US20210161870A1 - Roflumilast formulations with an improved pharmacokinetic profile - Google Patents
Roflumilast formulations with an improved pharmacokinetic profile Download PDFInfo
- Publication number
- US20210161870A1 US20210161870A1 US17/155,679 US202117155679A US2021161870A1 US 20210161870 A1 US20210161870 A1 US 20210161870A1 US 202117155679 A US202117155679 A US 202117155679A US 2021161870 A1 US2021161870 A1 US 2021161870A1
- Authority
- US
- United States
- Prior art keywords
- roflumilast
- composition
- patient
- formulation
- cream
- 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
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 title claims abstract description 409
- 229960002586 roflumilast Drugs 0.000 title claims abstract description 323
- 239000000203 mixture Substances 0.000 title claims abstract description 291
- 238000009472 formulation Methods 0.000 title description 186
- 238000000034 method Methods 0.000 claims abstract description 45
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 38
- 230000036470 plasma concentration Effects 0.000 claims abstract description 28
- 208000035475 disorder Diseases 0.000 claims abstract description 24
- 230000002829 reductive effect Effects 0.000 claims abstract description 23
- 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 20
- 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 20
- 208000017520 skin disease Diseases 0.000 claims abstract description 17
- 230000006872 improvement Effects 0.000 claims abstract description 16
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 14
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 12
- 230000005764 inhibitory process Effects 0.000 claims abstract description 11
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 8
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 claims abstract description 6
- 208000006673 asthma Diseases 0.000 claims abstract description 6
- 208000008742 seborrheic dermatitis Diseases 0.000 claims abstract description 6
- 239000006071 cream Substances 0.000 claims description 97
- 238000011282 treatment Methods 0.000 claims description 50
- 229940006829 daliresp Drugs 0.000 claims description 30
- 239000006260 foam Substances 0.000 claims description 23
- 230000004580 weight loss Effects 0.000 claims description 14
- 206010067484 Adverse reaction Diseases 0.000 claims description 10
- 230000006838 adverse reaction Effects 0.000 claims description 10
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 8
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 claims 10
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims 10
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims 10
- 230000003111 delayed effect Effects 0.000 claims 5
- 206010048768 Dermatosis Diseases 0.000 claims 3
- 230000000694 effects Effects 0.000 abstract description 30
- 230000009885 systemic effect Effects 0.000 abstract description 24
- 238000011200 topical administration Methods 0.000 abstract description 14
- 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 abstract description 9
- 238000013103 analytical ultracentrifugation Methods 0.000 abstract description 9
- 210000004072 lung Anatomy 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 abstract description 2
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 abstract description 2
- 210000000056 organ Anatomy 0.000 abstract description 2
- 229910019142 PO4 Inorganic materials 0.000 description 85
- 239000010452 phosphate Substances 0.000 description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 84
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 69
- -1 cyclopropylmethoxy Chemical group 0.000 description 67
- 210000003491 skin Anatomy 0.000 description 53
- 230000000699 topical effect Effects 0.000 description 49
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 47
- 239000013078 crystal Substances 0.000 description 45
- 239000004094 surface-active agent Substances 0.000 description 45
- 239000004480 active ingredient Substances 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000000047 product Substances 0.000 description 42
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 39
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 39
- 239000002245 particle Substances 0.000 description 34
- 239000003814 drug Substances 0.000 description 33
- 229940051250 hexylene glycol Drugs 0.000 description 33
- 239000000243 solution Substances 0.000 description 33
- 229940079593 drug Drugs 0.000 description 30
- 239000003981 vehicle Substances 0.000 description 28
- 239000012071 phase Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000000839 emulsion Substances 0.000 description 26
- 238000003860 storage Methods 0.000 description 22
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 21
- 229940025703 topical product Drugs 0.000 description 20
- 241000282887 Suidae Species 0.000 description 17
- 230000008859 change Effects 0.000 description 17
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 16
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 16
- 201000010099 disease Diseases 0.000 description 14
- 239000000499 gel Substances 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 208000016261 weight loss Diseases 0.000 description 13
- 239000008186 active pharmaceutical agent Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- 230000002496 gastric effect Effects 0.000 description 12
- 238000002156 mixing Methods 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- 229940100611 topical cream Drugs 0.000 description 12
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 description 11
- 229940093541 dicetylphosphate Drugs 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 11
- PCGSQNPMMSALEJ-UHFFFAOYSA-N roflumilast n-oxide Chemical compound ClC1=C[N+]([O-])=CC(Cl)=C1NC(=O)C1=CC=C(OC(F)F)C(OCC2CC2)=C1 PCGSQNPMMSALEJ-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 150000001204 N-oxides Chemical class 0.000 description 10
- 229940082500 cetostearyl alcohol Drugs 0.000 description 10
- 238000009826 distribution Methods 0.000 description 10
- 239000002674 ointment Substances 0.000 description 10
- 238000001907 polarising light microscopy Methods 0.000 description 10
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 10
- 239000002562 thickening agent Substances 0.000 description 10
- 239000012049 topical pharmaceutical composition Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 230000035515 penetration Effects 0.000 description 9
- 239000011591 potassium Substances 0.000 description 9
- 229910052700 potassium Inorganic materials 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 244000291564 Allium cepa Species 0.000 description 8
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 8
- 229920002125 Sokalan® Polymers 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 230000002209 hydrophobic effect Effects 0.000 description 8
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 8
- 235000019271 petrolatum Nutrition 0.000 description 8
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 8
- 229940068196 placebo Drugs 0.000 description 8
- 239000000902 placebo Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 229940126534 drug product Drugs 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 239000000825 pharmaceutical preparation Substances 0.000 description 7
- 229960004063 propylene glycol Drugs 0.000 description 7
- 210000000434 stratum corneum Anatomy 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000004264 Petrolatum Substances 0.000 description 6
- 229920002675 Polyoxyl Polymers 0.000 description 6
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000282898 Sus scrofa Species 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 230000002411 adverse Effects 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 229940066842 petrolatum Drugs 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 6
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 6
- 229960003415 propylparaben Drugs 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 210000004761 scalp Anatomy 0.000 description 6
- 239000004909 Moisturizer Substances 0.000 description 5
- 206010028813 Nausea Diseases 0.000 description 5
- 206010047700 Vomiting Diseases 0.000 description 5
- 208000010668 atopic eczema Diseases 0.000 description 5
- 229960001631 carbomer Drugs 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 229940075529 glyceryl stearate Drugs 0.000 description 5
- 230000001333 moisturizer Effects 0.000 description 5
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 5
- 230000008693 nausea Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 5
- 239000003380 propellant Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 229910001220 stainless steel Inorganic materials 0.000 description 5
- 239000010935 stainless steel Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 241000233788 Arecaceae Species 0.000 description 4
- 206010010144 Completed suicide Diseases 0.000 description 4
- 206010012735 Diarrhoea Diseases 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- 239000004166 Lanolin Substances 0.000 description 4
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 4
- 206010042458 Suicidal ideation Diseases 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000036765 blood level Effects 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- YVIGPQSYEAOLAD-UHFFFAOYSA-L disodium;dodecyl phosphate Chemical compound [Na+].[Na+].CCCCCCCCCCCCOP([O-])([O-])=O YVIGPQSYEAOLAD-UHFFFAOYSA-L 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 239000003974 emollient agent Substances 0.000 description 4
- 210000002615 epidermis Anatomy 0.000 description 4
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 229960005150 glycerol Drugs 0.000 description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 4
- 210000004209 hair Anatomy 0.000 description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 4
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 4
- 210000003127 knee Anatomy 0.000 description 4
- 229940039717 lanolin Drugs 0.000 description 4
- 235000019388 lanolin Nutrition 0.000 description 4
- 239000006210 lotion Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 4
- 229940046947 oleth-10 phosphate Drugs 0.000 description 4
- 229940100460 peg-100 stearate Drugs 0.000 description 4
- 239000012466 permeate Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229920002884 Laureth 4 Polymers 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 238000001016 Ostwald ripening Methods 0.000 description 3
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 3
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 3
- 206010040880 Skin irritation Diseases 0.000 description 3
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 3
- 206010065604 Suicidal behaviour Diseases 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000013566 allergen Substances 0.000 description 3
- 230000000172 allergic effect Effects 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000002500 effect on skin Effects 0.000 description 3
- 239000008387 emulsifying waxe Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 229920001519 homopolymer Polymers 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 206010022437 insomnia Diseases 0.000 description 3
- 239000001282 iso-butane Substances 0.000 description 3
- 235000013847 iso-butane Nutrition 0.000 description 3
- 229940061515 laureth-4 Drugs 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 3
- 229960002216 methylparaben Drugs 0.000 description 3
- 239000004200 microcrystalline wax Substances 0.000 description 3
- 235000019808 microcrystalline wax Nutrition 0.000 description 3
- 244000309715 mini pig Species 0.000 description 3
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 3
- 229920005615 natural polymer Polymers 0.000 description 3
- 229940049964 oleate Drugs 0.000 description 3
- 239000007935 oral tablet Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 238000005192 partition Methods 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- 229940068917 polyethylene glycols Drugs 0.000 description 3
- RMGVATURDVPNOZ-UHFFFAOYSA-M potassium;hexadecyl hydrogen phosphate Chemical compound [K+].CCCCCCCCCCCCCCCCOP(O)([O-])=O RMGVATURDVPNOZ-UHFFFAOYSA-M 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 239000001294 propane Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000008299 semisolid dosage form Substances 0.000 description 3
- 230000008591 skin barrier function Effects 0.000 description 3
- 231100000475 skin irritation Toxicity 0.000 description 3
- 230000036556 skin irritation Effects 0.000 description 3
- 229940083542 sodium Drugs 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 229920001059 synthetic polymer Polymers 0.000 description 3
- 229940045136 urea Drugs 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 230000008673 vomiting Effects 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- HBXWUCXDUUJDRB-UHFFFAOYSA-N 1-octadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC HBXWUCXDUUJDRB-UHFFFAOYSA-N 0.000 description 2
- ULQISTXYYBZJSJ-UHFFFAOYSA-N 12-hydroxyoctadecanoic acid Polymers CCCCCCC(O)CCCCCCCCCCC(O)=O ULQISTXYYBZJSJ-UHFFFAOYSA-N 0.000 description 2
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 2
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- ASKIVFGGGGIGKH-UHFFFAOYSA-N 2,3-dihydroxypropyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OCC(O)CO ASKIVFGGGGIGKH-UHFFFAOYSA-N 0.000 description 2
- VOFRZBBLONRUHY-KVVVOXFISA-N 2-(2-hydroxyethylamino)ethanol;2-[2-[2-[(z)-octadec-9-enoxy]ethoxy]ethoxy]ethyl dihydrogen phosphate Chemical compound OCCNCCO.CCCCCCCC\C=C/CCCCCCCCOCCOCCOCCOP(O)(O)=O VOFRZBBLONRUHY-KVVVOXFISA-N 0.000 description 2
- PWQNOLAKMCLNJI-KTKRTIGZSA-N 2-[2-[2-[(z)-octadec-9-enoxy]ethoxy]ethoxy]ethyl dihydrogen phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCOCCOCCOP(O)(O)=O PWQNOLAKMCLNJI-KTKRTIGZSA-N 0.000 description 2
- NLMKTBGFQGKQEV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hexadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO NLMKTBGFQGKQEV-UHFFFAOYSA-N 0.000 description 2
- DSAOTEZSRTZBDS-UHFFFAOYSA-N 2-[3-[[dimethyl(trimethylsilyloxy)silyl]oxy-methyl-trimethylsilyloxysilyl]propoxy]ethyl dihydrogen phosphate Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(O[Si](C)(C)C)CCCOCCOP(O)(O)=O DSAOTEZSRTZBDS-UHFFFAOYSA-N 0.000 description 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 2
- ICIDSZQHPUZUHC-UHFFFAOYSA-N 2-octadecoxyethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCO ICIDSZQHPUZUHC-UHFFFAOYSA-N 0.000 description 2
- RMTFNDVZYPHUEF-XZBKPIIZSA-N 3-O-methyl-D-glucose Chemical compound O=C[C@H](O)[C@@H](OC)[C@H](O)[C@H](O)CO RMTFNDVZYPHUEF-XZBKPIIZSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 2
- 102000018832 Cytochromes Human genes 0.000 description 2
- 108010052832 Cytochromes Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- NWGKJDSIEKMTRX-BFWOXRRGSA-N [(2r)-2-[(3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)C1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-BFWOXRRGSA-N 0.000 description 2
- MEESPVWIOBCLJW-KTKRTIGZSA-N [(z)-octadec-9-enyl] dihydrogen phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCCOP(O)(O)=O MEESPVWIOBCLJW-KTKRTIGZSA-N 0.000 description 2
- ILYTUKNTXBTWLC-QXMHVHEDSA-N [ethoxy(hydroxy)phosphoryl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OP(O)(=O)OCC ILYTUKNTXBTWLC-QXMHVHEDSA-N 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 229960001164 apremilast Drugs 0.000 description 2
- 230000004888 barrier function Effects 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
- BUOSLGZEBFSUDD-BGPZCGNYSA-N bis[(1s,3s,4r,5r)-4-methoxycarbonyl-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 2,4-diphenylcyclobutane-1,3-dicarboxylate Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1C(C=2C=CC=CC=2)C(C(=O)O[C@@H]2[C@@H]([C@H]3CC[C@H](N3C)C2)C(=O)OC)C1C1=CC=CC=C1 BUOSLGZEBFSUDD-BGPZCGNYSA-N 0.000 description 2
- WFFZELZOEWLYNK-CLFAGFIQSA-N bis[(z)-octadec-9-enyl] hydrogen phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCCOP(O)(=O)OCCCCCCCC\C=C/CCCCCCCC WFFZELZOEWLYNK-CLFAGFIQSA-N 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940096529 carboxypolymethylene Drugs 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229940073639 ceteareth-6 Drugs 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229940117583 cocamine Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- USZAGAREISWJDP-UHFFFAOYSA-N crisaborole Chemical compound C=1C=C2B(O)OCC2=CC=1OC1=CC=C(C#N)C=C1 USZAGAREISWJDP-UHFFFAOYSA-N 0.000 description 2
- 229950008199 crisaborole Drugs 0.000 description 2
- 230000001351 cycling effect Effects 0.000 description 2
- 229940086555 cyclomethicone Drugs 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229940008099 dimethicone Drugs 0.000 description 2
- 229940066254 dimethicone peg-7 phosphate Drugs 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 2
- GWTCIAGIKURVBJ-UHFFFAOYSA-L dipotassium;dodecyl phosphate Chemical compound [K+].[K+].CCCCCCCCCCCCOP([O-])([O-])=O GWTCIAGIKURVBJ-UHFFFAOYSA-L 0.000 description 2
- KLJJISMFFCYLQO-XXAVUKJNSA-L disodium;[(z)-octadec-9-enyl] phosphate Chemical compound [Na+].[Na+].CCCCCCCC\C=C/CCCCCCCCOP([O-])([O-])=O KLJJISMFFCYLQO-XXAVUKJNSA-L 0.000 description 2
- CYFHLEMYBPQRGN-UHFFFAOYSA-N ditetradecyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCC CYFHLEMYBPQRGN-UHFFFAOYSA-N 0.000 description 2
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 2
- TVACALAUIQMRDF-UHFFFAOYSA-N dodecyl dihydrogen phosphate Chemical compound CCCCCCCCCCCCOP(O)(O)=O TVACALAUIQMRDF-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000004088 foaming agent Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229940074046 glyceryl laurate Drugs 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- NDSQWHRDZXKSHX-UHFFFAOYSA-N hexadecanoic acid octadecanoic acid phosphoric acid Chemical compound OP(O)(O)=O.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O NDSQWHRDZXKSHX-UHFFFAOYSA-N 0.000 description 2
- ZUVCYFMOHFTGDM-UHFFFAOYSA-N hexadecyl dihydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(O)=O ZUVCYFMOHFTGDM-UHFFFAOYSA-N 0.000 description 2
- GKKMCECQQIKAHA-UHFFFAOYSA-N hexadecyl dihydrogen phosphate;2-(2-hydroxyethylamino)ethanol Chemical compound OCCNCCO.CCCCCCCCCCCCCCCCOP(O)(O)=O GKKMCECQQIKAHA-UHFFFAOYSA-N 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 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 2
- 239000012052 hydrophilic carrier Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 229940059904 light mineral oil Drugs 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229940057917 medium chain triglycerides Drugs 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 239000007764 o/w emulsion Substances 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- HGASFNYMVGEKTF-UHFFFAOYSA-N octan-1-ol;hydrate Chemical compound O.CCCCCCCCO HGASFNYMVGEKTF-UHFFFAOYSA-N 0.000 description 2
- 229940093440 oleth-3-phosphate Drugs 0.000 description 2
- 229940093446 oleth-5 Drugs 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 238000013105 post hoc analysis Methods 0.000 description 2
- 229940033623 potassium lauryl phosphate Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000001185 psoriatic effect Effects 0.000 description 2
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 231100000245 skin permeability Toxicity 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229940114926 stearate Drugs 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- KRIXEEBVZRZHOS-UHFFFAOYSA-N tetradecyl dihydrogen phosphate Chemical compound CCCCCCCCCCCCCCOP(O)(O)=O KRIXEEBVZRZHOS-UHFFFAOYSA-N 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- 210000000115 thoracic cavity Anatomy 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- OHRVKCZTBPSUIK-UHFFFAOYSA-N tridodecyl phosphate Chemical compound CCCCCCCCCCCCOP(=O)(OCCCCCCCCCCCC)OCCCCCCCCCCCC OHRVKCZTBPSUIK-UHFFFAOYSA-N 0.000 description 2
- KENFVQBKAYNBKN-UHFFFAOYSA-N trihexadecyl phosphate Chemical compound CCCCCCCCCCCCCCCCOP(=O)(OCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC KENFVQBKAYNBKN-UHFFFAOYSA-N 0.000 description 2
- 229940072029 trilaureth-4 phosphate Drugs 0.000 description 2
- FDGZUBKNYGBWHI-UHFFFAOYSA-N trioctadecyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCOP(=O)(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC FDGZUBKNYGBWHI-UHFFFAOYSA-N 0.000 description 2
- 239000007762 w/o emulsion Substances 0.000 description 2
- 239000003871 white petrolatum Substances 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- QMMJWQMCMRUYTG-UHFFFAOYSA-N 1,2,4,5-tetrachloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl QMMJWQMCMRUYTG-UHFFFAOYSA-N 0.000 description 1
- ZWVMLYRJXORSEP-UHFFFAOYSA-N 1,2,6-Hexanetriol Chemical compound OCCCCC(O)CO ZWVMLYRJXORSEP-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- QHZLMUACJMDIAE-UHFFFAOYSA-N 1-monopalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)CO QHZLMUACJMDIAE-UHFFFAOYSA-N 0.000 description 1
- OVYMWJFNQQOJBU-UHFFFAOYSA-N 1-octanoyloxypropan-2-yl octanoate Chemical compound CCCCCCCC(=O)OCC(C)OC(=O)CCCCCCC OVYMWJFNQQOJBU-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- 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 1
- ZZNDQCACFUJAKJ-UHFFFAOYSA-N 1-phenyltridecan-1-one Chemical compound CCCCCCCCCCCCC(=O)C1=CC=CC=C1 ZZNDQCACFUJAKJ-UHFFFAOYSA-N 0.000 description 1
- AZLWQVJVINEILY-UHFFFAOYSA-N 2-(2-dodecoxyethoxy)ethanol Chemical compound CCCCCCCCCCCCOCCOCCO AZLWQVJVINEILY-UHFFFAOYSA-N 0.000 description 1
- UGDAWAQEKLURQI-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethanol;hydrate Chemical compound O.OCCOCCO UGDAWAQEKLURQI-UHFFFAOYSA-N 0.000 description 1
- HRYDBQDYSXYNHK-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethanol;octadecanoic acid Chemical compound OCCOCCO.CCCCCCCCCCCCCCCCCC(O)=O HRYDBQDYSXYNHK-UHFFFAOYSA-N 0.000 description 1
- PWVUXRBUUYZMKM-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCO PWVUXRBUUYZMKM-UHFFFAOYSA-N 0.000 description 1
- ILCOCZBHMDEIAI-UHFFFAOYSA-N 2-(2-octadecoxyethoxy)ethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCOCCO ILCOCZBHMDEIAI-UHFFFAOYSA-N 0.000 description 1
- FLPJVCMIKUWSDR-UHFFFAOYSA-N 2-(4-formylphenoxy)acetamide Chemical compound NC(=O)COC1=CC=C(C=O)C=C1 FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- KWVPFECTOKLOBL-KTKRTIGZSA-N 2-[(z)-octadec-9-enoxy]ethanol Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCO KWVPFECTOKLOBL-KTKRTIGZSA-N 0.000 description 1
- PSQFOYNNWBCJMY-UHFFFAOYSA-N 2-[2-(2-hydroxyethoxy)ethoxy]ethyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OCCOCCOCCO PSQFOYNNWBCJMY-UHFFFAOYSA-N 0.000 description 1
- MGYUQZIGNZFZJS-KTKRTIGZSA-N 2-[2-[(z)-octadec-9-enoxy]ethoxy]ethanol Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCOCCO MGYUQZIGNZFZJS-KTKRTIGZSA-N 0.000 description 1
- MQFYRUGXOJAUQK-UHFFFAOYSA-N 2-[2-[2-(2-octadecanoyloxyethoxy)ethoxy]ethoxy]ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOC(=O)CCCCCCCCCCCCCCCCC MQFYRUGXOJAUQK-UHFFFAOYSA-N 0.000 description 1
- MWEOKSUOWKDVIK-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCO MWEOKSUOWKDVIK-UHFFFAOYSA-N 0.000 description 1
- OIALAIQRYISUEV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]e Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO OIALAIQRYISUEV-UHFFFAOYSA-N 0.000 description 1
- UITSPQLTFPTHJZ-UHFFFAOYSA-N 2-[[3,4,5-tris(2-hydroxyethoxy)-6-methoxyoxan-2-yl]methoxy]ethanol Chemical compound COC1OC(COCCO)C(OCCO)C(OCCO)C1OCCO UITSPQLTFPTHJZ-UHFFFAOYSA-N 0.000 description 1
- ZVUNTIMPQCQCAQ-UHFFFAOYSA-N 2-dodecanoyloxyethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOC(=O)CCCCCCCCCCC ZVUNTIMPQCQCAQ-UHFFFAOYSA-N 0.000 description 1
- IISGCGDBIBXFOD-UHFFFAOYSA-N 2-dodecoxy-2-oxoethanesulfonic acid;sodium Chemical compound [Na].[Na].CCCCCCCCCCCCOC(=O)CS(O)(=O)=O IISGCGDBIBXFOD-UHFFFAOYSA-N 0.000 description 1
- AJKXDPSHWRTFOZ-UHFFFAOYSA-N 2-ethylhexane-1,6-diol Chemical compound CCC(CO)CCCCO AJKXDPSHWRTFOZ-UHFFFAOYSA-N 0.000 description 1
- GLCFQKXOQDQJFZ-UHFFFAOYSA-N 2-ethylhexyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCC(CC)CCCC GLCFQKXOQDQJFZ-UHFFFAOYSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 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
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 206010052613 Allergic bronchitis Diseases 0.000 description 1
- 239000004251 Ammonium lactate Substances 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010003055 Application site reaction Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- HGFCWFRSSOMWDF-UHFFFAOYSA-N C=C.P(O)(O)(O)=O.C=C Chemical group C=C.P(O)(O)(O)=O.C=C HGFCWFRSSOMWDF-UHFFFAOYSA-N 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102400000739 Corticotropin Human genes 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 208000037845 Cutaneous squamous cell carcinoma Diseases 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 208000006926 Discoid Lupus Erythematosus Diseases 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
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- FPVVYTCTZKCSOJ-UHFFFAOYSA-N Ethylene glycol distearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOC(=O)CCCCCCCCCCCCCCCCC FPVVYTCTZKCSOJ-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- UUOUOERPONYGOS-CLCRDYEYSA-N Fluocinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3C[C@H](F)C2=C1 UUOUOERPONYGOS-CLCRDYEYSA-N 0.000 description 1
- 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 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 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 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 1
- 206010019233 Headaches Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical compound C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 1
- 206010027940 Mood altered Diseases 0.000 description 1
- 101000898025 Mus musculus Acylcarnitine hydrolase Proteins 0.000 description 1
- AOMUHOFOVNGZAN-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)dodecanamide Chemical compound CCCCCCCCCCCC(=O)N(CCO)CCO AOMUHOFOVNGZAN-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 201000009053 Neurodermatitis Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033733 Papule Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 229920002507 Poloxamer 124 Polymers 0.000 description 1
- 229920002508 Poloxamer 181 Polymers 0.000 description 1
- 229920002509 Poloxamer 182 Polymers 0.000 description 1
- 229920002511 Poloxamer 237 Polymers 0.000 description 1
- 229920002669 Polyoxyl 20 Cetostearyl Ether Polymers 0.000 description 1
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 238000012356 Product development Methods 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 208000006311 Pyoderma Diseases 0.000 description 1
- 206010039509 Scab Diseases 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 206010042464 Suicide attempt Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 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 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 239000004012 Tofacitinib Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 229930003316 Vitamin D Chemical class 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- PCWZKQSKUXXDDJ-UHFFFAOYSA-N Xanthotoxin Natural products COCc1c2OC(=O)C=Cc2cc3ccoc13 PCWZKQSKUXXDDJ-UHFFFAOYSA-N 0.000 description 1
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 description 1
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 description 1
- 0 [1*]C1=C([2*])C=C(C(=O)N([3*])[H])C=C1 Chemical compound [1*]C1=C([2*])C=C(C(=O)N([3*])[H])C=C1 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 229960005339 acitretin Drugs 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- FJXOGVLKCZQRDN-PHCHRAKRSA-N alclometasone Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O FJXOGVLKCZQRDN-PHCHRAKRSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- IHUNBGSDBOWDMA-AQFIFDHZSA-N all-trans-acitretin Chemical compound COC1=CC(C)=C(\C=C\C(\C)=C\C=C\C(\C)=C\C(O)=O)C(C)=C1C IHUNBGSDBOWDMA-AQFIFDHZSA-N 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 229960003099 amcinonide Drugs 0.000 description 1
- ILKJAFIWWBXGDU-MOGDOJJUSA-N amcinonide Chemical compound O([C@@]1([C@H](O2)C[C@@H]3[C@@]1(C[C@H](O)[C@]1(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]13)C)C(=O)COC(=O)C)C12CCCC1 ILKJAFIWWBXGDU-MOGDOJJUSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 229940059265 ammonium lactate Drugs 0.000 description 1
- 235000019286 ammonium lactate Nutrition 0.000 description 1
- BTBJBAZGXNKLQC-UHFFFAOYSA-N ammonium lauryl sulfate Chemical compound [NH4+].CCCCCCCCCCCCOS([O-])(=O)=O BTBJBAZGXNKLQC-UHFFFAOYSA-N 0.000 description 1
- 229940063953 ammonium lauryl sulfate Drugs 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- NUZWLKWWNNJHPT-UHFFFAOYSA-N anthralin Chemical compound C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O NUZWLKWWNNJHPT-UHFFFAOYSA-N 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- RZOBLYBZQXQGFY-HSHFZTNMSA-N azanium;(2r)-2-hydroxypropanoate Chemical compound [NH4+].C[C@@H](O)C([O-])=O RZOBLYBZQXQGFY-HSHFZTNMSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium 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
- 229940125388 beta agonist Drugs 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- 229960001102 betamethasone dipropionate Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000000746 body region Anatomy 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical class OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 229960002882 calcipotriol Drugs 0.000 description 1
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940075508 carbomer homopolymer type b Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 229940073669 ceteareth 20 Drugs 0.000 description 1
- 229940073638 ceteareth-15 Drugs 0.000 description 1
- 229940073642 ceteareth-30 Drugs 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 229940093528 cetearyl ethylhexanoate Drugs 0.000 description 1
- 229940081620 ceteth-2 Drugs 0.000 description 1
- 229940056318 ceteth-20 Drugs 0.000 description 1
- 229940115464 ceteth-23 Drugs 0.000 description 1
- 229940074979 cetyl palmitate Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229960002842 clobetasol Drugs 0.000 description 1
- FCSHDIVRCWTZOX-DVTGEIKXSA-N clobetasol 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)(O)[C@@]1(C)C[C@@H]2O FCSHDIVRCWTZOX-DVTGEIKXSA-N 0.000 description 1
- 239000011280 coal tar Substances 0.000 description 1
- 229940098691 coco monoethanolamide Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940071160 cocoate Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000008406 cosmetic ingredient Substances 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 229960003662 desonide Drugs 0.000 description 1
- 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 1
- 229960002593 desoximetasone Drugs 0.000 description 1
- 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 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone 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-CXSFZGCWSA-N 0.000 description 1
- 229960004154 diflorasone Drugs 0.000 description 1
- WXURHACBFYSXBI-XHIJKXOTSA-N diflorasone 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)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-XHIJKXOTSA-N 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- UYAAVKFHBMJOJZ-UHFFFAOYSA-N diimidazo[1,3-b:1',3'-e]pyrazine-5,10-dione Chemical compound O=C1C2=CN=CN2C(=O)C2=CN=CN12 UYAAVKFHBMJOJZ-UHFFFAOYSA-N 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 229940047642 disodium cocoamphodiacetate Drugs 0.000 description 1
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
- 229940079868 disodium laureth sulfosuccinate Drugs 0.000 description 1
- 229940079886 disodium lauryl sulfosuccinate Drugs 0.000 description 1
- 229940080249 disodium oleamido mea-sulfosuccinate Drugs 0.000 description 1
- YGAXLGGEEQLLKV-UHFFFAOYSA-L disodium;4-dodecoxy-4-oxo-2-sulfonatobutanoate Chemical compound [Na+].[Na+].CCCCCCCCCCCCOC(=O)CC(C([O-])=O)S([O-])(=O)=O YGAXLGGEEQLLKV-UHFFFAOYSA-L 0.000 description 1
- KHIQYZGEUSTKSB-UHFFFAOYSA-L disodium;4-dodecoxy-4-oxo-3-sulfobutanoate Chemical compound [Na+].[Na+].CCCCCCCCCCCCOC(=O)C(S(O)(=O)=O)CC([O-])=O.CCCCCCCCCCCCOC(=O)C(S(O)(=O)=O)CC([O-])=O KHIQYZGEUSTKSB-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960000735 docosanol Drugs 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- XJFGDLJQUJQUEI-UHFFFAOYSA-N dodecyl decanoate dodecyl octanoate Chemical compound CCCCCCCCCCCCOC(=O)CCCCCCC.CCCCCCCCCCCCOC(=O)CCCCCCCCC XJFGDLJQUJQUEI-UHFFFAOYSA-N 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001667 episodic effect Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 208000024711 extrinsic asthma Diseases 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 229960004511 fludroxycortide Drugs 0.000 description 1
- 229940043075 fluocinolone Drugs 0.000 description 1
- 229960000785 fluocinonide Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229940074052 glyceryl isostearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229940096898 glyceryl palmitate Drugs 0.000 description 1
- 229940100608 glycol distearate Drugs 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 210000004919 hair shaft Anatomy 0.000 description 1
- 229960002383 halcinonide Drugs 0.000 description 1
- 229940115747 halobetasol Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- IIRDTKBZINWQAW-UHFFFAOYSA-N hexaethylene glycol Chemical class OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 229940093629 isopropyl isostearate Drugs 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 229940100491 laureth-2 Drugs 0.000 description 1
- 229940100556 laureth-23 Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 229940087305 limonene Drugs 0.000 description 1
- 235000001510 limonene Nutrition 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000647 material safety data sheet Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960004469 methoxsalen Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229940100485 methyl gluceth-10 Drugs 0.000 description 1
- 229940031722 methyl gluceth-20 Drugs 0.000 description 1
- 229940044591 methyl glucose dioleate Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 229940114937 microcrystalline wax Drugs 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 229960001664 mometasone Drugs 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 230000007510 mood change Effects 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229960004398 nedocromil Drugs 0.000 description 1
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000012875 nonionic emulsifier Substances 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- BARWIPMJPCRCTP-UHFFFAOYSA-N oleic acid oleyl ester Natural products CCCCCCCCC=CCCCCCCCCOC(=O)CCCCCCCC=CCCCCCCCC BARWIPMJPCRCTP-UHFFFAOYSA-N 0.000 description 1
- 229940099570 oleth-2 Drugs 0.000 description 1
- 229940095127 oleth-20 Drugs 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- BARWIPMJPCRCTP-CLFAGFIQSA-N oleyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC BARWIPMJPCRCTP-CLFAGFIQSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229940011530 otezla Drugs 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940094334 peg-25 propylene glycol stearate Drugs 0.000 description 1
- 229940032066 peg-4 dilaurate Drugs 0.000 description 1
- 229940032041 peg-8 laurate Drugs 0.000 description 1
- 229940100462 pegoxol 7 stearate Drugs 0.000 description 1
- 229960004439 pemirolast Drugs 0.000 description 1
- HIANJWSAHKJQTH-UHFFFAOYSA-N pemirolast Chemical compound CC1=CC=CN(C2=O)C1=NC=C2C=1N=NNN=1 HIANJWSAHKJQTH-UHFFFAOYSA-N 0.000 description 1
- 229940059574 pentaerithrityl Drugs 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 231100000435 percutaneous penetration Toxicity 0.000 description 1
- 239000008250 pharmaceutical cream Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- KASDHRXLYQOAKZ-ZPSXYTITSA-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-ZPSXYTITSA-N 0.000 description 1
- 229960005330 pimecrolimus Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229940093448 poloxamer 124 Drugs 0.000 description 1
- 229940085692 poloxamer 181 Drugs 0.000 description 1
- 229940093426 poloxamer 182 Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920000059 polyethylene glycol stearate Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960002794 prednicarbate Drugs 0.000 description 1
- 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 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- NEOZOXKVMDBOSG-UHFFFAOYSA-N propan-2-yl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OC(C)C NEOZOXKVMDBOSG-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940116423 propylene glycol diacetate Drugs 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 239000001944 prunus armeniaca kernel oil Substances 0.000 description 1
- 230000006825 purine synthesis Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 229960001755 resorcinol Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 208000020352 skin basal cell carcinoma Diseases 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 201000010106 skin squamous cell carcinoma Diseases 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229940048842 sodium xylenesulfonate Drugs 0.000 description 1
- QUCDWLYKDRVKMI-UHFFFAOYSA-M sodium;3,4-dimethylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1C QUCDWLYKDRVKMI-UHFFFAOYSA-M 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 229940098760 steareth-2 Drugs 0.000 description 1
- 229940100459 steareth-20 Drugs 0.000 description 1
- 229940100458 steareth-21 Drugs 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940057780 taclonex Drugs 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 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 1
- 239000003760 tallow Substances 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- LEHFPXVYPMWYQD-XHIJKXOTSA-N ulobetasol 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)(O)[C@@]2(C)C[C@@H]1O LEHFPXVYPMWYQD-XHIJKXOTSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229920006163 vinyl copolymer Polymers 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Chemical class 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 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
- A61K31/33—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K15/00—Anti-oxidant compositions; Compositions inhibiting chemical change
- C09K15/04—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds
- C09K15/06—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds containing oxygen
Definitions
- the invention pertains to methods for treating a patient having a disorder that is responsive to treatment with PDE-4 inhibition by the topical administration of a roflumilast formulation having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to administration of an equivalent amount of roflumilast in an oral composition.
- the methods of treatment of this invention provide a sufficiently high area under the plasma-roflumilast concentration curve (AUC) to attain a systemically effective level of roflumilast without rapid-onset peak plasma concentration (Cmax) (i.e., short Tmax). It has been discovered that these pharmacokinetic characteristics result in a reduction of undesirable side effects associated with oral roflumilast therapy.
- Roflumilast is known to be suitable as a bronchial therapeutic agent as well as for the treatment of inflammatory disorders.
- Compositions containing roflumilast are used in human and veterinary medicine and have been proposed for the treatment and prophylaxis of diseases including but not limited to: inflammatory and allergen-induced airway disorders (e.g. bronchitis, asthma, COPD); dermatoses (e.g. proliferative, inflammatory and allergen-induced skin disorders including psoriasis, seborrheic dermatitis, and atopic dermatitis), and generalized inflammations in the gastrointestinal region (Crohn's disease and ulcerative colitis).
- roflumilast is approved for systemic administration (oral) to treat inflammatory disorders involving the lungs, such as chronic obstructive pulmonary disease (COPD).
- COPD chronic obstructive pulmonary disease
- Topical application of potent pharmacological agents like roflumilast for treating skin diseases has been found to provide superior delivery, lower systemic exposure and greater ease of use for patients.
- the molecular structure of the compound ultimately dictates the ability of the drug to cross the epithelium of the tissue to which the product is applied.
- selection of the components of the formulation dictates the maximum skin permeation that the formulator can achieve.
- Creams, lotions, gels, ointments and foams are just a few of the more familiar forms of topical products that contain active pharmaceutical ingredients (API) for application to the skin.
- API active pharmaceutical ingredients
- the ability of a dissolved active ingredient to permeate the barrier of the skin is determined by its molecular structure.
- a well-known relationship between molecular structure and skin penetration is that increasing molecular weight decreases the rate that an active crosses the skin (J D Bos, M M Meinardi, Exp Dermatol. 2000 June; 9(3):165-9).
- Another well-understood relationship is that increasing the octanol-water partition coefficient of a hydrophilic active initially increases the rate that an active permeates the skin, but then decreases skin permeation once the active becomes too lipophilic to partition out of the stratum corneum and into the lower layers of the epidermis (D. W. Osborne and W. J. Lambert, Prodrugs for Dermal Delivery, K. B.
- the optimal octanol-water partition coefficient is usually at log P values of 2-3.
- the rate that an active ingredient crosses into the viable epidermis can be further modified based on the composition of the topical product.
- Final pH of the formulation may be critical, because dissolved ionized active ingredients typically do not permeate the skin as effectively as active ingredients that do not carry a charge (N. Li, X. Wu, W. Jia, M. C. Zhang, F. Tan, and J Zhang. Drug Dev Indust Pharm 38(8)985-994).
- Functional ingredients such as skin penetration enhancers (D. W. Osborne and J. J.
- formulators generally avoid developing a topical product that will have particles or crystals of the active ingredient precipitate during storage according to labeled storage instructions. Precipitation of the active ingredient can occur for various reasons. Particular active ingredients, when formulated with particular pharmaceutical excipients will tend to form supersaturated solutions. At the time of manufacture, all of the active ingredient will be in solution. After days, weeks, or months, this metastable topical product will equilibrate and active ingredient particles will form. If a topical product contains a volatile solvent such as ethanol, then evaporation of the solvent upon storage could result in precipitation of the active ingredient. A less soluble polymorph (Pudipeddi and Serajuddin, J. Pharm.
- a suspended active ingredient properties in addition to molecular structure influence skin permeation.
- the ratio of dissolved to suspended active ingredient can have a significant influence on the amount of active delivered after topical application. It has been shown that optimal drug delivery can be achieved for particular drugs and particular diseases by utilizing a topical composition that includes a dissolved active ingredient that has the capacity to permeate the stratum corneum layer of the epidermis and become available systemically, along with an active ingredient in a microparticulate state that does not readily cross the stratum corneum of the epidermis (U.S. Pat. No. 5,863,560 hereby incorporated by reference). Another property of a suspended active ingredient that affects its delivery is the distribution of suspended particle size.
- a topical product composition to modify the skin permeation is similar for suspended active ingredients and dissolved active ingredients. Because skin permeability is dependent on additional properties of the suspended active ingredients, consistent delivery from topical products containing suspended actives is more difficult to maintain than for topical products containing only dissolved active ingredients.
- Consistent delivery of a suspended active ingredient from a topical product is assured by formulation into a product in which the suspended particles do not significantly change in size or amount over the shelf life of the product.
- Change over time in the ratio of dissolved active ingredient to particulate active ingredient can dramatically change the skin permeation of the active ingredient.
- the same mechanisms described above (supersaturation, temperature changes, evaporation, polymorphic transformation) that can cause precipitation of dissolved active ingredients can alter the dissolved-to-particulate ratio for suspended active ingredients.
- Change over time in the particle size or particle size distribution of the dispersed active ingredient can also dramatically change the skin permeation of the active ingredient. Sometimes this change in particle size or particle size distribution can be explained by Ostwald ripening of the particles.
- Ostwald ripening occurs when small particles in the topical product dissolve and redeposit onto larger particles suspended in the same container of topical product. Over time this phenomenon shifts the particle size distribution toward larger particles at the expense of the smaller particles. Ostwald ripening and precipitation of a less soluble polymorph are two major problems in developing topical products containing suspended actives.
- DALIRESP® oral roflumilast tablets marketed in the U.S.
- psychiatric adverse reactions insomnia, anxiety, depression, suicidal ideation and suicidal behavior
- weight loss insomnia, anxiety, depression, suicidal ideation and suicidal behavior
- gastrointestinal side effects when patients are treated with 500 mcg once daily.
- the prescribing information pertaining to DALIRESP® instructs that it may be beneficial to take half of the therapeutically effective dose, 250 mcg, once daily for 4 weeks prior to commencing the therapeutically effective dose of 500 mcg per day so as to reduce the rate of treatment discontinuation.
- the prescribing information for DAXAS® (oral roflumilast tablets marketed outside the U.S.) does not instruct the patient to take a reduced non-therapeutically effective dosage prior to taking the therapeutic dose.
- the prescribing information for DAXAS® does report a high incidence of diarrhea, nausea, and abdominal pain associated with this medication.
- Bolle U.S. Patent Application Publication No. 2006/0084684 discloses topical formulations of roflumilast, salts of roflumilast, the N-oxide of roflumilast, and salts of the N-oxide.
- Bolle discloses that such formulations are useful to apply to skin lesions for the local treatment of skin disorders or to administer topically for the systemic treatment of skin disorders and other disorders, such as COPD.
- Bolle discloses that the systemic effect of topical application of the roflumilast formulations is comparable to that of an oral dosage form.
- Bolle further discloses, in paragraph 0080 that “Comparison with oral administration shows that, irrespective of the composition of the topical preparation, similar Cmax and AUCs and similar excretions with the urine are achieved.”
- Topical application of potent pharmacological agents like roflumilast has been found to provide superior delivery and greater ease of use for patients.
- the molecular structure of the compound ultimately dictates the ability of the drug to cross the epithelium of the tissue to which the product is applied.
- selection of the components of the formulation dictates the maximum skin permeation that the formulator can achieve.
- Creams, lotions, gels, ointments and foams are just a few of the more familiar forms of topical products that contain active pharmaceutical ingredients (API) for application to the skin.
- API active pharmaceutical ingredients
- AUCs systemic exposures
- an improved method of treating a patient having a disorder responsive to PDE-4 inhibition by administering a PDE-4-inhibiting amount of roflumilast involves administering the roflumilast topically in a composition having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to oral administration of a PDE4-inhibiting amount of roflumilast.
- disorders include inflammatory disorders such as inflammatory dermatoses, including psoriasis, atopic dermatitis and seborrheic dermatitis.
- a disorder is responsive to PDE-4 inhibition if such inhibition results in a prevention of the disorder or a diminution of its severity, duration or recurrence, such disorders also include inflammatory diseases in a variety of organs, especially the lungs (asthma, COPD).
- PK pharmacokinetics
- the topically applied composition contains from about 0.1% w/w to about 0.5% w/w roflumilast. In a preferred embodiment, the topically applied composition is in the form of a cream or a foam.
- the composition has a roflumilast release profile that results in a reduced Cmax, longer Tmax and flattened plasma concentration time curve relative to that achieved with oral administration of an effective amount of roflumilast in an oral composition marketed under the trademarks DALIRESP® and DAXAS®.
- topical roflumilast compositions having the above-described PK properties produce reduced gastrointestinal, psychiatric, and weight loss side effects as compared to prior art orally administered compositions.
- the present invention provides a method of treating a patient suffering from a disorder that can be treated by PDE-4 inhibition that comprises: administering a topical pharmaceutical composition comprising 0.5% w/w of roflumilast and a pharmaceutically acceptable carrier, wherein administration of said composition results in reduced gastrointestinal and other side effects relative to oral administration of roflumilast in a composition of roflumilast marketed under the trademark DALIRESP® or DAXAS®.
- FIG. 1 shows Sample 19-2 “dry” roflumilast crystals from ferrer-Interquim S.A. Batch A14367P, the drug substance used in all the examples in this specification.
- the roflumilast crystals are 0.01 mm-0.02 mm in length.
- FIG. 2 shows Sample 20-3 roflumilast crystals suspended in equimolar hexylene glycol:water solution after storage for six weeks at room temperature under 10 ⁇ power.
- the roflumilast crystals are 0.01 mm-0.02 mm in length.
- FIG. 3 shows Sample 20-2 roflumilast crystals suspended in equimolar diethylene glycol monoethyl ether:water solution after storage for six weeks at room temperature.
- the roflumilast crystals are 0.04 mm-0.20 mm in length and 0.01 mm-0.02 mm in width.
- FIG. 4 shows Sample 20-3 roflumilast crystals suspended in equimolar hexylene glycol:water solution after storage for six weeks at room temperature under 4 ⁇ power.
- the roflumilast crystals are 0.01 mm-0.02 mm in length.
- FIG. 5 shows Sample 21-2 roflumilast crystals suspended in equimolar ethanol:water solution after storage for six weeks at room temperature.
- the roflumilast crystals are 0.05 mm-0.25 mm in length and 0.02 mm in width.
- FIG. 6 shows Sample 21-3 roflumilast crystals suspended in equimolar PEG 400:water solution after storage for six weeks at room temperature.
- the roflumilast crystals are 0.05 mm-0.07 mm in length and 0.02 mm in width.
- FIG. 7 shows Sample 21-4 roflumilast crystals suspended in equimolar DMSO:water solution after storage for six weeks at room temperature.
- the roflumilast crystals are 0.10 mm-0.67 mm in length and 0.02 mm-0.10 mm in width.
- FIG. 8 shows Sample 21-5 roflumilast crystals suspended in equimolar propylene glycol:water solution after storage for six weeks at room temperature.
- the roflumilast crystals are 0.20 mm-1.60 mm in length and 0.02 mm in width.
- FIG. 9 shows Sample 20-1 roflumilast crystals suspended in equimolar NMP:water solution after storage for six weeks at room temperature.
- the roflumilast crystals are 0.10 mm-1.55 mm in length and 0.02 mm-0.13 mm in width.
- the roflumilast crystals are 0.02 mm-0.04 mm in length and 0.02 mm in width.
- FIGS. 11A and 11B show roflumilast particles precipitated in a cream composition after one freeze thaw cycle.
- FIG. 11 a shows Sample 36-1 roflumilast particles precipitated in a cream composition with diethylene glycol monoethyl ether (DEGEE) and without hexylene glycol. The three largest roflumilast particles were measured (0.07 mm ⁇ 0.09 mm; 0.06 mm ⁇ 0.06 mm; and 0.10 mm ⁇ 0.05 mm) and found to have a mean surface area of 5,000 square microns.
- FIG. 11 b shows Sample 36-2 roflumilast particles precipitated in a cream composition with both diethylene glycol monoethyl ether (DEGEE) and hexylene glycol. The three largest roflumilast particles were measured (0.05 mm ⁇ 0.03 mm; 0.05 mm ⁇ 0.03 mm and 0.05 mm ⁇ 0.03 mm) and found to have a mean surface area of 1,500 square microns
- FIG. 12 is a line graph comparing the pharmacokinetic (PK) profile of two formulations of the invention, Formulation 3 and Formulation 4, and a PK profile of a formulation of the prior art, Formulation 5.
- PK pharmacokinetic
- FIG. 14 is a line graph showing Day 1 and Day 28 PK profiles after once daily dosing of 0.15% roflumilast topical cream.
- FIG. 15 is a line graph showing Day 1 and Day 14 PK profiles after once daily dosing of 0.3% roflumilast topical cream.
- FIG. 16 is a line graph showing Day 1 and Day 28 PK profiles after once daily dosing of 0.5% roflumilast topical cream.
- FIG. 17 is a line graph showing Day 1 and Day 28 PK profiles after once daily dosing of 1.0% roflumilast topical cream.
- FIGS. 18A, 18B and 18C show changes in baseline in Target Plaque Severity Score and/or Target Plaque Area for 0.15% roflumilast topical cream and 0.5% roflumilast topical cream.
- FIGS. 19A and 19B show roflumilast and roflumilast N-oxide plasma concentrations at day 1 and day 28 (pharmacokinetic population) for 0.15% roflumilast topical cream and 0.5% roflumilast topical cream.
- FIGS. 20A and 20B are line graphs showing day 1 and day 8 PK profiles after once daily dosing of Crodafos-CES creams containing either 0.3% crisaborole or 0.3% roflumilast.
- FIG. 21 is a line graph comparing roflumilast plasma concentration over time after 500 mcg once daily oral roflumilast (closed circles) and topical 0.5% ARQ-151 cream (closed squares) 0-24 hours on day 28 of once a day dosing.
- the oral roflumilast data (closed circles) was extracted from a plot in the publication T. D Bethke and G. Lahu, 2011, Int J of Clin Pharm and Ther, 49(1):51-57.
- roflumilast refers to roflumilast, its salts, the N-oxide of roflumilast, and its salts unless specified otherwise or unless it is clear in context that reference is to roflumilast itself.
- N-oxide of roflumilast and “salts of either roflumilast or of the N-oxide of roflumilast” refer specifically to the N-oxide or salts of either roflumilast or the N-oxide thereof.
- Roflumilast formulations can be prepared by methods known in the art (e.g. see the '298 patent and U.S. application Ser. No. 14/075,035).
- Roflumilast is a compound of the formula (I)
- R1 is difluoromethoxy
- R2 is cyclopropylmethoxy
- R3 is 3,5-dichloropyrid-4-yl.
- This compound has the chemical name N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamid-e (INN: roflumilast).
- salts when referring to roflumilast or the N-oxide of roflumilast, means a salt as described in paragraphs [0012] and [0013] of U.S. Patent Application Publication No. US 2006/0084684, the disclosure of which is incorporated herein by reference.
- Hexylene glycol (PharmaGrade. USP/NF) is 2-methyl-2,4-pentanediol of the formula (II).
- One aspect of present invention is directed to the addition of hexylene glycol to a roflumilast-containing pharmaceutical composition that contains a pharmaceutically acceptable solvent, including water, to inhibit growth of roflumilast crystals in the composition.
- a pharmaceutically acceptable solvent including water
- the addition of hexylene glycol to a composition containing roflumilast will inhibit (i.e., prevent or substantially reduce in comparison to compositions that do not contain a hexylene glycol) changes in particle size distribution over the shelf life of the product and assure consistent bioavailability.
- hexylene glycol inhibits the growth of precipitated roflumilast particles.
- Typical storage conditions for a topical pharmaceutical cream are: Store at room temperature: 60° F./15° C.-80° F./26° C. Do not freeze. It is understood by product development scientists and regulatory agency reviewers that a topical product will not always be stored over this temperature range. Therefore, the FDA requires that all topical products undergo freeze-thaw cycling and temperature excursion studies. The active is neither required nor expected to remain in solution when the product is exposed to temperatures of ⁇ 20° C., dramatically below 15° C. (60° F.) of the labeled storage condition.
- Hexylene glycol can be added between 0.1% and 20% on a weight/weight basis, preferably between 0.25% and 8% on a weight/weight basis and most preferably between 0.5% and 2% on a weight/weight basis.
- the topical roflumilast product formulations that benefit from the addition of hexylene glycol include but are not limited to aerosols, foams, sprays, emulsions (which can also be called creams, lotions, or ointments), gels (two phase or single phase), liquids, ointments, pastes, shampoos, suspensions, and systems. These are the tier two terms within compendia taxonomy for dosage forms containing pharmaceutical active ingredients (US Pharmacopeia ⁇ 1151>).
- a pharmaceutical formulation such as a topically applied pharmaceutical formulation containing roflumilast, provides an altered PK (pharmacokinetic) profile with a reduced Cmax or a reduced absorption rate to reach Cmax when the formulations contain one or more phosphate ester surfactants compared to pharmaceutical formulations containing roflumilast without a phosphate ester surfactant(s).
- a pharmaceutical formulation containing roflumilast and one or more phosphate ester surfactants when topically administered to an individual, provides a systemically effective level of the PDE-4 inhibitor comparable to, or even greater than, that achieved with oral administration by slow absorption and without a Cmax spike of the PDE-4 inhibitor into the bloodstream.
- a formulation containing roflumilast, and a phosphate ester surfactant when administered to an individual, such as by applying topically to the skin of an individual, provides a sufficiently high Area Under the Curve (AUC) to attain a systemically effective level of roflumilast without rapidly producing a peak plasma concentration (Cmax) that is associated with gastrointestinal side effects. That is, the absorption rate of the drug to reach Cmax is decreased when the formulation of the present application is administered, compared with the administration of formulations of the prior art.
- AUC Area Under the Curve
- the term “absorption rate to reach Cmax” means the slope of the PK curve between the administration of a formulation containing drug until Cmax, or the slope of the PK curve between a trough and the adjacent peak following serial multiple dose administrations of the formulation.
- the formulations of the present application unexpectedly have a markedly different PK profile compared to prior art formulations containing roflumilast.
- the formulations of the present application provide a sufficiently high AUC to attain a systemically effective level of roflumilast without producing a spike in Cmax.
- the gradual ascent to Cmax obtained following topical application of the formulations of the present invention is markedly different from that of prior art formulations, but the AUC is similar.
- the PK profile lacks the initial Cmax spike and the peak to trough pattern that is obtained following multiple daily dosing with prior art formulations containing the drug.
- the formulations of the present invention can result in higher systemic exposure levels (AUC) than are possible with prior art formulations and without the side effects associated with a Cmax spike, such as those of the G.I. system. Such previously unobtainable exposure levels will provide a greater efficacy in the treatment of diseases.
- AUC systemic exposure levels
- the PK profile obtained after multiple doses of the formulation of the present application is extremely and unexpectedly flat and prolonged with an extremely small peak to trough fluctuation following administration for 28 days. This flatness of the PK profile is especially pronounced when the formulation further contains diethylene glycol monoethyl ether.
- roflumilast from the formulation in an amount required to provide a therapeutic effect is not dependent on a spike in absorption to provide a high Cmax and because the absorption of roflumilast is stable and has a flat PK profile, an individual user of a formulation producing such a PK profile may miss one or more doses from time to time and still maintain efficacy of the treatment.
- An important advantage of the present invention is that, a slow ascent to Cmax without a concomitant Cmax spike permit the obtaining of higher systemic exposure levels (AUC) than are possible with prior art formulations and without the side effects associated with Cmax spike, such as those of the G.I. system. Such previously unobtainable exposure levels will provide a greater efficacy in the treatment of diseases.
- AUC systemic exposure levels
- a pharmaceutical formulation of the present invention contains roflumilast in a concentration which is sufficient to ameliorate a medical condition that is responsive to the administration of a PDE-4 inhibitor drug, such as psoriatic arthritis, psoriasis, atopic dermatitis, asthma and COPD.
- concentration of roflumilast, in the formulation is that which is sufficient to obtain a desired systemic pharmacologic effect when the formulation is applied to the skin of an individual. This concentration will necessarily differ based on the type of formulation and the disease or condition to be treated.
- the concentration of roflumilast within the formulation is typically in the range of 0.001 to 25% w/w, with a preferred range between 0.01 to 5%, a more preferred range between 0.05 and 1%, and a most preferred range between 0.1 and 0.5%.
- the concentration of roflumilast in the formulation is between 0.05 and 0.5%, such as 0.05%, 0.15%, 0.3%, and 0.5% w/w.
- the formulation may contain a means for inhibiting crystal growth and changes in particle size distribution which can be hexylene glycol.
- the formulation may further contain a means for providing a sufficiently high AUC to attain a systemically effective level of roflumilast without producing a spike in Cmax, which can be one or more phosphate ester surfactants.
- phosphate ester surfactants examples include but are not limited to potassium cetyl phosphate, potassium C9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassium lauryl phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate, cetheth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate, disodium oleyl phosphate, lauryl phosphate, myristyl phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-3
- the concentration of the phosphate ester surfactant in the formulation is that which is sufficient to produce a stable emulsion having uniform globule size. If desired, lower concentrations of the phosphate ester surfactant may be combined with other emulsifiers to produce a stable emulsion having uniform globule size.
- the phosphate ester surfactant may also increase the solubility of the roflumilast in the cream.
- the concentration of the phosphate ester surfactant generally may be any concentration between 1.0% to 25% w/w. The preferred concentration can be different for different administration forms.
- the concentration of the phosphate ester surfactant is between 2.5% and 20%, with a more preferred concentration range between 5% and 15%, and a most preferred concentration being about 10% w/w.
- the concentration is preferably between 1.0%-10%, more preferably between 1.0%-10%, and most preferably 2%.
- the formulation can optionally contain, a means for increasing the solubility of roflumilast, which can be diethylene glycol monoethyl ether.
- Diethylene glycol monoethyl ether is also known as 2-(2-ethoxyethoxy)ethanol, or as DEGEE, and is marketed under the several tradenames, including TRANSCUTOL® (Gattefosse Corporation, Paramus, N.J.), CARBITOLTM (The Dow Chemical Company, Midland, Mich.), DIOXITOL® (Shell Oil Company, Houston, Tex.), and POLY-SOLV DM (Monument Chemical, Houston, Tex.).
- DEGEE is often added to topical products as a co-solvent to increase solubility of the drug in the formulation. Addition of DEGEE to a topical formulation has also been shown to enhance skin penetration, i.e. increase Cmax, of topically administered pharmaceutical actives. See D. W. Osborne and J. Musakhanian, “Skin Penetration and Permeation Properties of TRANSCUTOL®—Neat or Diluted Mixtures”, AAPS Pharm SciTech. 19(8):3512-3533 (2016) DOI: 10.1208/s12249-018-1196-8; and Javadzadeh et al, Chapter 12 pages 195-205, in Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement: Modification of the Stratum Corneum (N. Dragicevic, H. I. Maibach, eds) Springer-Verlag Berlin Heidelberg 2016.
- the concentration of the diethylene glycol monoethyl ether, if present, in the formulation is that which is sufficient to dissolve the active pharmaceutical ingredient.
- Diethylene glycol monoethyl ether may also enhance the skin penetration of the roflumilast.
- the concentration of the diethylene glycol monoethyl ether is between 5% and 50% w/w, with a preferred range of concentrations between 10% and 40% w/w, a more preferred range between 15% and 30% w/w, and a particular preferred concentration being about 15-25% w/w.
- water is formulated as about 20-90% (w/w) in topical products. For blends of DEGEE and water the ratio can range from 1:10 to 20:1.
- DEGEE:water ratio is 1:4 to 9:1 in a formulation containing roflumilast.
- DEGEE-water blends can be used to dissolve up to 2.0% roflumilast (in the finished product) or preferably up to 0.5% roflumilast (in the finished product).
- the formulation for topical application to the skin is preferably a semi-solid dosage form that is cosmetically acceptable for use on the skin and which is easily spreadable on the skin.
- semi-solid dosage forms include emulsions, ointments, creams, gels, and pastes.
- the formulation may alternatively be in a form other than a semi-solid dosage form, such as a liquid, which may be administered as a spray, or a foam.
- a formulation for topical administration is in one of the following forms:
- An oil-in-water emulsion The product may be formulations in which hexylene glycol is added to an emulsion comprising a discrete phase of a hydrophobic component and a continuous aqueous phase that includes water and optionally one or more polar hydrophilic excipients as well as solvents, co-solvents, salts, surfactants, emulsifiers, and other components.
- emulsions may include water-soluble or water-swellable polymers that help to stabilize the emulsion.
- a water-in-oil emulsion The compositions may be formulations in which roflumilast is incorporated into an emulsion that includes a continuous hydrophobic phase and an aqueous phase that includes the DEGEE-water blend and optionally one or more polar hydrophilic carrier(s) as well as salts or other components.
- These emulsions may include oil-soluble or oil-swellable polymers as well as one or more emulsifier(s) that help to stabilize the emulsion.
- Roflumilast can be added pre-dissolved in the continuous aqueous phase containing the DEGEE-water blend.
- roflumilast can be pre-dissolved in the hydrophobic discrete phase of the emulsion that is then mixed with the DEGEE-water blend and optional hydrophilic excipients that do not contain the active ingredient.
- Roflumilast can be pre-dissolved in both the oil phase and water phase of the emulsion or added pre-dissolved in DEGEE or a DEGEE-water blend after the emulsion has been formed.
- Some emulsions undergo phase inversion over a specific temperature range during cooling of the emulsion.
- roflumilast may be added to a water-in-oil emulsion above the phase inversion temperature, with the final drug product being an oil-in-water emulsion at controlled room temperature, or vice versa.
- Thickened Aqueous gels include the DEGEE-water blend with dissolved roflumilast and optionally one or more polar hydrophilic carrier(s) such as hexylene glycol which has been thickened by suitable natural, modified natural, or synthetic thickeners such as described below.
- the thickened aqueous gels can be thickened using suitable polyethoxylate alky chain surfactants or other nonionic, cationic, or anionic systems.
- Thickened Hydroalcoholic gels These systems include a blend of water and alcohol as the polar phase which has been thickened by suitable natural, modified natural, or synthetic polymers such as described below.
- the thickened hydroalcoholic gels can be thickened using suitable polyethoxylate alky chain surfactants or other nonionic, cationic, or anionic systems.
- the alcohol can be ethanol, isopropyl alcohol or other pharmaceutically acceptable alcohol.
- Hydrophilic gels These are systems in which the continuous phase includes at least one water soluble or water dispersible hydrophilic component other than water.
- the formulations may optionally also contain water up to 60% by weight. Higher levels may be suitable in some compositions.
- Suitable hydrophilic components include one or more glycols such as polyols such as glycerin, propylene glycol, butylene glycols, polyethylene glycols (PEG), random or block copolymers of ethylene oxide, propylene oxide, and/or butylene oxide, polyalkoxylated surfactants having one or more hydrophobic moieties per molecule, silicone copolyols, blend of ceteareth-6 and stearyl alcohol as well as combinations thereof, and the like.
- glycols such as polyols such as glycerin, propylene glycol, butylene glycols, polyethylene glycols (PEG), random or block copolymers of ethylene oxide, propylene oxide, and/or butylene
- a hydrophilic or hydrophobic ointment The compositions are formulated with a hydrophobic base (e.g. petrolatum, thickened or gelled water insoluble oils, and the like) and optionally having a minor amount of a water soluble phase. Hydrophilic ointments generally contain one or more surfactants or wetting agents
- compositions according to the present invention may include a means for obtaining the desired level of active ingredient solubility in the topical product which can be one or more solvents or co-solvents.
- the solvent may also modify skin permeation or the activity of other excipients contained in the formulation.
- Means for obtaining the desired level of active ingredient solubility in the topical product include but are not limited to acetone, ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, N-methyl pyrrolidinone, polyethylene glycol, glycerol, propylene glycol and SD alcohol.
- compositions according to the present invention may include a moisturizer to increase the level of hydration.
- the moisturizer is often a component of the discrete or continuous hydrophobic phase.
- the moisturizer can be a hydrophilic material including humectants or it can be a hydrophobic material including emollients.
- Suitable moisturizers include but are not limited to: 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, light mineral oil, lanolin limonene, medium-chain triglycerides, menthol, myristyl alcohol
- compositions according to the present invention optionally can include one or more surfactants to emulsify the composition and to help wet the surface of the actives or excipients.
- surfactant means an amphiphile (a molecule possessing both polar and nonpolar regions which are covalently bound) capable of reducing the surface tension of water and/or the interfacial tension between water and an immisicible liquid.
- Surfactants include but are not limited to alkyl aryl sodium sulfonate, Amerchol-CAB, ammonium lauryl sulfate, apricot kernel oil PEG-6 esters, Arlacel, benzalkonium chloride, Ceteareth-6, Ceteareth-12, Ceteareth-15, Ceteareth-30, cetearyl alcohol/ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-10 phosphate, ceteth-2, ceteth-20, ceteth-23, choleth-24, cocamide ether sulfate, cocamine oxide, coco betaine, coco diethanolamide, coco monoethanolamide, coco-caprylate/caprate, dicetyl phosphate, disodium cocoamphodiacetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, diso
- Phosphate ester surfactants can also act as a means for reducing a spike in Cmax while producing an AUC sufficient to attain a systemically effective level of roflumilast.
- Suitable phosphate ester surfactants include but are not limited to potassium cetyl phosphate, potassium C9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassium lauryl phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate, cetheth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate, disodium oleyl phosphate, lauryl phosphate, myristyl phosphat
- soluble, swellable, or insoluble organic polymeric thickeners such as natural and synthetic polymers or inorganic thickeners such as acrylates copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, and methylcellulose.
- soluble, swellable, or insoluble organic polymeric thickeners such as natural and synthetic polymers or inorganic thickeners such as acrylates copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrage
- the formulation may contain one or more thickening agent to provide viscosity so that the formulation may be provided in the form of a semisolid, such as a lotion, gel, cream, or ointment.
- suitable thickening agents include but are not limited to soluble, swellable, or insoluble organic polymeric thickeners such as natural and synthetic polymers or inorganic thickeners including but not limited to acrylates copolymer, carbomer 1382, copolymer type B, carbomer homopolymer type A, homopolymer type B, carbomer homopolymer type C, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, acacia, alginic acid, bentonite, carbomers, also known as carboxy vinyl polymers, such as sold under the tradename Carbopol® (Lubrizol, Wickliffe, Ohio), carboxymethylcellulose, ethylcellulose, gelatin,
- the thickening agent may reside in the oil or lipophilic portion of the formulation.
- suitable lipophilic thickening agents include cetyl alcohol, stearyl alcohol, glyceryl stearate, white beeswax, microcrystalline wax, hydrogenated polyisobutane polymers, and emulsifying wax.
- compositions according to the present invention may be formulated with additional components such as fillers, carriers and excipients conventionally found in cosmetic and pharmaceutical topical products.
- Additional components including but not limited to foaming agents, propellants preservatives (e.g. p-hydroxybenzoic esters, benzyl alcohol, phenylmercury salts, chlorocresol), antioxidants, sequestering agents, stabilizers, buffers, pH adjusting solutions, skin penetration enhancers, film formers, dyes, pigments, diluents, bulking agents, fragrances and other excipients to improve the stability or aesthetics of the product, may be added to the composition.
- propellants preservatives e.g. p-hydroxybenzoic esters, benzyl alcohol, phenylmercury salts, chlorocresol
- antioxidants e.g. p-hydroxybenzoic esters, benzyl alcohol, phenylmercury salts, chlorocresol
- the formulation may contain other pharmaceutically acceptable excipients if desired.
- the formulation may contain a humectant such as glycerin, sorbitol, hexylene glycol, urea, or propylene glycol.
- the formulation may contain an emollient such as petrolatum, lanolin, mineral oil, light mineral oil, stearic acid, cyclomethicone, or dimethicone. Additional optional excipients include stabilizers, foaming agents, preservatives such as methylparaben, pH adjusting agents such as sodium hydroxide, chelating agents such as EDTA and its salts, and buffers.
- the roflumilast is in the form of an aerosolized foam which is particularly suitable for application to the scalp.
- Any suitable propellant can be used to prepare the aerosolized foam.
- Particularly preferred propellants are Isobutane A-31, Aeropin 35, Butane 48, Dimethyl Ether/N-Butane-(53/47), Propane/Iso-Butane/N-Butane, Propane/Isobutane-A70, and Propane/Isobutane A-46, N-Butane A-17.
- compositions according to the present invention may be formulated with additional active agents depending on the condition being treated.
- additional active agents include but are not limited to NSAIDs (e.g. Aspirin, Ibuprofen, Ketoprofen, Naproxen), Apremilast and other PDE4 inhibitors, JAK inhibitors (e.g. Tofacitinib, Ruxolitinib, Oclacit), leukotriene inhibitors (e.g. Zileuton, Zafirlukast, Montelukast), mast cell stabilizers (e.g.
- NSAIDs e.g. Aspirin, Ibuprofen, Ketoprofen, Naproxen
- JAK inhibitors e.g. Tofacitinib, Ruxolitinib, Oclacit
- leukotriene inhibitors e.g. Zileuton, Zafirlukast, Montelukast
- mast cell stabilizers e.g
- Nedocromil Cromolyn sodium, Ketotifen, Pemirolast
- Anthralin dithranol
- purine synthesis inhibitors e.g. Azathioprine
- Coal tar Methotrexate, Methoxsalen, Salicylic acid, Ammonium lactate, Urea, Hydroxyurea, 5-fluorouracil, Propylthouracil, 6-thioguanine, Sulfasalazine, Mycophenolate mofetil, Fumaric acid esters, Corticosteroids (e.g.
- calcipotriene calcitriol
- retinoids e.g., Acitretin, Tazarotene
- calcineurin inhibitors eg, cyclosporine, tacrolimus, pimecrolimus
- Resorcinol Colchicine
- bronchodilators e.g. beta-agonists, anticholinergics, theophylline
- antibiotics and other anti-infectives e.g. erythromycin, ciprofloxacin, metronidazole, and anti-fungals such as miconazole and terbinafine
- Suitable pharmaceutical dosage forms include but are not limited to emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels, foams transdermal patches and solutions (e.g. injectable, oral).
- the composition preferably contains roflumilast, salts of roflumilast, the N-oxide of roflumilast or salts thereof in an amount of 0.005-2% w/w, more preferably 0.05-1% w/w, and most preferably 0.1-0.5% w/w per dosage unit.
- the composition preferably contains a means for inhibiting crystal growth and changes in particle size which is preferably hexylene glycol in an amount of between 0.1% and 20% w/w, more preferably between 0.25% and 8% w/w and most preferably between 0.5% and 2% w/w.
- the composition preferably contains one or more phosphate ester surfactants.
- concentration of the phosphate ester surfactant generally may be any concentration between 1.0% to 25% w/w.
- the composition preferably contains a component for increasing the solubility of roflumilast, which is preferably diethylene glycol monoethyl ether.
- a component for increasing the solubility of roflumilast which is preferably diethylene glycol monoethyl ether.
- the concentration of the diethylene glycol monoethyl ether may be any concentration between 5% and 50% w/w.
- the topical formulation containing roflumilast is applied to the skin in an amount that is sufficient to obtain the desired pharmacologic effect, which typically is to ameliorate the signs and/or symptoms of a medical disorder.
- the amount of the formulation that is applied may vary depending on the concentration of roflumilast within the formulation, and the frequency with which the formulation is applied. Generally, the formulation is applied with a frequency between weekly to several times daily, preferably between every other day to three times daily, and most preferably one or two times daily.
- the formulation containing roflumilast may be used in veterinary and in human medicine to treat a systemic medical condition that is ameliorated by or responsive to systemic administration of roflumilast.
- medical conditions include but are not limited to acute and chronic airway disorders such as bronchitis, allergic bronchitis, asthma, and COPD; proliferative, inflammatory and allergic dermatoses such as psoriasis, scalp psoriasis, or inverse psoriasis, irritant and allergic contact eczema and other varieties of eczema, hand eczema, atopic dermatitis, seborrheic dermatitis, lichen simplex chronicus, sunburn, aphthous ulcers, lichen planus, vitiligo, pruritus in the genital, anal or other body regions, alopecia areata, hypertrophic scars, discoid lupus erythematos
- the systemic dose of a drug administered topically depends on the concentration in the formulation, on the surface area to which the drug is applied and on the disease/anatomical site being treated.
- the thick plaques of psoriasis decrease the systemic dose, but cracks and fissures in and around the plaques provide a shunt pathway to increase the systemic dose.
- % BSA Body Surface Areas
- AD skin has an inherent skin barrier defect that always results in a higher systemic dose after topical treatment
- higher % BSA areas require treatment in AD (>20% BSA) compared to psoriasis (on average 7% BSA) because AD covers more of the body's skin surface area than psoriasis
- psoriasis is primarily a disease of adults while AD is a disease in children.
- the ratio of skin surface area to body weight is higher in a child compared to an adult.
- Topical products such as roflumilast cream
- topical creams do not have rigid dose units, and for children too young to self-administer product, the product does not need to be reformulated for a caregiver to administer the product.
- the challenge in topically dosing children is that the ratio of skin surface area to body weight changes dramatically from birth to adulthood. This is a major concern when dosing neonates with topical products, but of less concern when dosing children who are at least 3-months old and proportionately less concern when dosing pediatric patients 2 years or older.
- the ratio of surface area to body weight for pediatric patients compared to an adult is shown below.
- the greater ratio of skin surface area to body weight corresponds to a lower volume of distribution within the pediatric population after topical administration of the drug product. While the stratum corneum is intact shortly after birth ( ⁇ 1 month), the way human skin stores, and transports water becomes adult-like only after the first year of life (Batchelor, et al., Formulations for children: problems and solutions , British Journal of Clinical Pharmacology, 79:3, pp. 405-418 2013.
- the lower volume of distribution in the very young pediatric population compared to an adult results in children experiencing a higher systemic dose compared to an adult administered the exact same drug concentration applied over the same body surface area afflicted with the same severity of skin disease.
- a higher systemic dose in children can lead to an increase in adverse events such as psychiatric, weight loss and gastrointestinal side effects.
- the present formulations for topical application are suitable for administration to atopic dermatitis patients as young as 3 months and psoriasis patients as young as 2 years of age due to a roflumilast release profile that produces a flattened plasma concentration time curve and a reduced Cmax thereby decreasing adverse events in pediatric populations.
- the formulation for topical application containing roflumilast may be prepared by processes typically used in the field of manufacture of pharmaceutical formulations for topical application.
- a single-phase formulation such as a liquid
- the constituents of the formulation may be combined and mixed until a homogenous solution or suspension of the active ingredient is obtained.
- a multiphase formulation such as an emulsion
- the components of the aqueous phase and of the oil phase may be separately combined and mixed until homogenous solutions are obtained and then the aqueous solution and the oil solution may be combined and mixed, such as by shear mixing, to form the formulation.
- the one or more drug actives may be dissolved (molecularly dispersed), complexed, or associated with an excipient or other active, or may be particulate (amorphous or crystalline).
- the oil phase may be added to the water phase, or the water phase may be added to the oil phase.
- the phases may be combined and mixed, such as at elevated temperatures of 50-90° C. or at room temperature, that is between 20-30° C., or at a temperature between room temperature and the elevated temperatures.
- CrodafosTM CES (Croda Inc., Edison, N.J.), containing the phosphate ester surfactants dicetyl phosphate and ceteth-10 phosphate, is utilized as a representative example of phosphate ester surfactants.
- roflumilast API (Batch A14367P from Interquim S.A.) dry powder was tapped onto a microscope slide, a coverslip was moved into place and crystal habit and particle size of the API were examined using polarized light microscopy using a 10 ⁇ objective ( FIG. 1 , microscope sample 19-2).
- roflumilast Batch A14367P from Interquim S.A.
- Polyethylene glycol 400 (lot 1DE0880, Spectrum) was added dropwise with mixing to the vial containing roflumilast to produce a suspension of roflumilast in excess of the solubility limit.
- the tightly capped vial was returned to a water bath set at 25° C. It required 0.5486 grams of propylene glycol 400 to completely dissolve the 0.0180 grams of roflumilast and give a 3.18% roflumilast in polyethylene glycol 400 solution.
- This sample (labeled as “PEG 400” page 1) was a solution at 25° C. and was then stored undisturbed at about 15-18° C., protected from the light for six weeks. Roflumilast crystals precipitated due to the cooler storage temperature. A sample of the roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 4 ⁇ objective ( FIG. 6 , microscope sample 21-3).
- This sample (labeled 7-2) was then stored undisturbed at about 15-18° C., protected from the light for six weeks.
- a sample of precipitated roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 4 ⁇ objective ( FIG. 8 , microscope sample 21-5).
- Formulation 1 (comparative) Roflumilast 0.5% w/w White Petrolatum 10.0% w/w Isopropyl Palmitate 5.0% w/w Crodafos CES 10.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 25% w/w Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (49.25%)
- Formulation 2 Roflumilast 0.5% w/w White Petrolatum 10.0% w/w Isopropyl Palmitate 5.0% w/w Crodafos CES 10.0% w/w Hexylene glycol 2.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 25.0% w/w Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (47.25%)
- formulation 1 was sealed in a 1.0 mL CryoTubeTM vial and labeled as 36-1.
- 0.3961 grams of formulation 2 was sealed in a 1.0 mL CryoTubeTM vial and labeled as 36-2.
- the two CryoTubeTM vials were secured in an envelope end-to-end and placed in the freezer for 17.5 hours. Quickly upon removal from the freezer, a microscopic slide was prepared of each sample and after “thawing” the sample to room temperature (18° C.) a photomicrograph image was captured to characterize differences in precipitated roflumilast crystal growth. See FIGS. 11A and 11B .
- a formulation of the invention hereafter referred to as Formulation 3, was made by combining roflumilast with a phosphate ester surfactant and water. The formulation was buffered with NaOH to obtain a pH of 6.5.
- a formulation of the invention hereafter referred to as Formulation 4, was made by combining the above constituents and adding diethylene glycol monoethyl ether. This formulation was buffered with NaOH to obtain a pH of 6.5.
- Comparative Formulation 5 A formulation that is not of the invention, hereafter referred to as Comparative Formulation 5, was made by combining roflumilast with diethylene glycol monoethyl ether. This formulation was gelled with hydroxylpropyl cellulose so that it would have a similar viscosity and spread on the skin like the two phosphate ester surfactant emulsion Formulations 3, and 4. This semisolid formulation was likewise buffered with NaOH to obtain a pH of 6.5.
- compositions of these formulations are shown below in Table 1.
- Example 6 Single Dose Testing of Formulations of Example 5
- pigs dosed with Comparative Formulation 5 of the prior art showed a rapid spike to Cmax within 3 hours of dosing.
- Formulation 3 of the invention containing the phosphate ester surfactant Crodafos CES showed little or no spike to Cmax.
- the higher Cmax obtained with Formulation 4 was higher than that for Formulation 3.
- the PK data results in the graph of FIG. 12 show that the single dose PK profile data for the formulation containing phosphate ester surfactants lacks a significant spike to Cmax and has a low Cmax of 0.36 ng/mL, while maintaining a mean plasma concentration of 0.34 ng/ml through the 4 hour sample point. This is in contrast to PK data for the DEGEE formulation that rapidly raises to a Cmax of 0.85 ng/ml at 2 hours and then just as quickly drops to 0.57 ng/mL at 4 hours.
- the phosphate ester surfactant When the phosphate ester surfactant is added to DEGEE the formulation of the invention, it lacks a significant spike to Cmax and has a low Cmax, while maintaining AUC, in contrast to PK data for the DEGEE formulation which does not contain phosphate ester surfactants.
- This PK data is especially surprising in view of the fact that the prior art (Bolle) teaches that Cmax and AUC are similar for topical preparations containing roflumilast, irrespective of the composition of the topical formulation.
- Formulation 3, containing phosphate ester surfactant lacks a significant spike to Cmax.
- a third embodiment of the invention hereafter referred to as Formulation 6, was made by combining roflumilast at a concentration of 0.3% w/w with a phosphate ester surfactant and water.
- the formulation was buffered with NaOH to obtain a pH of 5.5.
- This formulation is similar to Formulation 3 except that the concentration of roflumilast is 0.3% rather than 0.15% and the emulsion is buffered to a pH value of 5.5 rather than a pH value of 6.5.
- Comparative Formulation 7 A formulation that is not of the invention, hereafter referred to as Comparative Formulation 7, was made by combining roflumilast at a concentration of 0.3% containing a phosphate ester surfactant, a polyoxyl stearyl ether surfactant and diethylene glycol monoethyl ether, as well as other excipients.
- This formulation is a cream formulation containing a frequently used phosphate ester surfactant that is not Crodafos CES.
- Comparative Formulation 8 A formulation that is not of the invention, hereafter referred to as Comparative Formulation 8, was made by combining roflumilast at a concentration of 0.2%. This formulation is that of the closest prior art known to the inventors and is disclosed in Example 3 of Bolle et al, U.S. Patent Application No. US 2006/0084684.
- compositions of these formulations are shown below in Table 2.
- Crodafos CES ad pH 5.5 q.s. ad pH 5.5 — Purified Water, USP q.s. ad 100% q.s. ad 100% q.s. ad 100% *The exact ratio of cetostearyl alcohol to dicetyl phosphate to cetheth-10 phosphate in Crodafos CES is consistent between batches of product but is not publicly disclosed by the manufacturer (Croda).
- the safety data sheet for Crodafos CES states that this emulsifier is composed of 60-80% cetostearyl alcohol, 10-20% dicetyl phosphate and 10-20% cetheth-10 phosphate.
- Medium-Chain Triglycerides is the nomenclature used by the US Food and Drug Administration to describe the cosmetic ingredient Capryli/Capric Triglyceride which is sold using tradenames including Miglyol ® 812 and Crodamol ® GTCC.
- Example 8 14-Day Dose Testing of Formulations of Example 7
- Male and female swine (Gottingen Minipig® breed) are ordered to weigh 8 to 12 kg at arrival. On the day prior to administration of one of the topical cream semisolid formulations of Example 7, the hair is clipped from the back of each animal. The pigs are sedated for the shaving procedure. Care is taken to avoid abrading the skin.
- pigs dosed with Formulation 7 of the prior art show a rapid spike to a Cmax value of 6.6 ng/mL at 1 hour after the 14th consecutive daily dose.
- Formulation 6 of the invention containing the phosphate ester surfactant Crodafos CES show little or no spike to Cmax.
- a fourth formulation of the invention is shown in Table 3, hereafter referred to as Formulation 9, was made by combining the above constituents and adding diethylene glycol monoethyl ether, as well as other ingredients to create a complete formulation. This formulation was buffered with NaOH to obtain a pH of 5.5. The qualitative and quantitative composition of Formulation 9 varies only in the amount of roflumilast added to the cream. As a fraction of 1% roflumilast is added, a fraction of 1% of water is removed from the cream.
- mice Male and female swine (Gottingen Minipig® breed) were ordered to weigh 8 to 12 kg at arrival. On the day prior to administration of a topical cream containing roflumilast, the hair was clipped from the back of each animal. The pigs were sedated for the shaving procedure. Care was taken to avoid abrading the skin.
- ARQ-151 is a topical cream which contains roflumilast. This phase 1 ⁇ 2a clinical trial enrolled two cohorts: Cohort 1 evaluated a single administration of ARQ-151 cream 0.5% and Cohort 2 evaluated ARQ-151 cream 0.5% or 0.15% applied once daily for 28 days. In Cohort 1, subjects applied ARQ-151 cream 0.5% to 25 cm 2 of psoriatic plaque(s). Subjects were screened (Visit 1), returned to the clinic for treatment (Visit 2) and PK blood draws, had a follow-up visit at 24 hours after the baseline visit for a PK blood draw (Visit 3), and received a follow-up telephone contact for safety evaluation 7 days after Visit 3. Subjects enrolled in Cohort 1 could be enrolled in Cohort 2 if they met eligibility criteria; subjects from Cohort 1 who rolled into Cohort 2 had all of their plaque(s) treated in Cohort 2 up to 5% body surface area (BSA).
- BSA body surface area
- Cohort 2 used a parallel-group, double-blind, vehicle-controlled study design. Subjects were randomly assigned in a 1:1:1 ratio to ARQ-151 cream 0.5%, ARQ-151 cream 0.15%, or a matched vehicle, which was applied to all psoriatic plaques (except on the face, intertriginous areas, scalp, palms, and soles) up to an application area of 5% BSA. Subjects in Cohort 2 had screening and baseline visits, follow-up visits at weeks 1, 2, 3, and 4, an additional visit at day 29 for a final pharmacokinetic sample collection, and a follow-up telephone call for safety evaluation at week 5.
- Cohort 1 received open-label treatment, without assignment or blinding. Assignment to treatment arm in Cohort 2 was performed using a computer-generated randomization list. Randomization was generated using SAS by an unblinded Premier Research statistician who was otherwise not involved in study conduct. The block size was 3; 72 total blocks were used. everyone was blinded to treatment.
- a target amount of 480 grams sterile water for irrigation-USP was accurately weighed into a 1000 ml glass beaker and 20 grams of sodium hydroxide pellets-NF was added and mixed using a stir bar until complete dissolution. This solution was set aside and labeled 1 N Sodium Hydroxide.
- Target weights pf 1,000 grams white petrolatum-USP, 500 grams isopropyl palmitate-NF, and 1,000 grams of phosphate-ester self-emulsifying wax (CRODAFOSTM CES) were weighed into a 4 L glass beaker and heated on a hot plate to 75° C. to 80° C. while mixing with a propeller mixer. The mixture was labeled Oil Phase and was maintained at 75° C. to 80° C.
- a target weight of 4,225 grams of sterile water for irrigation-USP and a target weight 300 grams 1N sodium hydroxide were added and heated on a hot plate to 75° C. to 80° C. This was recorded as the Aqueous Phase and was maintained at 75° C. to 80° C.
- Target weights of 2,400 grams of Transcutol P-NF, 200 grams of hexylene glycol-NF, 20.0 grams of methylparaben-NF, and 5.0 grams of propylparaben NF were accurately weighed into a 7 L stainless steel beaker and propeller mixed until a clear homogeneous solution was obtained. Sufficient potency corrected roflumilast was added to this solution to obtain either a 0.15% roflumilast cream or a 0.5% roflumilast cream and this was labeled the API Phase.
- the Oil Phase that was maintained at 75° C. to 80° C. was slowly added to the Aqueous Phase maintained at 75° C. to 80° C. in the Main Manufacturing Vessel with homogenizer mixing until a smooth, homogeneous cream was obtained.
- the API Phase was slowly added to the cream in the main manufacturing vessel and was mixed with the homogenizer.
- the pH of the finished cream was measured and adjusted to within the pH range of 5.1 to 5.9 using 1 N Sodium Hydroxide or Diluted Hydrochloric Acid, 10% (w/v)-NF.
- the cream was filled into aluminum 3 ⁇ 4′′ ⁇ 33 ⁇ 4′′ #16 sealed white tubes and the tubes crimped to provide the primary container closure system.
- TPSS Target Plaque Severity Score
- non-plaque forms of psoriasis non-plaque forms of psoriasis, drug-induced psoriasis, skin conditions that would interfere with study assessments, known allergies to excipients in ARQ-151 cream, hypersensitivity to PDE-4 inhibitors, inability to discontinue use of strong P-450 cytochrome inducers or P-450 cytochrome inhibitors, inability to refrain from use of a tanning bed, inability to discontinue systemic or topical therapies for the treatment of psoriasis, active infection requiring oral or intravenous antibiotics, antifungal, or antiviral agents within 7 days of baseline, or current or history of cancer within 5 years except for fully excised skin basal cell carcinoma, cutaneous squamous cell carcinoma, or cervical carcinoma.
- Formulation 9 also known as ARQ-151 cream, contained 0.5% or 0.15% roflumilast. Vehicle contained all ingredients in the ARQ-151 cream except roflumilast.
- ARQ-151 cream 0.5% was applied in the clinic to 25 cm 2 of psoriatic plaque(s).
- all psoriatic lesions up to 5% BSA were treated at home by subjects once daily for 4 weeks. Subjects were instructed by study staff on proper dosing and administration of ARQ-151 cream and vehicle.
- TPSS Target Plaque Severity Score
- TPA Target Plaque Area
- roflumilast and its active metabolite roflumilast N-oxide 12 were determined from plasma. Blood samples for pharmacokinetic analyses were collected on day 1 at 1, 2, 4, and 6 hours after ARQ-151 application. On day 28, samples were collected before dosing (trough level) and at 1, 2, 4, 6, and 24 hours after application.
- Safety endpoints included the type and incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs); application site reactions; and changes in physical examinations, vital signs, electrocardiograms, and clinical laboratory parameters. Safety was assessed at all study visits and at telephone follow-up. Skin irritation was assessed on days 1 and 2 for Cohort 1 and at baseline and visits 3 (week 1), 4 (week 2), 5 (week 3), and 6 (week 4) for Cohort 2. Skin irritation was evaluated using a scale developed by Berger and Bowman ranging from 0 (no evidence of irritation) to 7 (strong reaction spreading beyond application site). Additionally, other clinical signs of irritation were scored on an ‘A’ (slight glazed appearance) to ‘F’ (small petechial erosions and/or scabs) scale.
- Depressive Symptomatology Questionnaire 14 which was administered at screening, week 2, and week 4.
- the questionnaire is a 16-item inventory of depressive symptoms, with each item scored on a range of 0 to 3. Depression severity is based on score category, where total score ⁇ 5 represents no depression; 6-10 represents mild depression; 11-15 represents moderate depression; 16-20 represents severe depression; and ⁇ 21 represents very severe depression.
- TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1, and severity was graded on a 5-point scale of Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening consequences), or Grade 5 (death related to AE).
- MedDRA Medical Dictionary for Regulatory Activities
- Pharmacokinetic parameters were calculated using the plasma concentration values of roflumilast and roflumilast N-oxide (ng/mL) at each nominal time point with Phoenix WinNonlin (v8.0) using standard noncompartmental analysis.
- the area under the concentration time curve (AUC) was estimated using the linear trapezoidal interpolation method.
- the maximum plasma concentration (Cmax) and time to reach maximum concentration (Tmax) were based on direct assessment. Sample concentration values reported to be below the limit of quantification (BLQ; ⁇ 0.100 ng/mL) were ignored.
- the primary efficacy endpoint was the difference in mean percentage change from baseline at week 4 in the product of TPSS ⁇ TPA between each dose of ARQ-151 cream and vehicle control.
- the primary efficacy endpoint was analyzed using a mixed model for repeated measures with center within country, treatment, study visit, and treatment-by-study-visit interaction as fixed effects and baseline TPSS ⁇ TPA score as a covariate. Mean differences between visit value and baseline were calculated for each treatment. Mean percentage change from baseline for each ARQ-151 dose and corresponding vehicle were compared using an unstructured covariance structure unless the model did not converge; in that case the appropriate covariance structure was investigated.
- Secondary efficacy endpoints included the difference in mean percentage change from baseline at weeks 1, 2, and 3 in composite TPSS ⁇ TPA score, TPSS, and TPA between each dose of ARQ-151 cream and vehicle control.
- Safety analyses were conducted with the safety population, which comprised all subjects who received at least 1 dose of study drug and were based on treatment received.
- Pharmacokinetic analyses were conducted with the pharmacokinetic population, which included all subjects who consented for sampling and received active drug with sufficient plasma concentrations of roflumilast to define a profile.
- Efficacy analyses were conducted with the modified intent-to-treat population, which was composed of all subjects in Cohort 2 who received ⁇ 1 dose of study drug and had ⁇ 1 post-baseline efficacy evaluation.
- the mean age (standard deviation [SD]) was 51.6 (16.9) years for Cohort 1 and mean age ranged from 47.5 to 55.3 years across Cohort 2 treatment arms (Table 5). Most subjects were white. The average BSA of involvement was ⁇ 2% in all treatment groups. Of the 89 subjects enrolled in Cohort 2, 35 (39.3%) had target plaques located on the knees, elbows, or both.
- Formulation 9 (ARQ-151 cream) 0.5% and 0.15% was well tolerated, safe, and effective for the treatment of chronic plaque psoriasis.
- Formulation 9 (ARQ-151 cream) at both doses tested demonstrated strong efficacy as shown by statistically significant reductions in plaque severity and size compared to vehicle.
- TPSS ⁇ TPA TPSS ⁇ TPA values were already reduced by 66%-67% from baseline based on LS means.
- TPSS ⁇ TPA did not plateau in subjects treated with ARQ-151, suggesting that a longer duration of treatment might provide even greater efficacy.
- the TPSS ⁇ TPA endpoint was chosen to be analogous to whole-body Psoriasis Area and Severity Index (PASI) measurements.
- Formulation 9 (ARQ-151 cream) at both 0.5% and 0.15% was similar to vehicle, which is explained, at least in part, by the pharmacokinetic findings.
- roflumilast When administered orally for COPD, roflumilast may be associated with gastrointestinal side effects (diarrhea, nausea, vomiting), psychiatric disturbances (insomnia, anxiety, depression, suicidal thoughts or other mood changes), weight loss in a minority of patients, and headache.
- gastrointestinal side effects diarrhea, nausea, vomiting
- psychiatric disturbances insomnia, anxiety, depression, suicidal thoughts or other mood changes
- weight loss in a minority of patients
- headache Typically, clinical development of PDE-4 inhibitors for oral use has been limited by gastrointestinal effects such as nausea and vomiting. Indeed, nausea, vomiting, psychiatric disturbances, and weight loss are believed to be mediated at the level of the brain.
- topical administration of roflumilast in our study was associated with a slow ascent to maximum plasma concentrations over multiple days, and a flat exposure to roflumilast and its active metabolite roflumilast N-oxide throughout the dosing period (i.e. C max ⁇ C min across dosing interval).
- C max ⁇ C min across dosing interval The lack of nausea and vomiting seen in the present study could possibly be attributed the lack of ‘peak to trough’ Cmax variation; lower Cmax values than observed following oral administration; or bypassing of the gastrointestinal tract with topical administration.
- the absence of psychiatric disturbances and weight loss seen in our studies may also be explained by the markedly different PK of topical vs oral administration.
- PDE-4 inhibition represents a validated mechanism of action for oral psoriasis therapy (Otezla), but a new mechanism of action for topical psoriasis therapy.
- Patients with mild to moderate disease represent the majority of the psoriasis population. This patient population has not benefited from the recent introduction of biologic therapies, which are used in patients with more severe disease.
- roflumilast is an effective modality for the treatment of psoriasis.
- Roflumilast is a highly potent PDE-4 inhibitor, exhibiting half maximal inhibitory concentration (IC 50 ) values of both roflumilast and roflumilast N-oxide for the different PDE-4 isoforms and subtypes at subnanomolar potency.
- Rolumilast is 50- to 300-fold more potent than either apremilast or crisaborole against the different PDE-4 isoforms and subtypes.
- the oral dose of roflumilast at only 0.5 mg per day, is reflective of this extremely high potency.
- Formulation 10 is a foam concentrate which can be mixed with a propellant to produce a foam. Sixty four grams of the foam concentrate was blended with 8-10 grams of AP-70 propellant to make a foam.
- DALIRESP® 500 mcg tablets Treatment of 4,438 patients with once daily DALIRESP® 500 mcg tablets was associated with an increase in psychiatric adverse reactions and weight loss. In 8 controlled clinical trials 5.9% (263) of patients treated with DALIRESP® 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with DALIRESP® 500 mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP® versus 1.0%, 0.9%, and 0.9% for placebo, respectively). Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Materials Engineering (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
- This application is a continuation in part of U.S. Ser. No. 17/102,056 filed Nov. 23, 2020, which is a continuation of U.S. Ser. No. 16/136,804 filed Sep. 20, 2018, which is a continuation of U.S. Ser. No. 15/848,505 filed Dec. 20, 2017, which issued as U.S. Pat. No. 10,105,354 on Oct. 23, 2018, which is a continuation of U.S. Ser. No. 15/676,356 filed Aug. 14, 2017, which issued as U.S. Pat. No. 9,884,050 issued on Feb. 6, 2018, which is a divisional of U.S. Ser. No. 15/616,409 filed Jun. 7, 2017, which issued as U.S. Pat. No. 9,895,359, issued Feb. 20, 2018, the disclosures of which are incorporated herein in their entirety by reference.
- The invention pertains to methods for treating a patient having a disorder that is responsive to treatment with PDE-4 inhibition by the topical administration of a roflumilast formulation having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to administration of an equivalent amount of roflumilast in an oral composition. The methods of treatment of this invention provide a sufficiently high area under the plasma-roflumilast concentration curve (AUC) to attain a systemically effective level of roflumilast without rapid-onset peak plasma concentration (Cmax) (i.e., short Tmax). It has been discovered that these pharmacokinetic characteristics result in a reduction of undesirable side effects associated with oral roflumilast therapy.
- Roflumilast is known to be suitable as a bronchial therapeutic agent as well as for the treatment of inflammatory disorders. Compositions containing roflumilast are used in human and veterinary medicine and have been proposed for the treatment and prophylaxis of diseases including but not limited to: inflammatory and allergen-induced airway disorders (e.g. bronchitis, asthma, COPD); dermatoses (e.g. proliferative, inflammatory and allergen-induced skin disorders including psoriasis, seborrheic dermatitis, and atopic dermatitis), and generalized inflammations in the gastrointestinal region (Crohn's disease and ulcerative colitis). Currently, roflumilast is approved for systemic administration (oral) to treat inflammatory disorders involving the lungs, such as chronic obstructive pulmonary disease (COPD).
- Roflumilast and its synthesis were described in U.S. Pat. No. 5,712,298 (the “'298 patent”), incorporated herein by reference.* It has long been recognized that pharmaceutical compounds having phosphodiesterase (PDE)-inhibiting properties, such as roflumilast, are useful for treating inflammatory disorders, including inflammatory dermatoses, such as psoriasis and atopic dermatitis ('298 patent, col 11 lines 52-61) and other chronic inflammatory and allergen-induced dermatoses. For treatment of such dermatoses, roflumilast emulsions, suspensions, gels or solutions for topical application have been described ('298 patent,
col 12, lines 37-64). Although oral tablets of roflumilast have been commercialized, the low aqueous solubility of the compound has been reported to be only 0.53 mg/l at 21° C. in WO95/01338 (corresponding to the '298 patent and incorporated herein by reference in its entirety). This low aqueous solubility has been problematic for the development of parenteral preparations and topical emulsions, suspensions, gels or solutions containing water. In U.S. Pat. No. 9,205,044 (incorporated herein by reference), the poor water solubility of roflumilast was overcome by using an alkoxylated fat, specifically polyoxyethylated 12-hydroxystearic acid, as a co-solvent for parenteral administration. In EP 1511516B1 (corresponding to published U.S. application Ser. No. 14/075,035 incorporated herein by reference), the low water solubility of roflumilast was overcome in topical emulsion (cream) formulations by formulating with polyethylene glycol 400 (PEG 400) in concentrations over 62% (w/w) while keeping water weight percentages under 10%. * Unless otherwise indicated, references incorporated herein by reference are incorporated in their entireties for all purposes. - Topical application of potent pharmacological agents like roflumilast for treating skin diseases has been found to provide superior delivery, lower systemic exposure and greater ease of use for patients. The molecular structure of the compound ultimately dictates the ability of the drug to cross the epithelium of the tissue to which the product is applied. For topical application to skin, selection of the components of the formulation dictates the maximum skin permeation that the formulator can achieve. Creams, lotions, gels, ointments and foams are just a few of the more familiar forms of topical products that contain active pharmaceutical ingredients (API) for application to the skin. To assure consistent delivery of the API into or across the skin, it must remain either: 1) dissolved over the shelf life of the topical product, or 2) suspended as particles having unchanged crystal habit and unchanged particle size distribution over the shelf life of the topical product.
- The ability of a dissolved active ingredient to permeate the barrier of the skin is determined by its molecular structure. A well-known relationship between molecular structure and skin penetration is that increasing molecular weight decreases the rate that an active crosses the skin (J D Bos, M M Meinardi, Exp Dermatol. 2000 June; 9(3):165-9). Another well-understood relationship is that increasing the octanol-water partition coefficient of a hydrophilic active initially increases the rate that an active permeates the skin, but then decreases skin permeation once the active becomes too lipophilic to partition out of the stratum corneum and into the lower layers of the epidermis (D. W. Osborne and W. J. Lambert, Prodrugs for Dermal Delivery, K. B. Sloane ed., Marcel Dekker, New York 163-178 (1992)). The optimal octanol-water partition coefficient is usually at log P values of 2-3. The rate that an active ingredient crosses into the viable epidermis can be further modified based on the composition of the topical product. Final pH of the formulation may be critical, because dissolved ionized active ingredients typically do not permeate the skin as effectively as active ingredients that do not carry a charge (N. Li, X. Wu, W. Jia, M. C. Zhang, F. Tan, and J Zhang. Drug Dev Indust Pharm 38(8)985-994). Functional ingredients such as skin penetration enhancers (D. W. Osborne and J. J. Henke, Pharmaceutical Technology 21(11)58-66 (1997)) can be added to the topical product to increase skin permeation. For a dissolved active in the topical product, the closer the drug concentration is to the amount of active required to saturate the drug product, the greater the thermodynamic driving force of the active to cross the skin, i.e. the greater the skin flux of the active. The scientific literature guides formulators on how to increase penetration through the polar route, the nonpolar route, and the intercellular lipid pathway or transfollicular penetration. While these theories and mechanisms are sometimes conflicting, it is generally accepted that the most consistent skin permeation of a drug from a topical product occurs when the active ingredient is dissolved in the formulation. For this reason, formulators generally avoid developing a topical product that will have particles or crystals of the active ingredient precipitate during storage according to labeled storage instructions. Precipitation of the active ingredient can occur for various reasons. Particular active ingredients, when formulated with particular pharmaceutical excipients will tend to form supersaturated solutions. At the time of manufacture, all of the active ingredient will be in solution. After days, weeks, or months, this metastable topical product will equilibrate and active ingredient particles will form. If a topical product contains a volatile solvent such as ethanol, then evaporation of the solvent upon storage could result in precipitation of the active ingredient. A less soluble polymorph (Pudipeddi and Serajuddin, J. Pharm. Sci., 94(5) 929-939 (2005)) may nucleate in the topical product and form active ingredient particles that will not re-dissolve. Other products may be formulated too close to the saturation limit of the active ingredient with the result that minor shifts in storage temperatures will cause precipitation. It should be noted that the dramatic temperature shifts that can occur during shipping are expected to cause the reversible precipitation of the active ingredient. Regardless of the reason, irreversible precipitation of the active ingredient during storage of a topical product can have profound effects on the bioavailability and efficacy of a topical product, because only dissolved active ingredients can penetrate into intact stratum corneum, the outermost layer of epithelium of the skin.
- For a suspended active ingredient, properties in addition to molecular structure influence skin permeation. The ratio of dissolved to suspended active ingredient can have a significant influence on the amount of active delivered after topical application. It has been shown that optimal drug delivery can be achieved for particular drugs and particular diseases by utilizing a topical composition that includes a dissolved active ingredient that has the capacity to permeate the stratum corneum layer of the epidermis and become available systemically, along with an active ingredient in a microparticulate state that does not readily cross the stratum corneum of the epidermis (U.S. Pat. No. 5,863,560 hereby incorporated by reference). Another property of a suspended active ingredient that affects its delivery is the distribution of suspended particle size. It has been shown that a 6 micron particle will target the hair follicle and penetrate to a depth of 500 micrometers in a terminal hair. For a suspended particle of 0.75 microns to 1.5 microns in size, the particle penetrates the terminal hair shaft to a depth of 800 micrometers (A Patzelt, F Knorr, U Blume-Peytavi, W Sterry, J Lademann, Drug Discovery Today: Disease Mechanisms, 5(2)2008 pages e173-e181). Thus, for suspended active ingredients, skin permeability depends on the following properties: 1) molecular structure of dissolved active ingredient, 2) particulate/crystalline structure of the suspended active ingredient, 3) particle size of the suspended active ingredient, and 4) particle size distribution of the suspended active ingredient. The ability of a topical product composition to modify the skin permeation is similar for suspended active ingredients and dissolved active ingredients. Because skin permeability is dependent on additional properties of the suspended active ingredients, consistent delivery from topical products containing suspended actives is more difficult to maintain than for topical products containing only dissolved active ingredients.
- Consistent delivery of a suspended active ingredient from a topical product is assured by formulation into a product in which the suspended particles do not significantly change in size or amount over the shelf life of the product. Change over time in the ratio of dissolved active ingredient to particulate active ingredient can dramatically change the skin permeation of the active ingredient. The same mechanisms described above (supersaturation, temperature changes, evaporation, polymorphic transformation) that can cause precipitation of dissolved active ingredients can alter the dissolved-to-particulate ratio for suspended active ingredients. Change over time in the particle size or particle size distribution of the dispersed active ingredient can also dramatically change the skin permeation of the active ingredient. Sometimes this change in particle size or particle size distribution can be explained by Ostwald ripening of the particles. Ostwald ripening occurs when small particles in the topical product dissolve and redeposit onto larger particles suspended in the same container of topical product. Over time this phenomenon shifts the particle size distribution toward larger particles at the expense of the smaller particles. Ostwald ripening and precipitation of a less soluble polymorph are two major problems in developing topical products containing suspended actives.
- In addition to crystal growth and changes in particle size which can dramatically change the skin permeation of roflumilast, successful treatment can be also affected by side effects which can lead to treatment discontinuation. The prescribing information pertaining to DALIRESP® (oral roflumilast tablets marketed in the U.S.) warns of psychiatric adverse reactions (insomnia, anxiety, depression, suicidal ideation and suicidal behavior), weight loss and gastrointestinal side effects when patients are treated with 500 mcg once daily. Because of the high incidence of gastrointestinal side effects, including severe nausea and diarrhea, the prescribing information pertaining to DALIRESP® instructs that it may be beneficial to take half of the therapeutically effective dose, 250 mcg, once daily for 4 weeks prior to commencing the therapeutically effective dose of 500 mcg per day so as to reduce the rate of treatment discontinuation. The prescribing information for DAXAS® (oral roflumilast tablets marketed outside the U.S.) does not instruct the patient to take a reduced non-therapeutically effective dosage prior to taking the therapeutic dose. However, the prescribing information for DAXAS® does report a high incidence of diarrhea, nausea, and abdominal pain associated with this medication.
- When roflumilast is orally administered, the drug is rapidly absorbed, resulting in a sharp spike in plasma concentration. According to documents filed in the FDA, upon initial administration of a roflumilast tablet, a Cmax (peak plasma concentration) of 7.34 mcg/I that spiked at a Tmax (time after administration to reach Cmax) 1 hour after administration occurred with a 500 mcg tablet and a Cmax of 3.99 mcg/I that spiked at a Tmax of 1 hour occurred with a 250 mcg tablet. The spike in Cmax followed a clear dose-response relationship. A similar dose-response relationship was shown for the occurrence of gastrointestinal side effects, suggesting a possibility that these side effects are associated with the spike in Cmax.
- When multiple doses of oral roflumilast are administered, exposure follows a “peak to trough” pattern. This pattern results in an episodic variation in blood levels of drug and continued gastrointestinal side effects.
- Bolle, U.S. Patent Application Publication No. 2006/0084684 discloses topical formulations of roflumilast, salts of roflumilast, the N-oxide of roflumilast, and salts of the N-oxide. Bolle discloses that such formulations are useful to apply to skin lesions for the local treatment of skin disorders or to administer topically for the systemic treatment of skin disorders and other disorders, such as COPD. Bolle discloses that the systemic effect of topical application of the roflumilast formulations is comparable to that of an oral dosage form. Bolle further discloses, in paragraph 0080 that “Comparison with oral administration shows that, irrespective of the composition of the topical preparation, similar Cmax and AUCs and similar excretions with the urine are achieved.”
- Although Bolle does not discuss the incidence of side effects that occur following topical administration of the roflumilast formulations, because Cmax with the topical formulations, irrespective of the composition of the topical formulation, is similar to that which is obtained with orally administered formulations, and because side effects are correlated with Cmax and Tmax, it would be expected that administration of the topical formulations of Bolle would cause an incidence of side effects similar to that caused by orally administered formulations.
- Although oral tablets of roflumilast have been commercialized, topical and parenteral administration require different formulations due to the low aqueous solubility of the compound which has been reported to be only 0.53 mg/l at 21° C. in WO95/01338 (corresponding to the '298 patent and incorporated herein by reference). This low aqueous solubility has been problematic for the development of parenteral preparations and topical emulsions, suspensions, gels or solutions containing water. In U.S. Pat. No. 9,205,044 (incorporated herein by reference), the poor water solubility of roflumilast was overcome by using an alkoxylated fat, specifically polyoxyethylated 12-hydroxystearic acid, as a co-solvent for parenteral administration. In EP 151151681 (corresponding to published U.S. application Ser. No. 14/075,035 incorporated herein by reference), the low water solubility of roflumilast was overcome in topical emulsion (cream) formulations by formulating with polyethylene glycol 400 (PEG 400) in concentrations over 62% (w/w) while keeping water weight percentages under 10%.
- Topical application of potent pharmacological agents like roflumilast has been found to provide superior delivery and greater ease of use for patients. The molecular structure of the compound ultimately dictates the ability of the drug to cross the epithelium of the tissue to which the product is applied. For topical application to skin, selection of the components of the formulation dictates the maximum skin permeation that the formulator can achieve. Creams, lotions, gels, ointments and foams are just a few of the more familiar forms of topical products that contain active pharmaceutical ingredients (API) for application to the skin.
- A need exists for a method of treating patients having PDE-4 inhibitor responsive disorders with roflumilast, that results in a therapeutically effective systemic dose, does not result in a spike in Cmax, while still providing a high AUC, and which, therefore, is pharmaceutically efficacious but is associated with a decreased incidence of side effects. Indeed, the absence or reduced side effects allow for therapeutic doses to be administered that provide higher systemic exposures (AUCs) than are possible orally and with greater disease efficacy.
- In accordance with the present invention, an improved method of treating a patient having a disorder responsive to PDE-4 inhibition by administering a PDE-4-inhibiting amount of roflumilast, involves administering the roflumilast topically in a composition having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to oral administration of a PDE4-inhibiting amount of roflumilast. Such disorders include inflammatory disorders such as inflammatory dermatoses, including psoriasis, atopic dermatitis and seborrheic dermatitis. As used herein, a disorder is responsive to PDE-4 inhibition if such inhibition results in a prevention of the disorder or a diminution of its severity, duration or recurrence, such disorders also include inflammatory diseases in a variety of organs, especially the lungs (asthma, COPD). Because of reduced side effects with topical administration due to the above-described pharmacokinetics (PK) findings, it may be possible to provide higher systemic exposures (AUCs) with topical administration, resulting in greater therapeutic efficacy than with the oral route of administration.
- In a preferred embodiment, the topically applied composition contains from about 0.1% w/w to about 0.5% w/w roflumilast. In a preferred embodiment, the topically applied composition is in the form of a cream or a foam.
- In a preferred embodiment, the composition has a roflumilast release profile that results in a reduced Cmax, longer Tmax and flattened plasma concentration time curve relative to that achieved with oral administration of an effective amount of roflumilast in an oral composition marketed under the trademarks DALIRESP® and DAXAS®.
- It has been discovered that topical roflumilast compositions having the above-described PK properties produce reduced gastrointestinal, psychiatric, and weight loss side effects as compared to prior art orally administered compositions.
- Thus, in another embodiment, the present invention provides a method of treating a patient suffering from a disorder that can be treated by PDE-4 inhibition that comprises: administering a topical pharmaceutical composition comprising 0.5% w/w of roflumilast and a pharmaceutically acceptable carrier, wherein administration of said composition results in reduced gastrointestinal and other side effects relative to oral administration of roflumilast in a composition of roflumilast marketed under the trademark DALIRESP® or DAXAS®.
- The patent or application file contains at least one figure executed in color. Copies of this patent or patent application publication with color figures will be provided by the Office upon request and payment of the necessary fee.
-
FIG. 1 shows Sample 19-2 “dry” roflumilast crystals from ferrer-Interquim S.A. Batch A14367P, the drug substance used in all the examples in this specification. The roflumilast crystals are 0.01 mm-0.02 mm in length. -
FIG. 2 shows Sample 20-3 roflumilast crystals suspended in equimolar hexylene glycol:water solution after storage for six weeks at room temperature under 10× power. The roflumilast crystals are 0.01 mm-0.02 mm in length. -
FIG. 3 shows Sample 20-2 roflumilast crystals suspended in equimolar diethylene glycol monoethyl ether:water solution after storage for six weeks at room temperature. The roflumilast crystals are 0.04 mm-0.20 mm in length and 0.01 mm-0.02 mm in width. -
FIG. 4 shows Sample 20-3 roflumilast crystals suspended in equimolar hexylene glycol:water solution after storage for six weeks at room temperature under 4× power. The roflumilast crystals are 0.01 mm-0.02 mm in length. -
FIG. 5 shows Sample 21-2 roflumilast crystals suspended in equimolar ethanol:water solution after storage for six weeks at room temperature. The roflumilast crystals are 0.05 mm-0.25 mm in length and 0.02 mm in width. -
FIG. 6 shows Sample 21-3 roflumilast crystals suspended in equimolar PEG 400:water solution after storage for six weeks at room temperature. The roflumilast crystals are 0.05 mm-0.07 mm in length and 0.02 mm in width. -
FIG. 7 shows Sample 21-4 roflumilast crystals suspended in equimolar DMSO:water solution after storage for six weeks at room temperature. The roflumilast crystals are 0.10 mm-0.67 mm in length and 0.02 mm-0.10 mm in width. -
FIG. 8 shows Sample 21-5 roflumilast crystals suspended in equimolar propylene glycol:water solution after storage for six weeks at room temperature. The roflumilast crystals are 0.20 mm-1.60 mm in length and 0.02 mm in width. -
FIG. 9 shows Sample 20-1 roflumilast crystals suspended in equimolar NMP:water solution after storage for six weeks at room temperature. The roflumilast crystals are 0.10 mm-1.55 mm in length and 0.02 mm-0.13 mm in width. -
FIG. 10 shows Sample 21-1 roflumilast crystals suspended in HG:NMP:Water (water mole fraction=1.2) solution after storage for six weeks at room temperature. The roflumilast crystals are 0.02 mm-0.04 mm in length and 0.02 mm in width. -
FIGS. 11A and 11B show roflumilast particles precipitated in a cream composition after one freeze thaw cycle.FIG. 11a shows Sample 36-1 roflumilast particles precipitated in a cream composition with diethylene glycol monoethyl ether (DEGEE) and without hexylene glycol. The three largest roflumilast particles were measured (0.07 mm×0.09 mm; 0.06 mm×0.06 mm; and 0.10 mm×0.05 mm) and found to have a mean surface area of 5,000 square microns.FIG. 11b shows Sample 36-2 roflumilast particles precipitated in a cream composition with both diethylene glycol monoethyl ether (DEGEE) and hexylene glycol. The three largest roflumilast particles were measured (0.05 mm×0.03 mm; 0.05 mm×0.03 mm and 0.05 mm×0.03 mm) and found to have a mean surface area of 1,500 square microns. -
FIG. 12 is a line graph comparing the pharmacokinetic (PK) profile of two formulations of the invention,Formulation 3 andFormulation 4, and a PK profile of a formulation of the prior art, Formulation 5. -
FIG. 13 is a graph comparing the slow rise to Cmax of Formulation 4 (dicetyl phosphate/ceteth-10 phosphate) with the significantly greater roflumilast Cmax peak values (compared to trough T=0 plasma concentrations) following dosing with comparative formulation 5 (potassium cetyl phosphate) and comparative formulation 6 (Cetostearyl Alcohol and Glyceryl Stearate/PEG-100 Stearate). -
FIG. 14 is a linegraph showing Day 1 andDay 28 PK profiles after once daily dosing of 0.15% roflumilast topical cream. -
FIG. 15 is a linegraph showing Day 1 andDay 14 PK profiles after once daily dosing of 0.3% roflumilast topical cream. -
FIG. 16 is a linegraph showing Day 1 andDay 28 PK profiles after once daily dosing of 0.5% roflumilast topical cream. -
FIG. 17 is a linegraph showing Day 1 andDay 28 PK profiles after once daily dosing of 1.0% roflumilast topical cream. -
FIGS. 18A, 18B and 18C show changes in baseline in Target Plaque Severity Score and/or Target Plaque Area for 0.15% roflumilast topical cream and 0.5% roflumilast topical cream. -
FIGS. 19A and 19B show roflumilast and roflumilast N-oxide plasma concentrations atday 1 and day 28 (pharmacokinetic population) for 0.15% roflumilast topical cream and 0.5% roflumilast topical cream. -
FIGS. 20A and 20B are linegraphs showing day 1 andday 8 PK profiles after once daily dosing of Crodafos-CES creams containing either 0.3% crisaborole or 0.3% roflumilast. -
FIG. 21 is a line graph comparing roflumilast plasma concentration over time after 500 mcg once daily oral roflumilast (closed circles) and topical 0.5% ARQ-151 cream (closed squares) 0-24 hours onday 28 of once a day dosing. The oral roflumilast data (closed circles) was extracted from a plot in the publication T. D Bethke and G. Lahu, 2011, Int J of Clin Pharm and Ther, 49(1):51-57. [n=20 subjects; Time=0 (day 28 pre-dose blood draw) 1.33 ng/mL; Time=1.0 hour 1.34 ng/mL; Time=2.0 hour 1.26 ng/mL; Time=4.0 hour 1.18 ng/mL; Time=6.0 hour 1.25 ng/mL; Time=24.0 hour 1.15 ng/mL]. - The term “roflumilast” as used in this application refers to roflumilast, its salts, the N-oxide of roflumilast, and its salts unless specified otherwise or unless it is clear in context that reference is to roflumilast itself. The terms “N-oxide of roflumilast” and “salts of either roflumilast or of the N-oxide of roflumilast” refer specifically to the N-oxide or salts of either roflumilast or the N-oxide thereof. Roflumilast formulations can be prepared by methods known in the art (e.g. see the '298 patent and U.S. application Ser. No. 14/075,035).
- Roflumilast is a compound of the formula (I)
- wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy and R3 is 3,5-dichloropyrid-4-yl.
- This compound has the chemical name N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamid-e (INN: roflumilast).
- The term “salts”, when referring to roflumilast or the N-oxide of roflumilast, means a salt as described in paragraphs [0012] and [0013] of U.S. Patent Application Publication No. US 2006/0084684, the disclosure of which is incorporated herein by reference.
- Hexylene glycol (PharmaGrade. USP/NF) is 2-methyl-2,4-pentanediol of the formula (II).
- One aspect of present invention is directed to the addition of hexylene glycol to a roflumilast-containing pharmaceutical composition that contains a pharmaceutically acceptable solvent, including water, to inhibit growth of roflumilast crystals in the composition. For topical products designed to contain suspended roflumilast particles or crystals, the addition of hexylene glycol to a composition containing roflumilast, will inhibit (i.e., prevent or substantially reduce in comparison to compositions that do not contain a hexylene glycol) changes in particle size distribution over the shelf life of the product and assure consistent bioavailability. For topical products designed to have roflumilast completely dissolved, hexylene glycol inhibits the growth of precipitated roflumilast particles.
- Drug products that have fully dissolved drug substance for the labeled storage conditions over product shelf life will have the active precipitate if the product is formulated to maintain significant thermodynamic driving force. Typical storage conditions for a topical pharmaceutical cream are: Store at room temperature: 60° F./15° C.-80° F./26° C. Do not freeze. It is understood by product development scientists and regulatory agency reviewers that a topical product will not always be stored over this temperature range. Therefore, the FDA requires that all topical products undergo freeze-thaw cycling and temperature excursion studies. The active is neither required nor expected to remain in solution when the product is exposed to temperatures of −20° C., dramatically below 15° C. (60° F.) of the labeled storage condition. Since topical products containing completely dissolved drug are usually formulated near saturation, i.e. near maximum thermodynamic driving force, most topical products experience precipitation of the active ingredient during freeze-thaw cycling or temperature excursion studies. The addition of hexylene glycol prevents crystal growth of roflumilast when precipitation occurs due to temperature excursions below the labeled storage conditions. Inhibiting crystal growth assures that any precipitated active will quickly return to being completely dissolved once the product is returned to controlled room temperature. The prompt return of the precipitated roflumilast to a fully dissolved state assures consistent, reproducible bioavailability, efficacy and safety of the topically applied product. Hexylene glycol can be added between 0.1% and 20% on a weight/weight basis, preferably between 0.25% and 8% on a weight/weight basis and most preferably between 0.5% and 2% on a weight/weight basis.
- The topical roflumilast product formulations that benefit from the addition of hexylene glycol include but are not limited to aerosols, foams, sprays, emulsions (which can also be called creams, lotions, or ointments), gels (two phase or single phase), liquids, ointments, pastes, shampoos, suspensions, and systems. These are the tier two terms within compendia taxonomy for dosage forms containing pharmaceutical active ingredients (US Pharmacopeia <1151>).
- In a second aspect of the present invention, it has been unexpectedly discovered that, in direct contrast to the dogma of the prior art, a pharmaceutical formulation, such as a topically applied pharmaceutical formulation containing roflumilast, provides an altered PK (pharmacokinetic) profile with a reduced Cmax or a reduced absorption rate to reach Cmax when the formulations contain one or more phosphate ester surfactants compared to pharmaceutical formulations containing roflumilast without a phosphate ester surfactant(s). In particular, it has been unexpectedly discovered that a pharmaceutical formulation containing roflumilast and one or more phosphate ester surfactants, when topically administered to an individual, provides a systemically effective level of the PDE-4 inhibitor comparable to, or even greater than, that achieved with oral administration by slow absorption and without a Cmax spike of the PDE-4 inhibitor into the bloodstream.
- In pharmacokinetic terms, a formulation containing roflumilast, and a phosphate ester surfactant, when administered to an individual, such as by applying topically to the skin of an individual, provides a sufficiently high Area Under the Curve (AUC) to attain a systemically effective level of roflumilast without rapidly producing a peak plasma concentration (Cmax) that is associated with gastrointestinal side effects. That is, the absorption rate of the drug to reach Cmax is decreased when the formulation of the present application is administered, compared with the administration of formulations of the prior art.
- As used herein, the term “absorption rate to reach Cmax” means the slope of the PK curve between the administration of a formulation containing drug until Cmax, or the slope of the PK curve between a trough and the adjacent peak following serial multiple dose administrations of the formulation.
- Thus, in contrast to the teachings of the prior art, the formulations of the present application unexpectedly have a markedly different PK profile compared to prior art formulations containing roflumilast. The formulations of the present application provide a sufficiently high AUC to attain a systemically effective level of roflumilast without producing a spike in Cmax. The gradual ascent to Cmax obtained following topical application of the formulations of the present invention is markedly different from that of prior art formulations, but the AUC is similar. Additionally, following multiple doses of the formulation, the PK profile lacks the initial Cmax spike and the peak to trough pattern that is obtained following multiple daily dosing with prior art formulations containing the drug.
- This discovery provides several unexpected advantages. Primarily, it provides a means for treatment of medical conditions that are responsive to the administration of roflumilast, while minimizing the incidence of undesirable side effects, especially GI side effects. This in turn leads to greater patient compliance and reduced incidence of cessation of treatment due to the development of such side effects.
- Furthermore, because the ascent to Cmax is relatively slow, and a rapid Cmax spike is avoided, the formulations of the present invention can result in higher systemic exposure levels (AUC) than are possible with prior art formulations and without the side effects associated with a Cmax spike, such as those of the G.I. system. Such previously unobtainable exposure levels will provide a greater efficacy in the treatment of diseases.
- Moreover, it has been unexpectedly discovered that, following the attainment of Cmax after administration, there is a very flat and prolonged plateau in blood levels of the drug. Additionally, the PK profile obtained after multiple doses of the formulation of the present application is extremely and unexpectedly flat and prolonged with an extremely small peak to trough fluctuation following administration for 28 days. This flatness of the PK profile is especially pronounced when the formulation further contains diethylene glycol monoethyl ether.
- Because the absorption of roflumilast from the formulation in an amount required to provide a therapeutic effect is not dependent on a spike in absorption to provide a high Cmax and because the absorption of roflumilast is stable and has a flat PK profile, an individual user of a formulation producing such a PK profile may miss one or more doses from time to time and still maintain efficacy of the treatment.
- An important advantage of the present invention is that, a slow ascent to Cmax without a concomitant Cmax spike permit the obtaining of higher systemic exposure levels (AUC) than are possible with prior art formulations and without the side effects associated with Cmax spike, such as those of the G.I. system. Such previously unobtainable exposure levels will provide a greater efficacy in the treatment of diseases.
- A pharmaceutical formulation of the present invention contains roflumilast in a concentration which is sufficient to ameliorate a medical condition that is responsive to the administration of a PDE-4 inhibitor drug, such as psoriatic arthritis, psoriasis, atopic dermatitis, asthma and COPD. The concentration of roflumilast, in the formulation is that which is sufficient to obtain a desired systemic pharmacologic effect when the formulation is applied to the skin of an individual. This concentration will necessarily differ based on the type of formulation and the disease or condition to be treated. The concentration of roflumilast within the formulation is typically in the range of 0.001 to 25% w/w, with a preferred range between 0.01 to 5%, a more preferred range between 0.05 and 1%, and a most preferred range between 0.1 and 0.5%. In a particular preferred embodiment, the concentration of roflumilast in the formulation is between 0.05 and 0.5%, such as 0.05%, 0.15%, 0.3%, and 0.5% w/w.
- The formulation may contain a means for inhibiting crystal growth and changes in particle size distribution which can be hexylene glycol. The formulation may further contain a means for providing a sufficiently high AUC to attain a systemically effective level of roflumilast without producing a spike in Cmax, which can be one or more phosphate ester surfactants. Examples of phosphate ester surfactants that may be included in the formulations of this application include but are not limited to potassium cetyl phosphate, potassium C9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassium lauryl phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate, cetheth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate, disodium oleyl phosphate, lauryl phosphate, myristyl phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-3 phosphate, oleyl ethyl phosphate oleyl phosphate, PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5 ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4 phosphate, steartyl phosphate, DEA-cetyl phosphate, DEA-oleth-10 phosphate, DEA-oleth-3 phosphate, DEA-C8-C18 perfluoroalkylethyl phosphate, dicetyl phosphate, dilaureth-10 phosphate, dimyristyl phosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4 phosphate, trilaureth-4 phosphate, trilauryl phosphate, triolyeyl phosphate and tristearyl phosphate.
- The concentration of the phosphate ester surfactant in the formulation is that which is sufficient to produce a stable emulsion having uniform globule size. If desired, lower concentrations of the phosphate ester surfactant may be combined with other emulsifiers to produce a stable emulsion having uniform globule size. The phosphate ester surfactant may also increase the solubility of the roflumilast in the cream. The concentration of the phosphate ester surfactant generally may be any concentration between 1.0% to 25% w/w. The preferred concentration can be different for different administration forms. In a preferred embodiment, when the formulation is a cream or ointment, the concentration of the phosphate ester surfactant is between 2.5% and 20%, with a more preferred concentration range between 5% and 15%, and a most preferred concentration being about 10% w/w. When the formulation is in the form of a foam, the concentration is preferably between 1.0%-10%, more preferably between 1.0%-10%, and most preferably 2%.
- The formulation can optionally contain, a means for increasing the solubility of roflumilast, which can be diethylene glycol monoethyl ether. Diethylene glycol monoethyl ether is also known as 2-(2-ethoxyethoxy)ethanol, or as DEGEE, and is marketed under the several tradenames, including TRANSCUTOL® (Gattefosse Corporation, Paramus, N.J.), CARBITOL™ (The Dow Chemical Company, Midland, Mich.), DIOXITOL® (Shell Oil Company, Houston, Tex.), and POLY-SOLV DM (Monument Chemical, Houston, Tex.).
- DEGEE is often added to topical products as a co-solvent to increase solubility of the drug in the formulation. Addition of DEGEE to a topical formulation has also been shown to enhance skin penetration, i.e. increase Cmax, of topically administered pharmaceutical actives. See D. W. Osborne and J. Musakhanian, “Skin Penetration and Permeation Properties of TRANSCUTOL®—Neat or Diluted Mixtures”, AAPS Pharm SciTech. 19(8):3512-3533 (2018) DOI: 10.1208/s12249-018-1196-8; and Javadzadeh et al,
Chapter 12 pages 195-205, in Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement: Modification of the Stratum Corneum (N. Dragicevic, H. I. Maibach, eds) Springer-Verlag Berlin Heidelberg 2016. - The concentration of the diethylene glycol monoethyl ether, if present, in the formulation is that which is sufficient to dissolve the active pharmaceutical ingredient. Diethylene glycol monoethyl ether may also enhance the skin penetration of the roflumilast. Generally, the concentration of the diethylene glycol monoethyl ether is between 5% and 50% w/w, with a preferred range of concentrations between 10% and 40% w/w, a more preferred range between 15% and 30% w/w, and a particular preferred concentration being about 15-25% w/w. Likewise, water is formulated as about 20-90% (w/w) in topical products. For blends of DEGEE and water the ratio can range from 1:10 to 20:1. Preferably the DEGEE:water ratio is 1:4 to 9:1 in a formulation containing roflumilast. Generally, DEGEE-water blends can be used to dissolve up to 2.0% roflumilast (in the finished product) or preferably up to 0.5% roflumilast (in the finished product).
- The formulation for topical application to the skin is preferably a semi-solid dosage form that is cosmetically acceptable for use on the skin and which is easily spreadable on the skin. Examples of such semi-solid dosage forms include emulsions, ointments, creams, gels, and pastes. The formulation may alternatively be in a form other than a semi-solid dosage form, such as a liquid, which may be administered as a spray, or a foam. Preferably, a formulation for topical administration is in one of the following forms:
- An oil-in-water emulsion: The product may be formulations in which hexylene glycol is added to an emulsion comprising a discrete phase of a hydrophobic component and a continuous aqueous phase that includes water and optionally one or more polar hydrophilic excipients as well as solvents, co-solvents, salts, surfactants, emulsifiers, and other components. These emulsions may include water-soluble or water-swellable polymers that help to stabilize the emulsion.
- A water-in-oil emulsion: The compositions may be formulations in which roflumilast is incorporated into an emulsion that includes a continuous hydrophobic phase and an aqueous phase that includes the DEGEE-water blend and optionally one or more polar hydrophilic carrier(s) as well as salts or other components. These emulsions may include oil-soluble or oil-swellable polymers as well as one or more emulsifier(s) that help to stabilize the emulsion.
- For both oil-in-water and water-in-oil emulsions, order of addition may be important. Roflumilast can be added pre-dissolved in the continuous aqueous phase containing the DEGEE-water blend. Likewise, roflumilast can be pre-dissolved in the hydrophobic discrete phase of the emulsion that is then mixed with the DEGEE-water blend and optional hydrophilic excipients that do not contain the active ingredient. Roflumilast can be pre-dissolved in both the oil phase and water phase of the emulsion or added pre-dissolved in DEGEE or a DEGEE-water blend after the emulsion has been formed. Some emulsions undergo phase inversion over a specific temperature range during cooling of the emulsion. Thus, roflumilast may be added to a water-in-oil emulsion above the phase inversion temperature, with the final drug product being an oil-in-water emulsion at controlled room temperature, or vice versa.
- Thickened Aqueous gels: These systems include the DEGEE-water blend with dissolved roflumilast and optionally one or more polar hydrophilic carrier(s) such as hexylene glycol which has been thickened by suitable natural, modified natural, or synthetic thickeners such as described below. Alternatively, the thickened aqueous gels can be thickened using suitable polyethoxylate alky chain surfactants or other nonionic, cationic, or anionic systems.
- Thickened Hydroalcoholic gels: These systems include a blend of water and alcohol as the polar phase which has been thickened by suitable natural, modified natural, or synthetic polymers such as described below. Alternatively, the thickened hydroalcoholic gels can be thickened using suitable polyethoxylate alky chain surfactants or other nonionic, cationic, or anionic systems. The alcohol can be ethanol, isopropyl alcohol or other pharmaceutically acceptable alcohol.
- Hydrophilic gels: These are systems in which the continuous phase includes at least one water soluble or water dispersible hydrophilic component other than water. The formulations may optionally also contain water up to 60% by weight. Higher levels may be suitable in some compositions. Suitable hydrophilic components include one or more glycols such as polyols such as glycerin, propylene glycol, butylene glycols, polyethylene glycols (PEG), random or block copolymers of ethylene oxide, propylene oxide, and/or butylene oxide, polyalkoxylated surfactants having one or more hydrophobic moieties per molecule, silicone copolyols, blend of ceteareth-6 and stearyl alcohol as well as combinations thereof, and the like.
- A hydrophilic or hydrophobic ointment: The compositions are formulated with a hydrophobic base (e.g. petrolatum, thickened or gelled water insoluble oils, and the like) and optionally having a minor amount of a water soluble phase. Hydrophilic ointments generally contain one or more surfactants or wetting agents
- Compositions according to the present invention may include a means for obtaining the desired level of active ingredient solubility in the topical product which can be one or more solvents or co-solvents. The solvent may also modify skin permeation or the activity of other excipients contained in the formulation. Means for obtaining the desired level of active ingredient solubility in the topical product include but are not limited to acetone, ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, N-methyl pyrrolidinone, polyethylene glycol, glycerol, propylene glycol and SD alcohol.
- Compositions according to the present invention may include a moisturizer to increase the level of hydration. For emulsions, the moisturizer is often a component of the discrete or continuous hydrophobic phase. The moisturizer can be a hydrophilic material including humectants or it can be a hydrophobic material including emollients. Suitable moisturizers include but are not limited to: 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, light mineral oil, lanolin limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, Plastibase-50W, sorbitol, stearic acid, urea and stearyl alcohol.
- Compositions according to the present invention optionally can include one or more surfactants to emulsify the composition and to help wet the surface of the actives or excipients. As used herein the term “surfactant” means an amphiphile (a molecule possessing both polar and nonpolar regions which are covalently bound) capable of reducing the surface tension of water and/or the interfacial tension between water and an immisicible liquid. Surfactants include but are not limited to alkyl aryl sodium sulfonate, Amerchol-CAB, ammonium lauryl sulfate, apricot kernel oil PEG-6 esters, Arlacel, benzalkonium chloride, Ceteareth-6, Ceteareth-12, Ceteareth-15, Ceteareth-30, cetearyl alcohol/ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-10 phosphate, ceteth-2, ceteth-20, ceteth-23, choleth-24, cocamide ether sulfate, cocamine oxide, coco betaine, coco diethanolamide, coco monoethanolamide, coco-caprylate/caprate, dicetyl phosphate, disodium cocoamphodiacetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, disodium oleamido monoethanolamine sulfosuccinate, docusate sodium, laureth-2, laureth-23, laureth-4, lauric diethanolamide, lecithin, methoxy PEG-16, methyl gluceth-10, methyl gluceth-20, methyl glucose sesquistearate, oleth-2, oleth-20, PEG 6-32 stearate, PEG-100 stearate, PEG-12 glyceryl laurate, PEG-120 methyl glucose dioleate, PEG-15 cocamine, PEG-150 distearate, PEG-2 stearate, PEG-20 methyl glucose sesqustearate, PEG-22 methyl ether, PEG-25 propylene glycol stearate, PEG-4 dilaurate, PEG-4 laurate, PEG-45/dodecyl glycol copolymer, PEG-5 oleate, PEG-50 Stearate, PEG-54 hydrogenated castor oil, PEG-6 isostearate, PEG-60 hydrogenated castor oil, PEG-7 methyl ether, PEG-75 lanolin, PEG-8 laurate, PEG-8 stearate, Pegoxol 7 stearate, pentaerythritol cocoate, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237 poloxamer 407, polyglyceryl-3 oleate, polyoxyethylene alcohols, polyoxyethylene fatty acid esters, polyoxyl 20 cetostearyl ether, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polyoxyl 6 and polyoxyl 32, polyoxyl glyceryl stearate, polyoxyl stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, PPG-26 oleate, PROMULGEN™ 12, propylene glycol diacetate, propylene glycol dicaprylate, propylene glycol monostearate, sodium xylene sulfonate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, steareth-2, steareth-20, steareth-21, steareth-40, tallow glycerides, and emulsifying wax.
