against Malassezia furfur isolated from healthy adults and patients with atopic dermatitis | |
JP2021522323A (en) | Composition for the treatment of skin diseases | |
US20220331386A1 (en) | Anti-microbial seaweed extracts, compositions and uses thereof | |
MX2012004509A (en) | A skin external composition comprising a salt and sugar as active ingredients for preventing and treating vaginosis and the use thereof. | |
JP2015528822A (en) | Inhibition of pathogenic microorganism adhesion by sucrose stearate and / or sorbitan ester in cosmetic treatment of skin atopy | |
US11224619B2 (en) | Formulations and methods for treatment of inflammatory skin diseases | |
EP3914227A1 (en) | Compositions for use in preventing acne | |
RU2481828C2 (en) | 1-aminoalkylcyclohexane derivatives for treatment of inflammatory skin diseases | |
AU2013237576A1 (en) | Use of amphoteric surfactants for the prevention and treatment of pathogenic vaginal biofilms in vaginal infections | |
KR20020044851A (en) | Sphingolipid composition for preventing or treating acnes | |
US20230115784A1 (en) | Compositions and methods for treating acne vulgaris | |
KR20180135169A (en) | Composition for improving skin acne comprising quercetin and vitamin D | |
Phatangare | Formulation development and evaluation of Calcipotriol and Prednicarbate for topical treatment of psoriasis | |
Filaire et al. | Atopic Dermatitis Prevalence and How to Manage It | |
Al-Sabbagh et al. | Comparison between the Effect of Normal and Nanoparticles of ZnO Against Different Types of Bacteria Isolated from Patients with Acne | |
Tran | Effect of Oxyresveratrol on Inflammatory Skin Diseases|| | |
DE102014213654A1 (en) | Synergistic antibiotic compositions | |
WO2019079150A1 (en) | Compositions and methods to treat atopic dermatitis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |