CN115192557B - 用于治疗肥大细胞介导的炎性疾病的药物组合物 - Google Patents
用于治疗肥大细胞介导的炎性疾病的药物组合物 Download PDFInfo
- Publication number
- CN115192557B CN115192557B CN202110395403.0A CN202110395403A CN115192557B CN 115192557 B CN115192557 B CN 115192557B CN 202110395403 A CN202110395403 A CN 202110395403A CN 115192557 B CN115192557 B CN 115192557B
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- atovaquone
- mast cell
- dermatitis
- cells
- 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.)
- Active
Links
- 210000003630 histaminocyte Anatomy 0.000 title claims abstract description 34
- 208000027866 inflammatory disease Diseases 0.000 title claims abstract description 11
- 230000001404 mediated effect Effects 0.000 title claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 title description 47
- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 claims abstract description 37
- 229960003159 atovaquone Drugs 0.000 claims abstract description 37
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 201000004624 Dermatitis Diseases 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 15
- 208000024780 Urticaria Diseases 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 7
- 206010021247 idiopathic urticaria Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract description 5
- 241000124008 Mammalia Species 0.000 abstract description 3
- 208000030090 Acute Disease Diseases 0.000 abstract description 2
- 230000001154 acute effect Effects 0.000 abstract description 2
- 208000037976 chronic inflammation Diseases 0.000 abstract description 2
- 208000037893 chronic inflammatory disorder Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 32
- 239000004480 active ingredient Substances 0.000 description 23
- 208000035475 disorder Diseases 0.000 description 18
- 208000010668 atopic eczema Diseases 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 206010061218 Inflammation Diseases 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 230000004054 inflammatory process Effects 0.000 description 11
- 210000003491 skin Anatomy 0.000 description 11
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 10
- 102400000096 Substance P Human genes 0.000 description 10
- 101800003906 Substance P Proteins 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 206010020751 Hypersensitivity Diseases 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 206010012442 Dermatitis contact Diseases 0.000 description 8
- 208000002193 Pain Diseases 0.000 description 8
- 230000007815 allergy Effects 0.000 description 8
- 201000008937 atopic dermatitis Diseases 0.000 description 8
- 208000010247 contact dermatitis Diseases 0.000 description 8
- -1 hydroxy 1, 4-naphthaquinone Chemical compound 0.000 description 8
- 208000026278 immune system disease Diseases 0.000 description 8
- 208000029081 mast cell activation syndrome Diseases 0.000 description 8
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 208000026935 allergic disease Diseases 0.000 description 7
- 229910001424 calcium ion Inorganic materials 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 230000000172 allergic effect Effects 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 5
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- 239000006071 cream Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000036407 pain Effects 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 4
- 241000282465 Canis Species 0.000 description 4
- 102000019034 Chemokines Human genes 0.000 description 4
- 108010012236 Chemokines Proteins 0.000 description 4
- 208000011231 Crohn disease Diseases 0.000 description 4
- 206010012434 Dermatitis allergic Diseases 0.000 description 4
- 206010012438 Dermatitis atopic Diseases 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 208000030514 Leukocyte adhesion deficiency type II Diseases 0.000 description 4
- 201000009053 Neurodermatitis Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 208000008585 mastocytosis Diseases 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000027756 respiratory electron transport chain Effects 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 230000001953 sensory effect Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 238000011200 topical administration Methods 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 101000600903 Homo sapiens Substance-P receptor Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
- 240000007472 Leucaena leucocephala Species 0.000 description 3
- 208000007920 Neurogenic Inflammation Diseases 0.000 description 3
- 108090000189 Neuropeptides Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100037346 Substance-P receptor Human genes 0.000 description 3
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 3
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 235000017471 coenzyme Q10 Nutrition 0.000 description 3
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 3
- 239000003246 corticosteroid Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 210000001428 peripheral nervous system Anatomy 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 206010003645 Atopy Diseases 0.000 description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 2
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 2
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 2
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 2
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 201000009961 allergic asthma Diseases 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000000842 anti-protozoal effect Effects 0.000 description 2
- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 229960005370 atorvastatin Drugs 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- 235000012216 bentonite Nutrition 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940112141 dry powder inhaler Drugs 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 210000001640 nerve ending Anatomy 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 206010039083 rhinitis Diseases 0.000 description 2
- 210000001044 sensory neuron Anatomy 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- FRASJONUBLZVQX-UHFFFAOYSA-N 1,4-dioxonaphthalene Natural products C1=CC=C2C(=O)C=CC(=O)C2=C1 FRASJONUBLZVQX-UHFFFAOYSA-N 0.000 description 1
- JNODDICFTDYODH-UHFFFAOYSA-N 2-hydroxytetrahydrofuran Chemical compound OC1CCCO1 JNODDICFTDYODH-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 208000012657 Atopic disease Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 206010010904 Convulsion 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
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 description 1
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- OZLGRUXZXMRXGP-UHFFFAOYSA-N Fluo-3 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(Cl)C(=O)C=C3OC3=CC(O)=C(Cl)C=C32)N(CC(O)=O)CC(O)=O)=C1 OZLGRUXZXMRXGP-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 239000004378 Glycyrrhizin Substances 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 208000001718 Immediate Hypersensitivity Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 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
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 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
- 241000699670 Mus sp. Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 229930192627 Naphthoquinone Natural products 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 102000015925 Proto-oncogene Mas Human genes 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 101100402536 Rattus norvegicus Mrgpra gene Proteins 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 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
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940072056 alginate Drugs 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
- 230000009285 allergic inflammation Effects 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
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 102000007478 beta-N-Acetylhexosaminidases Human genes 0.000 description 1
- 108010085377 beta-N-Acetylhexosaminidases Proteins 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 1
- ZEWYCNBZMPELPF-UHFFFAOYSA-J calcium;potassium;sodium;2-hydroxypropanoic acid;sodium;tetrachloride Chemical compound [Na].[Na+].[Cl-].[Cl-].[Cl-].[Cl-].[K+].[Ca+2].CC(O)C(O)=O ZEWYCNBZMPELPF-UHFFFAOYSA-J 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- SPPIIOPGDLITJE-VLQRKCJKSA-N diazanium;(2s,3s,4s,5r,6s)-6-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxylato-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-5-[(2r,3r,4s,5s,6s)-6-carboxy-3,4,5-trihydroxyoxan-2-yl]oxy-3,4-dihy Chemical compound N.N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O SPPIIOPGDLITJE-VLQRKCJKSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 229950003468 dupilumab Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000001595 flow curve Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000000917 hyperalgesic effect Effects 0.000 description 1
- 230000005931 immune cell recruitment Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003960 inflammatory cascade Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940065725 leukotriene receptor antagonists for obstructive airway diseases Drugs 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 229940069445 licorice extract Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229940051866 mouthwash Drugs 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000005455 negative regulation of mast cell degranulation Effects 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 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
- 230000001766 physiological effect Effects 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
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 230000008786 sensory perception of smell Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及阿托伐醌用于治疗和预防哺乳动物中的急性和慢性炎性疾病，所述急性和慢性炎性疾病包括肥大细胞介导的炎性疾病。
Description
技术领域
本发明涉及医药技术领域，具体涉及炎性疾病的用药领域。
背景技术
炎症反应是机体对病原微生物感染、创伤、变态反应等发生的组织细胞反应。在生理学和病理生理学上是有益的，是伤口愈合、病毒或细菌感染的消退和恢复所必需的。然而，过度炎症反应是有害的，因为它们涉及过敏反应或类过敏反应、过敏性或特发性炎症。肥大细胞是起始和维持炎症的核心。
肥大细胞是炎症反应过程中的关键效应细胞之一，是连接神经系统和免疫系统的重要纽带，参与了术后疼痛、皮肤的炎症等多种病理过程。肥大细胞相对于其他天然免疫细胞具有显著的空间优势，可以更加靠近周围神经末梢的地方，是最先对感觉神经纤维激活做出反应的细胞之一。通过神经肽激活后的肥大细胞可以释放多种“促炎细胞因子”和“趋化因子”，参与招募多种天然免疫细胞，进一步促进炎症级联反应和外周感觉传入的致敏。
机体的外周神经系统具有接受外界环境变化刺激并将信息传导到中枢神经系统产生各种感觉的功能。分布在外周神经系统上的各种受体扮演着重要角色，G蛋白偶联受体是众多受体中的一类，在嗅觉、味觉、痛觉和痒觉等感觉中起重要作用。Mrgprs受体作为最近发现的、主要分布在外周神经系统上的G蛋白偶联受体家族，其功能越来越受到相关领域研究者的关注。Mrgprs是一类与Mas基因相关的G蛋白偶联受体，Young等人通过分析Mas氨基酸序列的疏水性图，并借助一种可以正确预测多种蛋白质跨膜片段的算法，发现其具有七个疏水性跨膜结构域，提示该蛋白属于G蛋白偶联受体(GPCRs)。
MrgprX2最初被发现在人DRG小直径伤害性感觉神经元中具有高水平表达，推测其在伤害性感受中起关键作用，MrgprX2被发现在肥大细胞中存在高水平表达；最新研究表明，MrgprX2还可在人的嗜酸性细胞和嗜碱性粒细胞中表达并介导其脱颗粒。肥大细胞作为免疫反应过程中的关键效应细胞之一，是连接神经系统和免疫系统的重要环节，由于肥大细胞能够非常接近神经末梢，相对其他先天性免疫细胞具有明显的空间优势，能够最先对感觉神经激活做出反应。当肥大细胞被激活时，释放出广泛的促炎性细胞因子和趋化因子可作用于感觉神经末梢上的特定受体，引起神经末梢释放P物质(SP)和血管活性肠肽(VIP)等神经肽，这些神经肽又激活肥大细胞上的受体，诱导肥大细胞进一步脱颗粒释放大量的促炎因子和趋化因子，引起神经源性炎症。除了这种肥大细胞与感觉神经的局部相互作用外，痛觉信号也可通过神经末梢Ca2+介导的轴突电位放大，引起末梢纤维的兴奋，产生的神经信号能沿轴突顺行到达中枢神经系统；神经源性的SP和VIP等肽类物质可通过MrgprX2受体激活肥大细胞，这表明MrgprX2有助于神经源性炎症和疼痛的发展。
最近的研究证实在术后痛模型和CFA诱导的炎性痛模型中，MrgprB2-/-小鼠的炎症和痛觉过敏反应较正常小鼠均显著减轻，MrgprB2-/-小鼠在损伤部位的先天免疫细胞募集明显减少，并提出了肥大细胞与神经细胞之间相互作用的假设：组织损伤后释放的SP通过MrgprB2激活肥大细胞，引起细胞因子和趋化因子的释放以及免疫细胞的募集，进而参与炎症和疼痛。随着对MrgprB2/MrgprX2研究的深入，发现MrgprB2/MrgprX2的功能越来越重要，该受体不仅广泛参与机体非IgE介导的超敏反应、神经源性炎症、疼痛和抽搐等反应，而且能促进皮肤和肠道对有害刺激或病原体入侵的固有免疫反应，因此，该受体被认为是寻找抗炎和镇痛药物研发的有力靶标。
发明内容
本发明提供了一种用于治疗和预防哺乳动物中的急性和慢性炎性疾病的药物，所述急性和慢性炎性疾病包括肥大细胞介导的炎性疾病。所述药物为阿托伐醌(Atovaquone)。
阿托伐醌，即羟基1,4-萘喹啉，是一种萘醌类化合物，是辅酶Q的同系物，具有抗几种原虫的活性。对疟原虫属其作用部位为细胞色素BCL结合点(结合点Ⅲ)。该药物可逆性地与多肽上的11500Da分子基团结合。二氢乳清酸脱氢酶是吡啶生物合成中重要的酶，通过辅酶Q连接线粒体作电子传递，通过抑制电子传递阻止吡啶的合成。一些代谢酶通过辅酶Q参与线粒体的电子传递，阿托伐醌抑制电子传递作用实际上是抑制了这些酶的活性，因此具有广谱抗原虫活性。