- Phosphate ester surfactants can also act as a means for reducing a spike in Cmax while producing an AUC sufficient to attain a systemically effective level of roflumilast. Suitable phosphate ester surfactants include but are not limited to potassium cetyl phosphate, potassium C9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassium lauryl phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate, cetheth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate, disodium oleyl phosphate, lauryl phosphate, myristyl phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-3 phosphate, oleyl ethyl phosphate oleyl phosphate, PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5 ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4 phosphate, steartyl phosphate, DEA-cetyl phosphate, DEA-oleth-10 phosphate, DEA-oleth-3 phosphate, DEA-C8-C18 perfluoroalkylethyl phosphate, dicetyl phosphate, dilaureth-10 phosphate, dimyristyl phosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4 phosphate, trilaureth-4 phosphate, trilauryl phosphate, triolyeyl phosphate and tristearyl phosphate.
- For certain applications, it may be desirable to formulate a product that is thickened with soluble, swellable, or insoluble organic polymeric thickeners such as natural and synthetic polymers or inorganic thickeners such as acrylates copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, and methylcellulose.
- The formulation may contain one or more thickening agent to provide viscosity so that the formulation may be provided in the form of a semisolid, such as a lotion, gel, cream, or ointment. Examples of suitable thickening agents include but are not limited to soluble, swellable, or insoluble organic polymeric thickeners such as natural and synthetic polymers or inorganic thickeners including but not limited to acrylates copolymer, carbomer 1382, copolymer type B, carbomer homopolymer type A, homopolymer type B, carbomer homopolymer type C, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, acacia, alginic acid, bentonite, carbomers, also known as carboxy vinyl polymers, such as sold under the tradename Carbopol® (Lubrizol, Wickliffe, Ohio), carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, poloxamers, polyvinyl alcohol, sodium alginate, tragacanth, and xanthan gum. The thickening agent may reside in the oil or lipophilic portion of the formulation. Examples of suitable lipophilic thickening agents include cetyl alcohol, stearyl alcohol, glyceryl stearate, white beeswax, microcrystalline wax, hydrogenated polyisobutane polymers, and emulsifying wax.
- Compositions according to the present invention may be formulated with additional components such as fillers, carriers and excipients conventionally found in cosmetic and pharmaceutical topical products. Additional components including but not limited to foaming agents, propellants preservatives (e.g. p-hydroxybenzoic esters, benzyl alcohol, phenylmercury salts, chlorocresol), antioxidants, sequestering agents, stabilizers, buffers, pH adjusting solutions, skin penetration enhancers, film formers, dyes, pigments, diluents, bulking agents, fragrances and other excipients to improve the stability or aesthetics of the product, may be added to the composition.
- The formulation may contain other pharmaceutically acceptable excipients if desired. For example, the formulation may contain a humectant such as glycerin, sorbitol, hexylene glycol, urea, or propylene glycol. The formulation may contain an emollient such as petrolatum, lanolin, mineral oil, light mineral oil, stearic acid, cyclomethicone, or dimethicone. Additional optional excipients include stabilizers, foaming agents, preservatives such as methylparaben, pH adjusting agents such as sodium hydroxide, chelating agents such as EDTA and its salts, and buffers.
- In one preferred embodiment, the roflumilast is in the form of an aerosolized foam which is particularly suitable for application to the scalp. Any suitable propellant can be used to prepare the aerosolized foam. Particularly preferred propellants are Isobutane A-31, Aeropin 35, Butane 48, Dimethyl Ether/N-Butane-(53/47), Propane/Iso-Butane/N-Butane, Propane/Isobutane-A70, and Propane/Isobutane A-46, N-Butane A-17.
- Compositions according to the present invention may be formulated with additional active agents depending on the condition being treated. The additional active agents include but are not limited to NSAIDs (e.g. Aspirin, Ibuprofen, Ketoprofen, Naproxen), Apremilast and other PDE4 inhibitors, JAK inhibitors (e.g. Tofacitinib, Ruxolitinib, Oclacit), leukotriene inhibitors (e.g. Zileuton, Zafirlukast, Montelukast), mast cell stabilizers (e.g. Nedocromil, Cromolyn sodium, Ketotifen, Pemirolast), Anthralin (dithranol), purine synthesis inhibitors (e.g. Azathioprine), Coal tar, Methotrexate, Methoxsalen, Salicylic acid, Ammonium lactate, Urea, Hydroxyurea, 5-fluorouracil, Propylthouracil, 6-thioguanine, Sulfasalazine, Mycophenolate mofetil, Fumaric acid esters, Corticosteroids (e.g. Aclometasone, Amcinonide, Betamethasone, Clobetasol, Clocotolone, Mometasone, Triamcinolone, Fluocinolone, Fluocinonide, Flurandrenolide, Diflorasone, Desonide, Desoximetasone, Dexamethasone, Halcinonide, Halobetasol, Hydrocortisone, Methylprednisolone, Prednicarbate, Prednisone), Corticotropin, Vitamin D analogues (e.g. calcipotriene, calcitriol), retinoids (e.g., Acitretin, Tazarotene), calcineurin inhibitors (eg, cyclosporine, tacrolimus, pimecrolimus), Resorcinol, Colchicine, bronchodilators (e.g. beta-agonists, anticholinergics, theophylline), and antibiotics and other anti-infectives (e.g. erythromycin, ciprofloxacin, metronidazole, and anti-fungals such as miconazole and terbinafine).
- Suitable pharmaceutical dosage forms include but are not limited to emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels, foams transdermal patches and solutions (e.g. injectable, oral).
- The composition preferably contains roflumilast, salts of roflumilast, the N-oxide of roflumilast or salts thereof in an amount of 0.005-2% w/w, more preferably 0.05-1% w/w, and most preferably 0.1-0.5% w/w per dosage unit.
- The composition preferably contains a means for inhibiting crystal growth and changes in particle size which is preferably hexylene glycol in an amount of between 0.1% and 20% w/w, more preferably between 0.25% and 8% w/w and most preferably between 0.5% and 2% w/w.
- The composition preferably contains one or more phosphate ester surfactants. The concentration of the phosphate ester surfactant generally may be any concentration between 1.0% to 25% w/w.
- The composition preferably contains a component for increasing the solubility of roflumilast, which is preferably diethylene glycol monoethyl ether. The concentration of the diethylene glycol monoethyl ether may be any concentration between 5% and 50% w/w.
- The topical formulation containing roflumilast, is applied to the skin in an amount that is sufficient to obtain the desired pharmacologic effect, which typically is to ameliorate the signs and/or symptoms of a medical disorder. The amount of the formulation that is applied may vary depending on the concentration of roflumilast within the formulation, and the frequency with which the formulation is applied. Generally, the formulation is applied with a frequency between weekly to several times daily, preferably between every other day to three times daily, and most preferably one or two times daily.
- The formulation containing roflumilast may be used in veterinary and in human medicine to treat a systemic medical condition that is ameliorated by or responsive to systemic administration of roflumilast. Non-limiting examples of such medical conditions include but are not limited to acute and chronic airway disorders such as bronchitis, allergic bronchitis, asthma, and COPD; proliferative, inflammatory and allergic dermatoses such as psoriasis, scalp psoriasis, or inverse psoriasis, irritant and allergic contact eczema and other varieties of eczema, hand eczema, atopic dermatitis, seborrheic dermatitis, lichen simplex chronicus, sunburn, aphthous ulcers, lichen planus, vitiligo, pruritus in the genital, anal or other body regions, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, endogenous and exogenous acne, acne rosacea, disorders which are based on an excessive release of TNF and leukotrienes, disorders of the heart which can be treated by PDE inhibitors, inflammations in the gastrointestinal system (including the liver) or central nervous system, disorders of the eye, disorders which can be treated by the tissue-relaxant action of roflumilast and other proliferative, inflammatory and allergic skin disorders; and immune mediated diseases such as arthritis including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, and psoriatic arthritis.
- The systemic dose of a drug administered topically depends on the concentration in the formulation, on the surface area to which the drug is applied and on the disease/anatomical site being treated. For example, the thick plaques of psoriasis decrease the systemic dose, but cracks and fissures in and around the plaques provide a shunt pathway to increase the systemic dose. These effects tend to cancel each other out so that the systemic dose found after topically treating psoriasis patients over similar Body Surface Areas (% BSA) is similar to the systemic dose obtained in treating normal volunteers. This also results in psoriatic patients tending to have the same systemic dose throughout treatment duration even though their disease is steadily resolving to become clear or nearly clear. When skin afflicted with atopic dermatitis (AD) is treated, there is a much higher systemic dosing for three reasons: (1) AD skin has an inherent skin barrier defect that always results in a higher systemic dose after topical treatment, (2) higher % BSA areas require treatment in AD (>20% BSA) compared to psoriasis (on average 7% BSA) because AD covers more of the body's skin surface area than psoriasis, and 3) psoriasis is primarily a disease of adults while AD is a disease in children. The ratio of skin surface area to body weight is higher in a child compared to an adult.
- Pediatric dosing of topical products such as roflumilast cream is much simpler than oral tablets because topical creams do not have rigid dose units, and for children too young to self-administer product, the product does not need to be reformulated for a caregiver to administer the product. The challenge in topically dosing children is that the ratio of skin surface area to body weight changes dramatically from birth to adulthood. This is a major concern when dosing neonates with topical products, but of less concern when dosing children who are at least 3-months old and proportionately less concern when dosing
pediatric patients 2 years or older. The ratio of surface area to body weight for pediatric patients compared to an adult is shown below. The greater ratio of skin surface area to body weight corresponds to a lower volume of distribution within the pediatric population after topical administration of the drug product. While the stratum corneum is intact shortly after birth (<1 month), the way human skin stores, and transports water becomes adult-like only after the first year of life (Batchelor, et al., Formulations for children: problems and solutions, British Journal of Clinical Pharmacology, 79:3, pp. 405-418 2013. At two years of age, the stratum corneum is still thinner compared to an adult (10 μm compared to 12 μm) and thus barrier function is slightly diminished (Walters, et al., Developmental Changes in Skin Barrier and Structure during the First 5 years of Life, Skin Pharmacol Physiol, 29:111-118, 2016). By the time a child reaches 3-5 years of age the skin barrier is similar to that of an adult. -
-
Patient Skin Surface Body Ratio Child Age Area Weight to Adult{circumflex over ( )} Neonate 2,100 cm2 3.4 kg 2.4 3-months 3,400 cm 26 kg 2.2 2-years 5,000 cm2 12.4 kg 1.6 of 66 kg and BSA of 17,000 cm2 - The lower volume of distribution in the very young pediatric population compared to an adult results in children experiencing a higher systemic dose compared to an adult administered the exact same drug concentration applied over the same body surface area afflicted with the same severity of skin disease. A higher systemic dose in children can lead to an increase in adverse events such as psychiatric, weight loss and gastrointestinal side effects. The present formulations for topical application are suitable for administration to atopic dermatitis patients as young as 3 months and psoriasis patients as young as 2 years of age due to a roflumilast release profile that produces a flattened plasma concentration time curve and a reduced Cmax thereby decreasing adverse events in pediatric populations.
- The formulation for topical application containing roflumilast, may be prepared by processes typically used in the field of manufacture of pharmaceutical formulations for topical application. In order to make a single-phase formulation, such as a liquid, the constituents of the formulation may be combined and mixed until a homogenous solution or suspension of the active ingredient is obtained. In order to make a multiphase formulation such as an emulsion, for example, the components of the aqueous phase and of the oil phase may be separately combined and mixed until homogenous solutions are obtained and then the aqueous solution and the oil solution may be combined and mixed, such as by shear mixing, to form the formulation. The one or more drug actives may be dissolved (molecularly dispersed), complexed, or associated with an excipient or other active, or may be particulate (amorphous or crystalline). The oil phase may be added to the water phase, or the water phase may be added to the oil phase. The phases may be combined and mixed, such as at elevated temperatures of 50-90° C. or at room temperature, that is between 20-30° C., or at a temperature between room temperature and the elevated temperatures.
- The following examples are provided to enable those of ordinary skill in the art to make and use the methods and compositions of the invention. These examples are not intended to limit the scope of what the inventor regards as the invention. Additional advantages and modifications will be readily apparent to those skilled in the art.
- In the following examples, Crodafos™ CES (Croda Inc., Edison, N.J.), containing the phosphate ester surfactants dicetyl phosphate and ceteth-10 phosphate, is utilized as a representative example of phosphate ester surfactants.
- A few mg of roflumilast API (Batch A14367P from Interquim S.A.) dry powder was tapped onto a microscope slide, a coverslip was moved into place and crystal habit and particle size of the API were examined using polarized light microscopy using a 10× objective (
FIG. 1 , microscope sample 19-2). - 0.0092 grams of roflumilast (Batch A14367P from Interquim S.A.) was weighed into a liquid scintillation vial. An equimolar blend of hexylene glycol (lot 1AC0818, Spectrum) and distilled water was added dropwise with mixing to the vial containing roflumilast to produce a suspension of roflumilast in excess of the solubility limit. An equimolar blend is 86.7% hexylene glycol and 13.3% water on a weight/weight percent basis. After mixing each addition of hexylene glycol:water blend, the tightly capped vial was returned to a water bath set at 25° C. It required 0.7962 grams of equimolar Hexylene Glycol:Water blend to completely dissolve the 0.0092 grams of roflumilast and give a 1.14% roflumilast in equimolar Hexylene Glycol:Water (wt/wt %) solution. 0.0064 grams of roflumilast was added to this sample (labeled 12-3) to form a finely dispersed suspension at 25° C. and the vial was then stored undisturbed at about 15-18° C., protected from the light for six weeks. A sample of the roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 10× objective (
FIG. 2 , microscope sample 20-3). - 0.0111 grams of roflumilast (Batch A14367P from Interquim S.A.) was weighed into a liquid scintillation vial. An equimolar blend of diethylene glycol (DEGEE) (Transcutol P, lot 146063, Gattefosse) and distilled water was added dropwise with mixing to the vial containing roflumilast to produce a suspension of roflumilast in excess of the solubility limit. An equimolar blend is 88.3% DEGEE and 11.7% water on a weight/weight percent basis. After mixing each addition of DEGEE:water blend, the tightly capped vial was returned to a water bath set at 25° C. It required 0.2477 grams of equimolar DEGEE:Water blend to completely dissolve the 0.0111 grams of roflumilast and give a 4.29% roflumilast in equimolar DEGEE:Water (wt/wt %) solution. This sample (labeled 13-1) was a solution of roflumilast at 25° C. and the vial was then stored undisturbed at about 15-18° C., protected from the light for six weeks. Roflumilast crystals precipitated due to the cooler storage temperature. A sample of the roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 10× objective (
FIG. 3 , microscope sample 20-2). - 0.0092 grams of roflumilast (Batch A14367P from Interquim S.A.) was weighed into a liquid scintillation vial. An equimolar blend of hexylene glycol (lot 1AC0818, Spectrum) and distilled water was added dropwise with mixing to the vial containing roflumilast to produce a suspension of roflumilast in excess of the solubility limit. An equimolar blend is 86.7% hexylene glycol and 13.3% water on a weight/weight percent basis. After mixing each addition of hexylene glycol:water blend, the tightly capped vial was returned to a water bath set at 25° C. It required 0.7962 grams of equimolar Hexylene Glycol:Water blend to completely dissolve the 0.0092 grams of roflumilast and give a 1.14% roflumilast in equimolar Hexylene Glycol:Water (wt/wt %) solution. 0.0064 grams of roflumilast was added to this sample (labeled 12-3) to form a finely dispersed suspension at 25° C. and the vial was then stored undisturbed at about 15-18° C., protected from the light for six weeks. A sample of the roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 4× objective (
FIG. 4 , microscope sample 20-3). - 0.0260 grams of roflumilast (Batch A14367P from Interquim S.A.) was weighed into a liquid scintillation vial. 1.0705 grams of an ethanol:water blend (Everclear which is 74.98% ethanol and 25.02% water on a weight/weight percent basis or 95% alcohol by volume) was added to produce a dispersion of roflumilast in an ethanol:water blend in excess of the solubility limit. This sample (labeled as “Alc” page 2) was then stored undisturbed at about 15-18° C., protected from the light for six weeks. A sample of the roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 4× objective (
FIG. 5 , microscope sample 20-3). - 0.0180 grams of roflumilast (Batch A14367P from Interquim S.A.) was weighed into a liquid scintillation vial. Polyethylene glycol 400 (lot 1DE0880, Spectrum) was added dropwise with mixing to the vial containing roflumilast to produce a suspension of roflumilast in excess of the solubility limit. After mixing each addition of polyethylene glycol 400, the tightly capped vial was returned to a water bath set at 25° C. It required 0.5486 grams of propylene glycol 400 to completely dissolve the 0.0180 grams of roflumilast and give a 3.18% roflumilast in polyethylene glycol 400 solution. This sample (labeled as “PEG 400” page 1) was a solution at 25° C. and was then stored undisturbed at about 15-18° C., protected from the light for six weeks. Roflumilast crystals precipitated due to the cooler storage temperature. A sample of the roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 4× objective (
FIG. 6 , microscope sample 21-3). - 0.0103 grams of roflumilast (Batch A14367P from Interquim S.A.) was weighed into a liquid scintillation vial and mixed with 0.2501 grams of dimethyl sulfoxide (lot US150, Gaylord Chemical) to give a 28.5% solution of roflumilast at 25° C. This sample (labeled as “DMSO” page 2) was then stored undisturbed at about 15-18° C., protected from the light for six weeks. A sample of precipitated roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 4× objective (
FIG. 7 , microscope sample 21-4). - 0.0061 grams of roflumilast (Batch A14367P from Interquim S.A.), 1.9332 grams of propylene glycol (
lot 1 EC0004, Spectrum) and 0.2335 grams distilled water was mixed to initially form a clear solution at 25° C. The composition of the sample was 0.28% roflumilast, 88.97% propylene glycol and 10.75% water on a weight/weight % basis. After 105 minutes of storage at 25° C. a “dusting” of fine roflumilast crystals were observed on the bottom of the vial. Six days later additional crystals had settled to the bottom of the vial. This sample (labeled 7-2) was then stored undisturbed at about 15-18° C., protected from the light for six weeks. A sample of precipitated roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 4× objective (FIG. 8 , microscope sample 21-5). - Dramatically greater roflumilast crystalline growth was observed in an equimolar N-methyl pyrrolidone:water solution containing roflumilast in excess of drug saturation compared to a 12:4:3 (wt/wt/wt) blend of hexylene glycol:N-methyl pyrrolidone:water (1.2 mole fraction of water) solution having roflumilast added in excess of the solubility limit.
- 0.0202 grams of roflumilast (Batch A14367P from Interquim S.A.) was mixed with 0.0682 grams of equimolar N-Methyl-2-pyrrolidone:water blend in a liquid scintillation vial. An equimolar blend is 84.5% N-Methyl-2-pyrrolidone (lot SYYN-HJ, TCI) and 15.5% water on a weight/weight percent basis. The 22.85% roflumilast in equimolar N-Methyl-2 pyrrolidone:water was completely dissolved at 25° C. This sample (labeled 13-2) was then stored undisturbed at about 15-18° C., protected from the light for six weeks. Roflumilast crystals precipitated due to the cooler storage temperature. A sample of the roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 4× objective (
FIG. 10 , microscope sample 20-1). - A 0.8152 gram sample of 3.6% roflumilast (Batch A14367P from Interquim S.A.), 60.8% hexylene glycol (lot 1AC0818, Spectrum), 20.0% N-Methyl-2-pyrrolidone (lot SYYN-HJ, TCI) and 15.6% distilled water was mixed on a weight/weight percent basis. This sample (labeled 13-4) was a finely dispersed suspension of roflumilast at 25° C. The sample was then stored undisturbed at about 15-18° C., protected from the light for six weeks. A sample of the roflumilast crystals was removed from the vial, placed on a microscope slide (with coverslip) and then examined using polarized light microscopy using a 4× objective (
FIG. 11 , microscope sample 21-1). - Roflumilast creams were prepared according to the following formulations.
-
Formulation 1 (comparative) Roflumilast 0.5% w/w White Petrolatum 10.0% w/w Isopropyl Palmitate 5.0% w/w Crodafos CES 10.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 25% w/w Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (49.25%) -
Formulation 2Roflumilast 0.5% w/w White Petrolatum 10.0% w/w Isopropyl Palmitate 5.0% w/w Crodafos CES 10.0% w/w Hexylene glycol 2.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 25.0% w/w Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (47.25%) - After preparation, 0.4222 grams of
formulation 1 was sealed in a 1.0 mL CryoTube™ vial and labeled as 36-1. Likewise, 0.3961 grams offormulation 2 was sealed in a 1.0 mL CryoTube™ vial and labeled as 36-2. The two CryoTube™ vials were secured in an envelope end-to-end and placed in the freezer for 17.5 hours. Quickly upon removal from the freezer, a microscopic slide was prepared of each sample and after “thawing” the sample to room temperature (18° C.) a photomicrograph image was captured to characterize differences in precipitated roflumilast crystal growth. SeeFIGS. 11A and 11B . - A formulation of the invention, hereafter referred to as
Formulation 3, was made by combining roflumilast with a phosphate ester surfactant and water. The formulation was buffered with NaOH to obtain a pH of 6.5. - A formulation of the invention, hereafter referred to as
Formulation 4, was made by combining the above constituents and adding diethylene glycol monoethyl ether. This formulation was buffered with NaOH to obtain a pH of 6.5. - A formulation that is not of the invention, hereafter referred to as Comparative Formulation 5, was made by combining roflumilast with diethylene glycol monoethyl ether. This formulation was gelled with hydroxylpropyl cellulose so that it would have a similar viscosity and spread on the skin like the two phosphate ester
surfactant emulsion Formulations - The compositions of these formulations are shown below in Table 1.
-
TABLE 1 Comparative Formulation 3 Formulation 4Formulation 5 Roflumilast 0.15% w/w 0.15% w/w 0.15% w/w Crodafos CES 10.0% w/w 10.0% w/w cetostearyl alcohol dicetyl phosphate ceteth-10 phosphate Diethylene Glycol 25.0% w/w 25.0% w/w Monoethyl Ether, NF Hydroxypropyl 0.5% w/w Cellulose 1N NaOH, NF q.s. ad pH 6.5 q.s. ad pH 6.5 q.s. ad pH 6.5 Purified Water, USP q.s. ad 100%q.s. ad 100%q.s. ad 100% - Male and female swine (Gottingen Minipig® breed) (Marshall BioResources, North Rose, N.Y.) were ordered to weigh 8 to 12 kg at arrival. On the day prior to administration of one of the topical cream semisolid formulations of Example 5 containing 0.15% roflumilast, the hair was clipped from the back of each animal. The pigs were sedated for the shaving procedure. Care was taken to avoid abrading the skin.
- Two (2) grams of one of the cream formulations of Example 5 for each kg of pig weight was distributed over the clipped skin area by gentle inunction with a glass stirring rod or stainless-steel spatula. The cream formulation was applied evenly with a thin, uniform film beginning at the scapular region and moving caudally over the test site. The width of the test site area was bilaterally divided by the spine. Six pigs (3 males and 3 females) were administered a single dose of the
Formulation 4. Blood was sampled from the anterior vena cava through the thoracic inlet or other suitable vein pre-dose (time=0) and at 1, 2, 4, 8 and 24 hours post dose administration. A one-week wash out (no product dosed) was sufficient to reduce plasma levels of roflumilast to zero as verified by the pre-dose (time=0) sample. After the washout period, a single dose offormulation 3 was applied. After a second one-week washout period, a single dose of Formulation 5 was applied. Blood samplings were the same for all three groups. The results are shown graphically inFIG. 12 . - As shown in
FIG. 12 , pigs dosed with Comparative Formulation 5 of the prior art showed a rapid spike to Cmax within 3 hours of dosing. In contrast, pigs dosed withFormulation 3 of the invention containing the phosphate ester surfactant Crodafos CES showed little or no spike to Cmax. Pigs dosed withFormulation 4 of the invention containing both a phosphate ester surfactant and diethylene glycol monoethyl ether, like those dosed withFormulation 3, showed a reduced spike to Cmax as compared to Formulation 5. However, the higher Cmax obtained withFormulation 4 was higher than that forFormulation 3. - The PK data results in the graph of
FIG. 12 show that the single dose PK profile data for the formulation containing phosphate ester surfactants lacks a significant spike to Cmax and has a low Cmax of 0.36 ng/mL, while maintaining a mean plasma concentration of 0.34 ng/ml through the 4 hour sample point. This is in contrast to PK data for the DEGEE formulation that rapidly raises to a Cmax of 0.85 ng/ml at 2 hours and then just as quickly drops to 0.57 ng/mL at 4 hours. When the phosphate ester surfactant is added to DEGEE the formulation of the invention, it lacks a significant spike to Cmax and has a low Cmax, while maintaining AUC, in contrast to PK data for the DEGEE formulation which does not contain phosphate ester surfactants. This PK data is especially surprising in view of the fact that the prior art (Bolle) teaches that Cmax and AUC are similar for topical preparations containing roflumilast, irrespective of the composition of the topical formulation. In contrast to what one would expect based on the teachings of the prior art,Formulation 3, containing phosphate ester surfactant, lacks a significant spike to Cmax. Moreover, the mean plasma concentration of 0.34 ng/ml was maintained throughout the 4 hour sample point. In contrast, Formulation 5 containing diethylene glycol monoethyl ether but lacking a phosphate ester surfactant, showed a rapid spike rise to Cmax of 0.85 ng/ml at two hours. When a phosphate ester surfactant was utilized in combination with diethylene glycol monoethyl ether,Formulation 4 administration produced no significant spike to Cmax and had a Cmax between those obtained withFormulations 3 and 5, while maintaining AUC. - A third embodiment of the invention, hereafter referred to as
Formulation 6, was made by combining roflumilast at a concentration of 0.3% w/w with a phosphate ester surfactant and water. The formulation was buffered with NaOH to obtain a pH of 5.5. This formulation is similar toFormulation 3 except that the concentration of roflumilast is 0.3% rather than 0.15% and the emulsion is buffered to a pH value of 5.5 rather than a pH value of 6.5. - A formulation that is not of the invention, hereafter referred to as
Comparative Formulation 7, was made by combining roflumilast at a concentration of 0.3% containing a phosphate ester surfactant, a polyoxyl stearyl ether surfactant and diethylene glycol monoethyl ether, as well as other excipients. This formulation is a cream formulation containing a frequently used phosphate ester surfactant that is not Crodafos CES. - A formulation that is not of the invention, hereafter referred to as
Comparative Formulation 8, was made by combining roflumilast at a concentration of 0.2%. This formulation is that of the closest prior art known to the inventors and is disclosed in Example 3 of Bolle et al, U.S. Patent Application No. US 2006/0084684. - The compositions of these formulations are shown below in Table 2.
-
TABLE 2 Comparative Comparative Formulation 6 Formulation 7Formulation 8Roflumilast 0.3% w/w 0.3% w/w 0.2% w/w Petrolatum, USP — 10.0% w/w — Isopropyl Palmitate, — 5.0% w/w — NF Medium-Chain — — 25.0% w/w Triglycerides Crodafos CES 10.0% w/w — — cetostearyl alcohol (6-8% w/w) dicetyl phosphate (1-2.5% w/w) ceteth-10 phosphate (1-2.5% w/w) Potassium Cetyl 2.0% w/w Phosphate Cetostearyl Alcohol 6.0% w/w 5.0% w/w Polyoxyl Stearyl Ether 2.0% w/w Glyceryl Stearate/ — 5.0% w/w PEG-100 Stearate Diethylene Glycol — 25.0% w/w — Monoethyl Ether, NF Hexylene Glycol, NF — 2.0% w/w — Methylparaben, NF — 0.20% w/w — Propylparaben, NF — 0.050% w/w — 1N NaOH, NF q.s. ad pH 5.5 q.s. ad pH 5.5 — Purified Water, USP q.s. ad 100%q.s. ad 100%q.s. ad 100%*The exact ratio of cetostearyl alcohol to dicetyl phosphate to cetheth-10 phosphate in Crodafos CES is consistent between batches of product but is not publicly disclosed by the manufacturer (Croda). The safety data sheet for Crodafos CES states that this emulsifier is composed of 60-80% cetostearyl alcohol, 10-20% dicetyl phosphate and 10-20% cetheth-10 phosphate. To emphasize the similarity in composition between Formulation 4 (phosphate-ester surfactant blend) and Comparative Formulation 5 (phosphate ester and nonionic surfactant blend) and Comparative Formulation 6 (nonionic surfactant blend), the cetostearyl alcohol portion of Crodafos CES is listed separately from the surfactant portion of Crodafos CES in Table 2. Glyceryl Stearate/PEG-100 Stearate is the nomenclature used by the US Food and Drug Administration to describe the nonionic emulsifier blend sold using the tradename Arlacel ® 165 and Tego Care ® 150.Medium-Chain Triglycerides is the nomenclature used by the US Food and Drug Administration to describe the cosmetic ingredient Capryli/Capric Triglyceride which is sold using tradenames including Miglyol ® 812 and Crodamol ® GTCC. - Male and female swine (Gottingen Minipig® breed) are ordered to weigh 8 to 12 kg at arrival. On the day prior to administration of one of the topical cream semisolid formulations of Example 7, the hair is clipped from the back of each animal. The pigs are sedated for the shaving procedure. Care is taken to avoid abrading the skin.
- Two (2) grams of one of the cream formulations of Example 7 for each kg of pig weight is distributed over the clipped skin area by gentle inunction with a glass stirring rod or stainless-steel spatula. The cream formulation is applied evenly with a thin, uniform film beginning at the scapular region and moving caudally over the test site. The width of the test site area is bilaterally divided by the spine. Eighteen pigs are divided into 3 groups of six pigs (3 males and 3 females) and the pigs of each group were dosed with one of the
formulations FIG. 13 . - As shown in
FIG. 13 , pigs dosed withFormulation 7 of the prior art show a rapid spike to a Cmax value of 6.6 ng/mL at 1 hour after the 14th consecutive daily dose. In contrast, pigs dosed withFormulation 6 of the invention containing the phosphate ester surfactant Crodafos CES show little or no spike to Cmax. - The results show in the graph of
FIG. 13 , that the steady state PK profile data after 14 days of once daily dosing for the formulation of the invention lacks a significant spike to Cmax and has a low Cmax, while maintaining AUC, in contrast to PK data for the prior art formulation or a formulation using a phosphate ester surfactant that was not Crodafos CES. These results are especially surprising in view of the fact that the prior art (Bolle) teaches that Cmax and AUC are similar for topical preparations containing roflumilast, irrespective of the composition of the topical formulation. - A fourth formulation of the invention is shown in Table 3, hereafter referred to as Formulation 9, was made by combining the above constituents and adding diethylene glycol monoethyl ether, as well as other ingredients to create a complete formulation. This formulation was buffered with NaOH to obtain a pH of 5.5. The qualitative and quantitative composition of Formulation 9 varies only in the amount of roflumilast added to the cream. As a fraction of 1% roflumilast is added, a fraction of 1% of water is removed from the cream.
-
TABLE 3 Formulation 9 Roflumilast 0.15, 0.3, 0.5 or 1.0% w/w Petrolatum, USP 10.0% w/w Isopropyl Palmitate, NF 5.0% w/w Crodafos CES 10.0% w/w cetostearyl alcohol (6-8% w/w) dicetyl phosphate (1-2% w/w) ceteth-10 phosphate (1-2% w/w) Diethylene Glycol Monoethyl Ether, NF 25.0% w/w Hexylene Glycol, NF 2.0% w/w Methylparaben, NF 0.20% w/w Propylparaben, NF 0.050% w/w 1N NaOH, NF q.s. ad pH 5.5 Purified Water, USP q.s. ad 100% - Male and female swine (Gottingen Minipig® breed) were ordered to weigh 8 to 12 kg at arrival. On the day prior to administration of a topical cream containing roflumilast, the hair was clipped from the back of each animal. The pigs were sedated for the shaving procedure. Care was taken to avoid abrading the skin.
- Two (2) grams of the
cream Formulation 7 having varying concentrations of roflumilast, for each kg of pig weight was distributed over the clipped skin area by gentle inunction with a glass stirring rod or stainless-steel spatula. The cream was applied evenly with a thin, uniform film beginning at the scapular region and moving caudally over the test site. The width of the test site area was bilaterally divided by the spine. Twenty pigs (10 males and 10 females) were dosed with 1% roflumilast cream, twelve pigs (6 males and 6 females) were dosed with 0.5% roflumilast cream, and twelve pigs (6 males and 6 females) were dosed with 0.15% roflumilast cream, each dosed daily for 28 days. Six pigs (3 males and 3 females) were each dosed daily with 0.3% roflumilast cream (formulation 7) for 14-days. Blood was sampled from a suitable vein pre-dose (time=0), and attimes day 1 and day 28 (orday 14 for 0.3% roflumilast) of dosing. The results are shown graphically inFIG. 14 (0.15% roflumilast cream), inFIG. 15 (0.3% roflumilast), inFIG. 16 (0.5% roflumilast cream), and inFIG. 17 (1.0% roflumilast cream) and in tabular form in Table 4. - As shown in each of
FIGS. 14 to 17 , the gradual ascent to Cmax is evident from theday 1 pharmacokinetic profile. What is most striking and surprising about the data shown inFIGS. 14 to 17 is the very flat and prolonged plateau in blood levels of the drug following Cmax in theday 28 or day 14 (0.3% roflumilast cream) pharmacokinetic profile, after reaching steady state drug delivery. -
TABLE 4 Trough (T = 0) Peak or Cmax Topical Product Dosed (ng/mL) (ng/mL) 0.15% Roflumilast Cream 4.5 (females) 4.9 (females) (FIG. 14--Steady State Day 28) 5.0 (males) 5.0 (males) 0.3% Roflumilast Cream 3.7 (females) 4.5 (females) (FIG. 15--Steady State Day 14) 6.6 (males) 6.6 (males) 0.5% Roflumilast Cream 8.5 (females) 10.7 (females) (FIG. 16--Steady State Day 28) 6.7 (males) 8.2 (males) 1% Roflumilast Cream 16.3 (females) 16.3 (females) (FIG. 17--Steady State Day 28) 8.4 (males) 10.0 (males) - Likewise, the data of Table 4 show an extremely small variation in blood concentration between the trough and peak (Cmax) following the attainment of steady state for each of the four concentrations of roflumilast when the formulation of the present invention is topically applied.
- ARQ-151 is a topical cream which contains roflumilast. This phase ½a clinical trial enrolled two cohorts:
Cohort 1 evaluated a single administration of ARQ-151 cream 0.5% andCohort 2 evaluated ARQ-151 cream 0.5% or 0.15% applied once daily for 28 days. InCohort 1, subjects applied ARQ-151 cream 0.5% to 25 cm2 of psoriatic plaque(s). Subjects were screened (Visit 1), returned to the clinic for treatment (Visit 2) and PK blood draws, had a follow-up visit at 24 hours after the baseline visit for a PK blood draw (Visit 3), and received a follow-up telephone contact forsafety evaluation 7 days afterVisit 3. Subjects enrolled inCohort 1 could be enrolled inCohort 2 if they met eligibility criteria; subjects fromCohort 1 who rolled intoCohort 2 had all of their plaque(s) treated inCohort 2 up to 5% body surface area (BSA). -
Cohort 2 used a parallel-group, double-blind, vehicle-controlled study design. Subjects were randomly assigned in a 1:1:1 ratio to ARQ-151 cream 0.5%, ARQ-151 cream 0.15%, or a matched vehicle, which was applied to all psoriatic plaques (except on the face, intertriginous areas, scalp, palms, and soles) up to an application area of 5% BSA. Subjects inCohort 2 had screening and baseline visits, follow-up visits atweeks -
Cohort 1 received open-label treatment, without assignment or blinding. Assignment to treatment arm inCohort 2 was performed using a computer-generated randomization list. Randomization was generated using SAS by an unblinded Premier Research statistician who was otherwise not involved in study conduct. The block size was 3; 72 total blocks were used. Everyone was blinded to treatment. - This study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The protocol was approved by Research Review Board, Inc., Richmond Hill, ON, Canada for all sites. All subjects provided written informed consent prior to initiation of any study-specific procedures. This trial was registered under ClinicalTrials.gov #NCT03392168.
- A target amount of 480 grams sterile water for irrigation-USP was accurately weighed into a 1000 ml glass beaker and 20 grams of sodium hydroxide pellets-NF was added and mixed using a stir bar until complete dissolution. This solution was set aside and labeled 1 N Sodium Hydroxide.
- Target weights pf 1,000 grams white petrolatum-USP, 500 grams isopropyl palmitate-NF, and 1,000 grams of phosphate-ester self-emulsifying wax (CRODAFOS™ CES) were weighed into a 4 L glass beaker and heated on a hot plate to 75° C. to 80° C. while mixing with a propeller mixer. The mixture was labeled Oil Phase and was maintained at 75° C. to 80° C.
- To the Main Manufacturing Vessel (a 20 L stainless steel vessel) a target weight of 4,225 grams of sterile water for irrigation-USP and a target weight 300 grams 1N sodium hydroxide were added and heated on a hot plate to 75° C. to 80° C. This was recorded as the Aqueous Phase and was maintained at 75° C. to 80° C.
- Target weights of 2,400 grams of Transcutol P-NF, 200 grams of hexylene glycol-NF, 20.0 grams of methylparaben-NF, and 5.0 grams of propylparaben NF were accurately weighed into a 7 L stainless steel beaker and propeller mixed until a clear homogeneous solution was obtained. Sufficient potency corrected roflumilast was added to this solution to obtain either a 0.15% roflumilast cream or a 0.5% roflumilast cream and this was labeled the API Phase.
- The Oil Phase that was maintained at 75° C. to 80° C. was slowly added to the Aqueous Phase maintained at 75° C. to 80° C. in the Main Manufacturing Vessel with homogenizer mixing until a smooth, homogeneous cream was obtained. Using propeller mixing, the cream was cooled to 45° C. to 50° C. The API Phase was slowly added to the cream in the main manufacturing vessel and was mixed with the homogenizer. The pH of the finished cream was measured and adjusted to within the pH range of 5.1 to 5.9 using 1 N Sodium Hydroxide or Diluted Hydrochloric Acid, 10% (w/v)-NF. After bulk product release, the cream was filled into aluminum ¾″×3¾″ #16 sealed white tubes and the tubes crimped to provide the primary container closure system.
- To be eligible for enrollment in
Cohort 1, subjects had to be ≥18 years of age with ≥25 cm2 of chronic plaque psoriasis. To be eligible for enrollment inCohort 2, subjects also had to have chronic plaque psoriasis of 6 months duration covering 0.5% to 5.0% of total BSA excluding the face, scalp, intertriginous areas, palms, and soles. Subjects needed to have at least 1 (and up to 3) target plaque(s)≥9 cm2 in size with a Target Plaque Severity Score (TPSS)≥4. Target plaques could be located anywhere on the body (excluding the face, scalp, intertriginous areas, palms, and soles), including the knees and elbows. Key exclusion criteria included: non-plaque forms of psoriasis, drug-induced psoriasis, skin conditions that would interfere with study assessments, known allergies to excipients in ARQ-151 cream, hypersensitivity to PDE-4 inhibitors, inability to discontinue use of strong P-450 cytochrome inducers or P-450 cytochrome inhibitors, inability to refrain from use of a tanning bed, inability to discontinue systemic or topical therapies for the treatment of psoriasis, active infection requiring oral or intravenous antibiotics, antifungal, or antiviral agents within 7 days of baseline, or current or history of cancer within 5 years except for fully excised skin basal cell carcinoma, cutaneous squamous cell carcinoma, or cervical carcinoma. - Formulation 9, also known as ARQ-151 cream, contained 0.5% or 0.15% roflumilast. Vehicle contained all ingredients in the ARQ-151 cream except roflumilast. In
Cohort 1, ARQ-151 cream 0.5% was applied in the clinic to 25 cm2 of psoriatic plaque(s). InCohort 2, all psoriatic lesions up to 5% BSA (except for those on the face, scalp, intertriginous areas, palms, and soles) were treated at home by subjects once daily for 4 weeks. Subjects were instructed by study staff on proper dosing and administration of ARQ-151 cream and vehicle. - Assessments of efficacy (
Cohort 2 only), pharmacokinetics (both cohorts), and safety (both cohorts) were conducted. The primary and secondary efficacy endpoints were calculated based on the product of Target Plaque Severity Score (TPSS) and Target Plaque Area (TPA). The TPSS was determined for each target plaque on each subject as the sum of erythema, thickness, and scaling scores, each rated on a scale of 0 (none) to 4 (very severe) and was identical to the severity scoring used in the PASI. TPA (cm2) was determined by multiplying the longest diameter (cm) of the target plaque by the widest perpendicular diameter (cm). Thus, the product of TPSS×TPA was roughly analogous to a PASI for the treated plaque. TPSS and TPA assessments were conducted at screening, baseline, andweeks - Pharmacokinetic profiles for roflumilast and its active metabolite roflumilast N-
oxide 12 were determined from plasma. Blood samples for pharmacokinetic analyses were collected onday 1 at 1, 2, 4, and 6 hours after ARQ-151 application. Onday 28, samples were collected before dosing (trough level) and at 1, 2, 4, 6, and 24 hours after application. - Safety endpoints included the type and incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs); application site reactions; and changes in physical examinations, vital signs, electrocardiograms, and clinical laboratory parameters. Safety was assessed at all study visits and at telephone follow-up. Skin irritation was assessed on
days Cohort 1 and at baseline and visits 3 (week 1), 4 (week 2), 5 (week 3), and 6 (week 4) forCohort 2. Skin irritation was evaluated using a scale developed by Berger and Bowman ranging from 0 (no evidence of irritation) to 7 (strong reaction spreading beyond application site). Additionally, other clinical signs of irritation were scored on an ‘A’ (slight glazed appearance) to ‘F’ (small petechial erosions and/or scabs) scale. An additional safety endpoint was the results from the Depressive Symptomatology Questionnaire, 14 which was administered at screening,week 2, andweek 4. The questionnaire is a 16-item inventory of depressive symptoms, with each item scored on a range of 0 to 3. Depression severity is based on score category, where total score ≤5 represents no depression; 6-10 represents mild depression; 11-15 represents moderate depression; 16-20 represents severe depression; and ≥21 represents very severe depression. - For
Cohort 2, a sample size of 24 subjects per arm (72 total subjects) was estimated to provide 80% power to detect a difference of 23% in the mean percentage change from baseline in the primary endpoint between the ARQ-151 cream and matching vehicle arm. This estimation was based on a 1-way analysis of variance at the α=0.025 significance level. To accommodate a 16% drop-out rate, the total sample size was increased to 84 subjects. - TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1, and severity was graded on a 5-point scale of Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening consequences), or Grade 5 (death related to AE).
- Pharmacokinetic parameters were calculated using the plasma concentration values of roflumilast and roflumilast N-oxide (ng/mL) at each nominal time point with Phoenix WinNonlin (v8.0) using standard noncompartmental analysis. The area under the concentration time curve (AUC) was estimated using the linear trapezoidal interpolation method. The maximum plasma concentration (Cmax) and time to reach maximum concentration (Tmax) were based on direct assessment. Sample concentration values reported to be below the limit of quantification (BLQ; <0.100 ng/mL) were ignored.
- The primary efficacy endpoint was the difference in mean percentage change from baseline at
week 4 in the product of TPSS×TPA between each dose of ARQ-151 cream and vehicle control. The primary efficacy endpoint was analyzed using a mixed model for repeated measures with center within country, treatment, study visit, and treatment-by-study-visit interaction as fixed effects and baseline TPSS×TPA score as a covariate. Mean differences between visit value and baseline were calculated for each treatment. Mean percentage change from baseline for each ARQ-151 dose and corresponding vehicle were compared using an unstructured covariance structure unless the model did not converge; in that case the appropriate covariance structure was investigated. The Bonferroni method was used to control for multiplicity, where the significance level for each of pairwise comparisons of active vs placebo was at α=0.025. - Secondary efficacy endpoints included the difference in mean percentage change from baseline at
weeks - In a post hoc analysis, the percentage of subjects with 75% and 90% improvement from baseline in TPSS×TPA (75% responders and 90% responders) at each study visit through
week 4 were also evaluated. - Safety analyses were conducted with the safety population, which comprised all subjects who received at least 1 dose of study drug and were based on treatment received. Pharmacokinetic analyses were conducted with the pharmacokinetic population, which included all subjects who consented for sampling and received active drug with sufficient plasma concentrations of roflumilast to define a profile. Efficacy analyses were conducted with the modified intent-to-treat population, which was composed of all subjects in
Cohort 2 who received ≥1 dose of study drug and had ≥1 post-baseline efficacy evaluation. - No imputation was used for missing data. Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and graphical representations (except for PK parameter estimation) were performed primarily using SAS (release 9.4). All PK parameter estimations were performed using WinNonlin® version 6.4 or later.
- Results
- Subjects were recruited from 7 study sites in Canada and from 1 site in the US between Dec. 5, 2017 (first patient enrolled) and May 2, 2018 (last follow-up visit). Eight subjects enrolled in
Cohort 1, and 89 subjects enrolled inCohort 2, including subjects randomly assigned to ARQ-151 cream 0.5% (N=30), ARQ-151 cream 0.15% (N=28), and vehicle (N=31). All subjects inCohort 1 received treatment and completed the study, and 6 also participated inCohort 2. Four subjects inCohort 2 discontinued early from the study because of loss to follow-up (n=3) or other reasons (n=1). There were no discontinuations due to AEs. The safety populations comprised all 8 subjects inCohort 1 and all 89 subjects inCohort 2. The PK population included 20 subjects who received Formulation 7 (ARQ-151 cream) 0.5% and 22 subjects who received Formulation 7 (ARQ-151 cream) 0.15%. The efficacy population comprised all subjects inCohort 2. - The mean age (standard deviation [SD]) was 51.6 (16.9) years for
Cohort 1 and mean age ranged from 47.5 to 55.3 years acrossCohort 2 treatment arms (Table 5). Most subjects were white. The average BSA of involvement was ˜2% in all treatment groups. Of the 89 subjects enrolled inCohort 2, 35 (39.3%) had target plaques located on the knees, elbows, or both. -
TABLE 5 Subject Characteristics (Safety Population) Cohort 1Cohort 2ARQ-151 ARQ-151 ARQ-151 0.5% 0.5% 0.15% Vehicle (N = 8) (N = 30) (N = 28) (N = 31) Age, mean years (SD) 51.6 (16.9) 49.9 (15.9) 55.3 (13.2) 47.5 (14.7) Sex, n (%) Male 1 (12.5) 16 (53.3) 19 (67.9) 18 (58.1) Female 7 (87.5) 14 (46.7) 9 (32.1) 13 (41.9) Race, n (%) 8 (100) 25 (83.3) 24 (85.7) 22 (71.0) White 0 2 (6.7) 2 (7.1) 8 (25.8) Asian 0 2 (6.7) 2 (7.1) 0 Black/African 0 1 (3.3) 0 1 (3.2) American Other Psoriasis-affected BSA, NC 3.06 (1.39) 2.73 (1.32) 2.21 (1.05) mean m2 (SD) BSA, body surface area; NC, not collected; SD, standard deviation. - The primary efficacy endpoint was met: the mean percentage change from baseline in TPSS×TPA at
week 4 was significantly different from vehicle for ARQ-151 cream 0.5% (P=0.0007) and ARQ-151 cream 0.15% (P=0.0011) (FIG. 7A ). For both concentrations of ARQ-151 cream, 66%-67% improvement from baseline was observed in the primary endpoint after 4 weeks of treatment vs 38% for vehicle, based on least square (LS) mean percentage change from baseline. Statistical separation from vehicle was reached for both drug product concentrations as early asweek 2 of treatment, and the difference between drug product and vehicle continued to increase throughweek 4. Both ARQ-151 cream 0.5% and 0.15% showed similar efficacy in this primary endpoint throughout the study duration. - Secondary efficacy endpoints of change from baseline in TPSS (
FIG. 7B ) and change from baseline in TPA (FIG. 7C ) were statistically significantly different between ARQ-151 at both active concentrations and vehicle after 4 weeks of treatment. For both active concentrations of ARQ-151 vs vehicle, change from baseline in TPSS, but not TPA, reached statistical significance as early as 2 weeks. - Patients receiving ARQ-151 cream 0.5%, 0.15% and vehicle after 4 weeks of treatment were compared to baseline, along with their respective TPSS×TPA scores. Of note, the vehicle-treated subjects seemed to have improvement mainly in the appearance of scaling (predictable for an emollient cream). Both subjects receiving ARQ-151 cream 0.5% and 0.15% show examples of substantial improvement in the elbows or knees, which can be treatment-resistant areas of psoriasis. Indeed, 39.3% of subjects had target plaques on the elbows and/or knees.
- In a post hoc analysis, 75% responder rates (75% improvement from baseline in TPSS×TPA) at
week 4 were also evaluated. In the ARQ-151 cream 0.5% group, 10 subjects (35.7%) achieved this level of improvement (P=0.0090), and in the ARQ-151 cream 0.15% group, 7 subjects (25.9%) were 75% responders (P=0.0700). There were two 75% responders (6.4%) in the vehicle group. In this same analysis, 90% responder rates atweek 4 were also evaluated. In the ARQ-151 cream 0.5% group, 4 subjects (14.3%) achieved this level of improvement, and in the ARQ-151 cream 0.15% group, 3 subjects (11.1%) were 90% responders; however, none of the 90% responder rates was statistically significant. There was one 90% responder (3.2%) in the vehicle group. - In
Cohort 1, limited evidence of systemic plasma exposure to roflumilast or roflumilast N-oxide was observed after a single topical administration of ARQ-151 0.5% to 25 cm2 of psoriatic plaques (data not shown). InCohort 2, systemic plasma exposure to roflumilast and roflumilast N-oxide was observed following single or multiple applications of Formulation 7 (ARQ-151) to psoriatic plaques covering 0.5% to 5% BSA (Table 8,FIG. 8A for 0.5% Formulation 7, ARQ-151 cream andFIG. 8B for 0.15% Formulation 7, ARQ-151 cream). Onday 1, roflumilast but not roflumilast N-oxide exposure appeared to increase in a dose-dependent manner. Atday 28, the plasma concentration vs time profiles were relatively flat (very small peak to trough differences) suggesting that roflumilast and roflumilast N-oxide exposure achieved steady state and appeared to increase in a dose-dependent manner. The ratio of N-oxide to roflumilast after topical administration ranged from 4.7 to 5.9, compared with 12 after oral administration of roflumilast, the latter being higher due to increased contribution from first pass metabolism. - As shown in
FIGS. 19A and 19B , when roflumilast is formulated in a cream containing the phosphate ester surfactant Crodafos CES, the gradual ascent to Cmax is evident in the single dose and steady-state pharmacokinetic profile. As shown inFIGS. 19A and 19B , there is a very flat and prolonged plateau in blood levels of the drug following Cmax for the 24-hours following the first application of 0.15% or 0.5% Formulation 9 (ARQ-151 cream) in human subjects. The pharmacokinetic profile of roflumilast after dosing the skin with Formulation 9 has the same low rise to Cmax shape when applied to humans or pigs. -
TABLE 6 Pharmacokinetic Parameters (Pharmacokinetic Population; Cohort 2) ARQ-151 ARQ-151 0.5% 0.15% Day 1 Roflumilast AUC0-last, mean h × ng/mL (SD) [n] 4.37 (5.84) [10] 2.34 (2.56) [7] Cmax, mean ng/mL (SD) [n] 1.38 (2.26) [10] 0.578 (0.468) [7] Tmax, mean h {minimum, maximum} [n] 3.20 {1.00, 6.00} [10] 3.71 {1.00, 6.00} [7] Roflumilast N-oxide AUC0-last, mean h × ng/mL (SD) [n] 2.61 (2.13) [4] 3.18 (2.54) [2] Cmax, mean ng/mL (SD) [n] 0.965 (0.858) [4] 1.07 (0.950) [2] Tmax, mean h [minimum, maximum] [n] 6.00 {6.00, 6.00} [4] 6.00 {6.00, 6.00} [2] Day 28 Roflumilast AUC0-last, mean h × ng/mL (SD) [n] 29.2 (19.9) [20] 24.4 (22.8) [21] Cmax, mean ng/mL (SD) [n] 1.48 (0.978) [20] 1.30 (1.06) [21] Tmax, mean h [minimum, maximum] [n] 3.70 {0.00, 24.0} [20] 4.95 {0.00, 24.0} [21] Roflumilast N-oxide AUC0-last, mean h × ng/mL (SD) [n] 172 (116) [20] 127 (119) [22] Cmax, mean ng/mL (SD) [n] 8.41 (5.54) [20] 6.11 (5.53) [22] Tmax, mean h [minimum, maximum] [n] 8.25 {0.00, 24.0} [20] 8.59 {0.00, 24.0} [22] AUC0-last, area under the concentration time curve until the last measurable time point; Cmax, maximum plasma concentration; Tmax, time to maximum plasma concentration. - In
Cohort 1, only 1 subject reported a TEAE, which was considered unrelated to treatment (Table 7). InCohort 2, the percent of TEAEs in the 0.15% group was lower than in the 0.5% or vehicle groups (7.1% vs 23.3% and 25.8%, respectively, for treatment-related TEAEs; and 25% vs 40% and 35.5%, respectively, for all TEAEs) (Table 7); all were mild or moderate in severity. No SAE was reported in this study, and no subject discontinued from the study because of a TEAE. All treatment-related TEAEs were associated with the application site, accounting for 17 events. Application site TEAEs were generally mild in severity and number (16 events were mild and 1 event was moderate) and showed no consistent differences between drug product and vehicle. No changes in physical examinations, vital signs, electrocardiograms, or clinical laboratory parameters were considered clinically meaningful. There were no clinically significant differences in weight changes between treatment groups. One subject in the 0.5% treatment group reported a single episode of nausea of moderate severity, but no further episodes in the remaining 3 weeks of the study. No subjects reported vomiting or diarrhea. No signs of skin irritation (dermal reactions) were noted inCohort 1. ForCohort 2, mean (SD) dermal reaction scores at baseline for ARQ-151 cream 0.5%, 0.15%, and vehicle were 0.2 (0.5), 0.0 (0.2), and 0.2 (0.4), respectively, and atweek 4 were 0.1 (0.5), 0.0 (0.0), and 0.1 (0.4). -
TABLE 7 Summary of Safety (Safety Population) Cohort 1Cohort 2ARQ-151 ARQ-151 ARQ-151 0.5% 0.5% 0.15% Vehicle (N = 8) (N = 30) (N = 28) (N = 31) Subjects with, n (%): ≥1 TEAE 1 (12.5) 12 (40.0) 7 (25.0) 11 (35.5) Treatment-related 0 7 (23.3) 2 (7.1) 8 (25.8) TEAE TEAE leading to 0 0 0 0 discontinuation SAE 0 0 0 0 Maximum severity of TEAEs, n (%) Mild 0 7 (23.3) 3 (10.7) 6 (19.4) Moderate 1 (12.5) 5 (16.7) 4 (14.3) 5 (16.1) Application site TEAEs, n (%) Erythema 0 4 (13.3) 1 (3.6) 4 (12.9) Pain 0 2 (6.7) 1 (3.6) 5 (16.1) Edema 0 1 (3.3) 0 1 (3.2) Papules 0 1 (3.3) 0 1 (3.2) Pruritus 0 1 (3.3) 1 (3.6) 0 SAE, serious adverse event; TEAE, treatment-emergent adverse event. - Discussion
- In this phase ½a clinical trial, Formulation 9 (ARQ-151 cream) 0.5% and 0.15% was well tolerated, safe, and effective for the treatment of chronic plaque psoriasis. Formulation 9 (ARQ-151 cream) at both doses tested demonstrated strong efficacy as shown by statistically significant reductions in plaque severity and size compared to vehicle.
- Statistically significant efficacy of ARQ-151 (Formulation 9 containing 0.15% or 0.5% roflumilast) as compared to vehicle in the primary study endpoint was observed with both active doses as early as 2 weeks after initiation of treatment, and differences between ARQ-151 and vehicle continued to increase through the last visit at 4 weeks. LS mean TPSS×TPA values decreased 38% with vehicle over the course of the study; the preponderance of this effect occurred during
week 1 of treatment, which was likely contributed to by apparently decreased scaling to the observer's eye caused by the emollient cream. There was no difference in efficacy between ARQ-151 cream 0.5% and 0.15% in the primary endpoint (percentage change from baseline in TPSS×TPA) atweek 4. However, the 75% responder rates atweek 4 suggested the 0.5% cream was somewhat more efficacious (35.7%; P=0.0090 vs vehicle) than the 0.15% concentration (25.9%; P=0.0700). With both active drug concentrations after 4 weeks of dosing, TPSS×TPA values were already reduced by 66%-67% from baseline based on LS means. However, TPSS×TPA did not plateau in subjects treated with ARQ-151, suggesting that a longer duration of treatment might provide even greater efficacy. The TPSS×TPA endpoint was chosen to be analogous to whole-body Psoriasis Area and Severity Index (PASI) measurements. Both use the same plaque severity scale, which was applied to 1-3 target lesions in the current study vs the entire body with PASI. The TPA ‘area’ function is different from the area of plaque involvement assessment in PASI, but we would propose that the product of TPSS×TPA provides an analogous assessment of ‘target plaque(s)’ to PASI for the entire body. Based on this assumption, the efficacy of topical ARQ-151 after 4 weeks of dosing (with 35.7% of subjects reaching 75% improvement for the 0.5% cream) may be comparable to that of theclass 1 steroid betamethasone dipropionate 0.064% (32.7% PASI 75 response rate after 4 weeks of dosing) in thephase 3 studies of Taclonex®. - The safety profile of Formulation 9 (ARQ-151 cream) at both 0.5% and 0.15% was similar to vehicle, which is explained, at least in part, by the pharmacokinetic findings. When administered orally for COPD, roflumilast may be associated with gastrointestinal side effects (diarrhea, nausea, vomiting), psychiatric disturbances (insomnia, anxiety, depression, suicidal thoughts or other mood changes), weight loss in a minority of patients, and headache. Typically, clinical development of PDE-4 inhibitors for oral use has been limited by gastrointestinal effects such as nausea and vomiting. Indeed, nausea, vomiting, psychiatric disturbances, and weight loss are believed to be mediated at the level of the brain. In contrast to oral administration, topical administration of roflumilast in our study was associated with a slow ascent to maximum plasma concentrations over multiple days, and a flat exposure to roflumilast and its active metabolite roflumilast N-oxide throughout the dosing period (i.e. Cmax˜Cmin across dosing interval). The lack of nausea and vomiting seen in the present study could possibly be attributed the lack of ‘peak to trough’ Cmax variation; lower Cmax values than observed following oral administration; or bypassing of the gastrointestinal tract with topical administration. The absence of psychiatric disturbances and weight loss seen in our studies may also be explained by the markedly different PK of topical vs oral administration. PDE-4 inhibition represents a validated mechanism of action for oral psoriasis therapy (Otezla), but a new mechanism of action for topical psoriasis therapy. Patients with mild to moderate disease represent the majority of the psoriasis population. This patient population has not benefited from the recent introduction of biologic therapies, which are used in patients with more severe disease. However, it is not surprising that roflumilast is an effective modality for the treatment of psoriasis. Roflumilast is a highly potent PDE-4 inhibitor, exhibiting half maximal inhibitory concentration (IC50) values of both roflumilast and roflumilast N-oxide for the different PDE-4 isoforms and subtypes at subnanomolar potency. Rolumilast is 50- to 300-fold more potent than either apremilast or crisaborole against the different PDE-4 isoforms and subtypes. The oral dose of roflumilast, at only 0.5 mg per day, is reflective of this extremely high potency.
- Further modifications, uses, and applications of the invention described herein will be apparent to those skilled in the art. It is intended that such modifications be encompassed in the following claims.
- A fifth formulation of the invention is shown in Table 8, hereinafter referred to as
Formulation 10.Formulation 10 is a foam concentrate which can be mixed with a propellant to produce a foam. Sixty four grams of the foam concentrate was blended with 8-10 grams of AP-70 propellant to make a foam. -
TABLE 8 Formulation 10Roflumilast 0.15, 0.3, 0.5 or 1.0% w/w Petrolatum, USP 5.0% w/w Isopropyl Palmitate, NF 2.5% w/ w Crodafos CES 2% w/w cetostearyl alcohol (1.2-1.6% w/w) dicetyl phosphate (0.2-0.5% w/w) ceteth-10 phosphate (0.2-0.5% w/w) Diethylene Glycol Monoethyl Ether, NF 25.0% w/w Hexylene Glycol, NF 2.0% w/w Methylparaben, NF 0.20% w/w Propylparaben, NF 0.050% w/w 1N NaOH, NF q.s. ad pH 5.5 Purified Water, USP q.s. ad 100% - Treatment of 4,438 patients with once daily DALIRESP® 500 mcg tablets was associated with an increase in psychiatric adverse reactions and weight loss. In 8 controlled clinical trials 5.9% (263) of patients treated with DALIRESP® 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with DALIRESP® 500 mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP® versus 1.0%, 0.9%, and 0.9% for placebo, respectively). Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving DALIRESP® compared to one patient (suicidal ideation) who received placebo. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression. Weight loss was a common adverse reaction in DALIRESP® clinical trials and was reported in 7.5% (331) of patients treated with DALIRESP® 500 mcg once daily compared to 2.1% (89) treated with placebo [see DALIRESP® 500 mcg package insert Adverse Reactions (6.1)]. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one-year duration. In these studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo. In addition, 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving DALIRESP®. (Section 5.2 and 5.3 of the Daliresp package insert)
- In contrast to the psychiatric adverse reactions and weight loss associated with orally administered roflumilast (Daliresp® 500 μg tablets), no significant safety concerns or signals have been identified during the completed or ongoing clinical studies of roflumilast cream or roflumilast foam. It is estimated that about 2,412 clinical trial subjects have been exposed to at least one dose of topical roflumilast cream or roflumilast foam. While adverse events associated with marketed oral roflumilast (Daliresp® 500 μg tablets), such as depression, weight loss and gastrointestinal adverse events, were assessed with regard to topical roflumilast cream and roflumilast foam studies, the side effects associated with oral administration of roflumilast have not been observed in roflumilast cream and roflumilast foam clinical studies. The pharmacokinetic profile of topical roflumilast appears to be distinct from that of oral roflumilast likely due to the lack of ‘peak to trough’ Cmax variation, lower Cmax values than observed following oral administration, and/or bypassing of the gastrointestinal tract with topical administration.
Claims (26)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/155,679 US20210161870A1 (en) | 2017-06-07 | 2021-02-05 | Roflumilast formulations with an improved pharmacokinetic profile |
PCT/US2022/013344 WO2022169615A1 (en) | 2021-02-05 | 2022-01-21 | Roflumilast formulations with an improved pharmacokinetic profile |
US18/453,674 US12016848B2 (en) | 2017-06-07 | 2023-08-22 | Roflumilast formulations with an improved pharmacokinetic profile |
US18/597,574 US12011437B1 (en) | 2017-06-07 | 2024-03-06 | Roflumilast formulations with an improved pharmacokinetic profile |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/616,409 US9895359B1 (en) | 2017-06-07 | 2017-06-07 | Inhibition of crystal growth of roflumilast |
US15/676,356 US9884050B1 (en) | 2017-06-07 | 2017-08-14 | Inhibition of crystal growth of roflumilast |
US15/848,505 US10105354B1 (en) | 2017-06-07 | 2017-12-20 | Inhibition of crystal growth of roflumilast |
US16/136,804 US10940142B2 (en) | 2017-06-07 | 2018-09-20 | Inhibition of crystal growth of roflumilast |
US17/102,056 US11793796B2 (en) | 2017-06-07 | 2020-11-23 | Inhibition of crystal growth of roflumilast |
US17/155,679 US20210161870A1 (en) | 2017-06-07 | 2021-02-05 | Roflumilast formulations with an improved pharmacokinetic profile |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/102,056 Continuation-In-Part US11793796B2 (en) | 2017-06-07 | 2020-11-23 | Inhibition of crystal growth of roflumilast |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US18/453,674 Continuation US12016848B2 (en) | 2017-06-07 | 2023-08-22 | Roflumilast formulations with an improved pharmacokinetic profile |
Publications (1)
Publication Number | Publication Date |
---|---|
US20210161870A1 true US20210161870A1 (en) | 2021-06-03 |
Family
ID=76092110
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/155,679 Abandoned US20210161870A1 (en) | 2017-06-07 | 2021-02-05 | Roflumilast formulations with an improved pharmacokinetic profile |
US18/453,674 Active US12016848B2 (en) | 2017-06-07 | 2023-08-22 | Roflumilast formulations with an improved pharmacokinetic profile |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US18/453,674 Active US12016848B2 (en) | 2017-06-07 | 2023-08-22 | Roflumilast formulations with an improved pharmacokinetic profile |
Country Status (1)
Country | Link |
---|---|
US (2) | US20210161870A1 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023129892A1 (en) * | 2021-12-28 | 2023-07-06 | Arcutis Biotherapeutics, Inc. | Topical aerosol foams |
WO2023129215A1 (en) * | 2021-12-28 | 2023-07-06 | Arcutis Biotherapeutics, Inc. | Topical roflumilast aerosol foams |
US11793796B2 (en) | 2017-06-07 | 2023-10-24 | Arcutis Biotherapeutics, Inc. | Inhibition of crystal growth of roflumilast |
US11819496B2 (en) | 2017-06-07 | 2023-11-21 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half-life |
US11992480B2 (en) | 2018-11-16 | 2024-05-28 | Arcutis Biotherapeutics, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
US12011437B1 (en) | 2017-06-07 | 2024-06-18 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
US12016848B2 (en) | 2017-06-07 | 2024-06-25 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
US12042487B2 (en) | 2018-11-16 | 2024-07-23 | Arcutis Biotherapeutics, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
US12042558B2 (en) | 2018-06-04 | 2024-07-23 | Arcutis Biotherapeutics, Inc. | Method and formulation for improving roflumilast skin penetration lag time |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10940142B2 (en) * | 2017-06-07 | 2021-03-09 | Arcutis, Inc. | Inhibition of crystal growth of roflumilast |
US11129818B2 (en) * | 2017-06-07 | 2021-09-28 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half life |
Family Cites Families (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4482537A (en) | 1983-09-19 | 1984-11-13 | Charles Of The Ritz Group Ltd. | Skin conditioning composition |
AU2259692A (en) | 1991-07-03 | 1993-02-11 | Sano Corporation | Composition and method for transdermal delivery of diclofenac |
PT706513E (en) | 1993-07-02 | 2002-10-31 | Byk Gulden Lomberg Chem Fab | BENZIMIDAZOIS SUBSTITUTED BY FLUORALCOXI AND ITS USE AS CYCLIC NUCLEOTIDIC PHOSPHODIESTERASE INHIBITORS |
ZA959368B (en) | 1994-11-04 | 1996-01-01 | Croda Inc | Fatty alcohol phosphate ester emulsifier compositions |
US5863560A (en) | 1996-09-11 | 1999-01-26 | Virotex Corporation | Compositions and methods for topical application of therapeutic agents |
GB9618974D0 (en) | 1996-09-11 | 1996-10-23 | Glaxo Group Ltd | Medicaments |
FR2753626B1 (en) | 1996-09-20 | 1998-11-06 | Centre International De Rech Dermatologiques Galderma Cird Galderma | NOVEL TOPICAL COMPOSITIONS IN THE FORM OF A FLUID O / W EMULSION WITH A HIGH PRO-PENETRATING GLYCOL CONTENT |
US6214322B1 (en) | 1999-06-15 | 2001-04-10 | Neutrogena Corporation | Self-tanning composition comprising carmine |
US6056955A (en) | 1999-09-14 | 2000-05-02 | Fischetti; Vincent | Topical treatment of streptococcal infections |
UA80393C2 (en) | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix |
ES2354971T3 (en) | 2002-05-28 | 2011-03-21 | Nycomed Gmbh | ROFLUMILAST OPHTHALMOLOGICAL USE FOR THE TREATMENT OF EYE DISEASES. |
US7470791B2 (en) | 2003-03-10 | 2008-12-30 | Nycomed Gmbh | Process for the preparation of roflumilast |
EP1675563A4 (en) | 2003-08-13 | 2009-07-15 | Qlt Usa Inc | Emulsive composition containing dapsone |
US20060204526A1 (en) | 2003-08-13 | 2006-09-14 | Lathrop Robert W | Emulsive composition containing Dapsone |
PL1670433T3 (en) | 2003-10-10 | 2013-03-29 | Ferring Bv | Transdermal pharmaceutical formulation for minimizing skin residues |
DE10347994A1 (en) | 2003-10-15 | 2005-06-16 | Pari GmbH Spezialisten für effektive Inhalation | Aqueous aerosol preparation |
US6949795B2 (en) | 2003-11-13 | 2005-09-27 | Micron Technology, Inc. | Structure and method of fabricating a transistor having a trench gate |
US20050112162A1 (en) | 2003-11-26 | 2005-05-26 | Drader Cathy M. | Cosmetic formulation containing sheep's milk and method of making a cosmetic formulation containing sheep's milk |
CN1657282A (en) | 2004-02-04 | 2005-08-24 | 松下电器产业株式会社 | Vacuum thermally insulating material and method for production thereof, thermally insulated equipment having the vacuum thermally insulating material, and thermally insulated board |
DE102004025282A1 (en) | 2004-05-19 | 2005-12-08 | Henkel Kgaa | Use of special polyols for the crystallization inhibition of onium aldehydes or ketones |
US8338648B2 (en) | 2004-06-12 | 2012-12-25 | Signum Biosciences, Inc. | Topical compositions and methods for epithelial-related conditions |
DE102004046236A1 (en) | 2004-09-22 | 2006-03-30 | Altana Pharma Ag | drug preparation |
DE102004046235A1 (en) | 2004-09-22 | 2006-03-30 | Altana Pharma Ag | drug preparation |
CA2548532C (en) | 2004-09-27 | 2014-12-02 | Jan De Rijk | Methods and compositions for treatment of water |
JPWO2006041121A1 (en) | 2004-10-13 | 2008-05-15 | 協和醗酵工業株式会社 | Treatment and / or prevention agent for chronic skin diseases |
US20060110415A1 (en) * | 2004-11-22 | 2006-05-25 | Bioderm Research | Topical Delivery System for Cosmetic and Pharmaceutical Agents |
US20060204452A1 (en) | 2005-03-10 | 2006-09-14 | Velamakanni Bhaskar V | Antimicrobial film-forming dental compositions and methods |
JP5846711B2 (en) | 2005-06-09 | 2016-01-20 | メダ アーベー | Methods and compositions for the treatment of inflammatory diseases |
US20070048241A1 (en) | 2005-08-30 | 2007-03-01 | Croda, Inc. | Emulsifying system |
US20070098660A1 (en) | 2005-10-27 | 2007-05-03 | Jim Taneri | Methods and compositions for epilation |
JP2007119432A (en) | 2005-10-31 | 2007-05-17 | Ichimaru Pharcos Co Ltd | Activator of peroxisome proliferator-activated receptor (ppar) |
US20070207107A1 (en) | 2006-03-03 | 2007-09-06 | Gareth Winckle | Silicone based emulsions for topical drug delivery |
FR2898499B1 (en) | 2006-03-15 | 2008-11-28 | Galderma Sa | NOVEL TOPIC COMPOSITIONS IN THE FORM OF O / W EMULSION COMPRISING PRO-PENETRANT GLYCOL |
EP2010145A2 (en) | 2006-04-25 | 2009-01-07 | Croda, Inc. | Modification of percutaneous absorption of topically active materials |
US20070258935A1 (en) | 2006-05-08 | 2007-11-08 | Mcentire Edward Enns | Water dispersible films for delivery of active agents to the epidermis |
FR2920967B1 (en) | 2007-09-14 | 2009-10-23 | Sederma Soc Par Actions Simpli | USE OF HYDROXYMETHIONINE AS ANTI-AGING AGENT |
US7893097B2 (en) | 2008-02-02 | 2011-02-22 | Dow Pharmaceutical Sciences, Inc. | Methods and compositions for increasing solubility of azole drug compounds that are poorly soluble in water |
CN102076333A (en) | 2008-06-26 | 2011-05-25 | 安特里奥公司 | Dermal delivery |
JP2009034537A (en) | 2008-10-14 | 2009-02-19 | Takara Standard Co Ltd | Mirror cabinet |
CN102482249B (en) | 2009-07-08 | 2016-06-08 | 德米拉(加拿大)公司 | For treating the TOFA analog of skin disorder or morbid state |
US20110117182A1 (en) | 2009-07-30 | 2011-05-19 | Allergan, Inc. | Combination of dapsone with other anti-acne agents |
JP5576693B2 (en) | 2010-04-02 | 2014-08-20 | 久光製薬株式会社 | Transdermal absorption enhancer, and transdermal preparation containing the transdermal absorption enhancer |
US8293288B2 (en) | 2011-02-23 | 2012-10-23 | Edna Ma | Pain relieving composition |
US8512768B2 (en) | 2011-02-23 | 2013-08-20 | Miss Smarty Pants Enterprises, Inc. | Pain relieving composition |
KR20140029426A (en) | 2011-03-31 | 2014-03-10 | 아코르다 쎄라퓨틱스 인코포레이티드 | Intranasal benzodiazepine pharmaceutical compositions |
EP2518070A1 (en) | 2011-04-29 | 2012-10-31 | Almirall, S.A. | Pyrrolotriazinone derivatives as PI3K inhibitors |
SI2704703T1 (en) | 2011-05-03 | 2019-12-31 | Aponia Laboratories, Inc. | Transdermal compositions of ibuprofen and methods of use thereof |
WO2013030789A1 (en) | 2011-08-30 | 2013-03-07 | Ranbaxy Laboratories Limited | Pharmaceutical oral solid dosage form containing a poorly water soluble pde - iv inhibitor |
WO2013081565A1 (en) | 2011-11-21 | 2013-06-06 | Mahmut Bilgic | Pharmaceutical compositions comprising roflumilast and terbutaline |
WO2014055801A1 (en) | 2012-10-05 | 2014-04-10 | Henkin Robert I | Phosphodiesterase inhibitors for treating taste and smell disorders |
US20140112959A1 (en) | 2012-10-18 | 2014-04-24 | MiCal Pharmaceuticals LLC - H Series, a Series of MiCal Pharmaceuticals LLC, a Multi-Division Limite | Topical steroid composition and method |
KR102154104B1 (en) | 2013-01-28 | 2020-09-09 | 인코젠 쎄라퓨틱스 프라이빗 리미티드 | Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast n-oxide |
US20150366890A1 (en) | 2013-02-25 | 2015-12-24 | Trustees Of Boston University | Compositions and methods for treating fungal infections |
US20140275265A1 (en) | 2013-03-12 | 2014-09-18 | Core Products International, Inc. | Therapeutic cream for application to skin |
US9511144B2 (en) | 2013-03-14 | 2016-12-06 | The Proctor & Gamble Company | Cosmetic compositions and methods providing enhanced penetration of skin care actives |
WO2014143453A1 (en) | 2013-03-15 | 2014-09-18 | Henkin Robert I | Phosphodiesterase inhibitor treatment |
UA119324C2 (en) | 2013-04-02 | 2019-06-10 | Теміс Медікер Лімітед | Compositions of pharmaceutical actives containing diethylene glycol monoethyl ether or other alkyl derivatives |
US20160120803A1 (en) | 2013-06-17 | 2016-05-05 | Contract Pharmaceuticals Limited | Non-aerosol foams for topical administration |
WO2015132708A1 (en) | 2014-03-07 | 2015-09-11 | Torrent Pharmaceuticals Limited | Pharmaceutical composition of roflumilast |
MX2017002438A (en) | 2014-08-27 | 2017-05-23 | Abbvie Inc | Topical formulation. |
EP3383363B1 (en) | 2015-11-30 | 2021-01-06 | Anacor Pharmaceuticals, Inc. | Topical pharmaceutical formulations for treating inflammatory-related conditions |
WO2017216738A1 (en) | 2016-06-15 | 2017-12-21 | Torrent Pharmaceuticals Limited | Topical compositions of apremilast |
WO2018144093A2 (en) | 2016-11-03 | 2018-08-09 | Pinsky Mark A | Formulations for improved skin care |
US20210161870A1 (en) | 2017-06-07 | 2021-06-03 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
US20200155524A1 (en) | 2018-11-16 | 2020-05-21 | Arcutis, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
US11534493B2 (en) | 2017-09-22 | 2022-12-27 | Arcutis Biotherapeutics, Inc. | Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents |
CA3102689C (en) | 2018-06-04 | 2023-08-29 | Arcutis, Inc. | Method and formulation for improving roflumilast skin penetration lag time |
EP4021456A1 (en) | 2020-05-07 | 2022-07-06 | Arcutis Biotherapeutics, Inc. | Treatment of skin conditions using high krafft temperature anionic surfactants |
AU2021393513A1 (en) | 2020-12-04 | 2023-07-06 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having antifungal properties |
IL313866A (en) | 2021-12-28 | 2024-08-01 | Arcutis Biotherapeutics Inc | Topical roflumilast aerosol foams |
US20230310345A1 (en) | 2022-03-14 | 2023-10-05 | Arcutis Biotherapeutics, Inc. | Self-preserving topical pharmaceutical compositions comprising diethylene glycol monoethyl ether |
-
2021
- 2021-02-05 US US17/155,679 patent/US20210161870A1/en not_active Abandoned
-
2023
- 2023-08-22 US US18/453,674 patent/US12016848B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10940142B2 (en) * | 2017-06-07 | 2021-03-09 | Arcutis, Inc. | Inhibition of crystal growth of roflumilast |
US11129818B2 (en) * | 2017-06-07 | 2021-09-28 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half life |
US11819496B2 (en) * | 2017-06-07 | 2023-11-21 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half-life |
Non-Patent Citations (2)
Title |
---|
DALIRESP trademark certificate Registration No. 4,004,351. (Year: 2011) * |
DALIRESP trademark certificate Registration No. 4,055,617. (Year: 2011) * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11793796B2 (en) | 2017-06-07 | 2023-10-24 | Arcutis Biotherapeutics, Inc. | Inhibition of crystal growth of roflumilast |
US11819496B2 (en) | 2017-06-07 | 2023-11-21 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half-life |
US12005052B2 (en) | 2017-06-07 | 2024-06-11 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half-life |
US12011437B1 (en) | 2017-06-07 | 2024-06-18 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
US12016848B2 (en) | 2017-06-07 | 2024-06-25 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
US12042558B2 (en) | 2018-06-04 | 2024-07-23 | Arcutis Biotherapeutics, Inc. | Method and formulation for improving roflumilast skin penetration lag time |
US11992480B2 (en) | 2018-11-16 | 2024-05-28 | Arcutis Biotherapeutics, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
US12042487B2 (en) | 2018-11-16 | 2024-07-23 | Arcutis Biotherapeutics, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
WO2023129892A1 (en) * | 2021-12-28 | 2023-07-06 | Arcutis Biotherapeutics, Inc. | Topical aerosol foams |
WO2023129215A1 (en) * | 2021-12-28 | 2023-07-06 | Arcutis Biotherapeutics, Inc. | Topical roflumilast aerosol foams |
Also Published As
Publication number | Publication date |
---|---|
US12016848B2 (en) | 2024-06-25 |
US20240000760A1 (en) | 2024-01-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11992480B2 (en) | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors | |
US12016848B2 (en) | Roflumilast formulations with an improved pharmacokinetic profile | |
US12005052B2 (en) | Topical roflumilast formulation having improved delivery and plasma half-life | |
JP7242222B2 (en) | Interference with crystal growth of roflumilast | |
US12042558B2 (en) | Method and formulation for improving roflumilast skin penetration lag time | |
JP7402301B2 (en) | Pharmaceutical compositions of roflumilast in an aqueous blend of water-miscible pharmaceutically acceptable solvents | |
US12011437B1 (en) | Roflumilast formulations with an improved pharmacokinetic profile | |
CA3166300A1 (en) | Topical roflumilast formulation having improved delivery and plasma half-life | |
US12042487B2 (en) | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors | |
WO2022169615A1 (en) | Roflumilast formulations with an improved pharmacokinetic profile |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ARCUTIS BIOTHERAPEUTICS, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WELGUS, HOWARD;THURSTON, ARCHIE W.;OSBORNE, DAVID W.;REEL/FRAME:055002/0821 Effective date: 20210121 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: APPLICATION DISPATCHED FROM PREEXAM, NOT YET DOCKETED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
AS | Assignment |
Owner name: SLR INVESTMENT CORP., AS AGENT, NEW YORK Free format text: SECURITY INTEREST;ASSIGNOR:ARCUTIS BIOTHERAPEUTICS, INC.;REEL/FRAME:058463/0187 Effective date: 20211222 |
|
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 |