虽然阿托伐醌的广谱抗原虫活性已经进行了广泛研究，但是对其其他药理活性的研究较少，本发明提供了阿托伐醌通过抑制肥大细胞脱颗粒来治疗和预防涉及过度炎症反应的各种疾病的新用途。这些用途涉及可有效治疗和预防涉及肥大细胞的各种炎性疾病。此类炎性病症包括但不限于过敏和特应症(过敏性哮喘、湿疹、鼻炎)，肥大细胞活化综合征(MCAS)，物理性和化学性荨麻疹，特发性荨麻疹，克罗恩病，炎性肠病，皮炎和接触性皮炎，关节炎和类风湿性关节炎，对刺痛(sting)或其他过敏性或类过敏性刺激的皮肤、组织或全身反应，犬肥大细胞增多症，牛、猪中的过敏和炎症等。进一步涉及成人或儿童或幼儿的皮肤湿疹，皮炎、特应性皮炎、接触性皮炎、神经性皮炎、荨麻疹等过敏性皮炎或其他过敏性疾病。
现有的使用皮质类固醇疗法治疗和/或预防涉及过度炎症反应有明显的副作用和使用依赖，相比阿托伐醌，来自人群中大量使用者报告结果表明：低副作用特征和长期使用没有明显的药物依赖现象。
因此，本发明对于治疗和预防各种炎性疾病具有重要价值。
本发明的一个方面提供一种药物组合物，其包含活性成分阿托伐醌。
在一些实施方案中，活性成分阿托伐醌的量至少30重量％。进一步阿托伐醌的量至少优选至少40重量％、45重量％、50重量％或60重量％。所述药物组合物通过抑制肥大细胞脱颗粒来治疗和预防涉及过度炎症反应的各种疾病，此类炎性病症包括但不限于过敏和特应症(过敏性哮喘、湿疹、鼻炎)，肥大细胞活化综合征(MCAS)，物理性和化学性荨麻疹，特发性荨麻疹，克罗恩病，炎性肠病，皮炎和接触性皮炎，关节炎和类风湿性关节炎，对刺痛(sting)或其他过敏性或类过敏性刺激的皮肤、组织或全身反应，犬肥大细胞增多症，牛、猪中的过敏和炎症等。进一步涉及成人或儿童或幼儿的皮肤湿疹，皮炎、特应性皮炎、接触性皮炎、神经性皮炎、荨麻疹等过敏性皮炎或其他过敏性疾病。
本发明的一些实施方案涉及药物组合物，所述药物组合物包含药物活性成分阿托伐醌和药学上可接受的载体或稀释剂。
在一些实施方案中，所述药物组合物是乳膏、乳液、霜剂、溶液、贴剂、凝胶、气溶胶、片剂、颗粒剂、注射剂等。
在一些实施方案中，药物组合物被配制用于通过吸入、通过蒸发器、通过喷雾器或通过气雾器施用。在一些实施方案中，药物组合物被配制用于口服施用、口腔施用或舌下施用。在一些实施方案中，药物组合物被配制用于静脉内、肌内或皮下施用。在一些实施方案中，药物组合物被配制用于鞘内或脑室内施用。在一些实施方案中，药物组合物被配制用于局部给药。
在一些实施方案中，所述药物活性成分以至少0.01、0.1、0.5或1mg/ml的浓度存在于药物组合物中。
在另一个方面，本发明提供一种治疗免疫系统疾病的方法，该方法包括给予有效量的本发明的药物组合物。
在一些实施方案中，免疫系统疾病是过敏或特应症。在一些实施方案中，免疫系统疾病是肥大细胞活化综合征(“MCAS”)、物理性和化学性荨麻疹，特发性荨麻疹，克罗恩病，炎性肠病，皮炎和接触性皮炎，关节炎和类风湿性关节炎，对刺痛(sting)或其他过敏性或类过敏性刺激的皮肤、组织或全身反应，犬肥大细胞增多症，牛、猪中的过敏和炎症等。进一步涉及成人或儿童或幼儿的皮肤湿疹，皮炎、特应性皮炎、接触性皮炎、神经性皮炎、荨麻疹等过敏性皮炎或其他过敏性疾病。
在一些实施方案中，免疫疾病是涉及CB1或CB2受体失调或肥大细胞的cAMP失调的疾病。在一些实施方案中，免疫疾病是涉及CB1或CB2受体的过度活化或肥大细胞的cAMP抑制的疾病。
在一些实施方案中，药物组合物通过吸入施用。在一些实施方案中，药物组合物经口服施用。在一些实施方案中，药物组合物通过口腔给药施用。在一些实施方案中，通过舌下给药递送药物组合物。在一些实施方案中，药物组合物通过注射施用。在一些实施方案中，药物组合物通过局部施用来施用，优选通过局部皮肤施用。
在一些实施方案中，阿托伐醌以每剂小于1.5g的量施用。在一些实施方案中，阿托伐醌以每剂小于1000mg的量施用。在一些实施方案中，阿托伐醌以每剂小于500mg的量施用。在一些实施方案中，阿托伐醌以每剂量小100mg的量施用。
在一些实施方案中，必要时施用药物组合物。在一些实施方案中，药物组合物每天施用一次。在一些实施方案中，药物组合物每天施用2-4次。在一些实施方案中，药物组合物每周施用2-4次。在一些实施方案中，药物组合物每周施用一次。在一些实施方案中，药物组合物每两周施用一次。
以下进一步详细描述本发明的这些和其他方面。
附图说明
图1:药物抑制肥大细胞脱颗粒百分比
图2：P物质作用于不同受体时的钙离子变化动态观察图
图3：不同药物浓度下钙离子流动曲线
具体实施方式
药物活性成分
在第一方面，本发明提供了药物组合物，其活性成分主要为阿托伐醌。
在一些实施方案中，活性成份可进一步包括抗组胺类药物、皮质类固醇药物、活性成分相对含量
在一些实施方案中，阿托伐醌占活性成分的40-100重量％(wt％)。
在某些实施方案中，阿托伐醌占活性成分的50-100重量％、活性成分的60-100重量％、活性成分的70-100重量％、活性成分的80-100重量％。
药物组合物
在另一方面，本发明提供了药物组合物。药物组合物包含活性成分阿托伐醌和药学上可接受的载体或稀释剂。进一步活性成分还包含不同于阿托伐醌的第二活性物质，所述第二活性物质选自抗组胺类药物、皮质类固醇激素类药物、肥大细胞稳定剂(如色甘酸钠等)、白三烯受体拮抗剂(如孟鲁司特等)、抗微生物感染药物(真菌、细菌、病毒、衣原体、支原体等感染，如伊曲康唑等)、含甘草提取物活性成分的药物(如：复方甘草酸苷，甘草酸二铵等)，钙调磷酸酶抑制剂(如他克莫司、吡美莫司等)，免疫抑制剂(如环孢素、硫唑嘌呤、甲氨蝶呤等)，单克隆抗体(如Dupilumab等)及具有治疗过敏性炎症的风湿免疫类药物等。
药物活性成分的含量
在典型的实施方案中，活性成分以至少0.01μg/ml、至少0.1μg/ml、至少0.5μg/ml或至少1μg/ml的浓度存在于药物组合物中。在某些实施方案中，活性成分以至少1μg/ml、2μg/ml、3μg/ml、4μg/ml、5μg/ml、10μg/ml、15μg/ml、20μg/ml或25μg/ml的浓度存在于药物组合物中。在某些实施方案中，活性成分以至少30μg/ml、35μg/ml、40μg/ml、45μg/ml或50μg/ml的浓度存在于药物组合物中。
药物的一般配制
药物组合物可以是适合于人用或兽医用的任何形式，包括乳膏、乳液、霜剂、溶液、贴剂、凝胶、气溶胶、片剂、颗粒剂、注射剂等。
可以配制药物组合物用于通过适合于人或兽医用的任何给药途径施用，包括肠内和肠胃外施用途径。
在各种实施方案中，配制药物组合物用于通过吸入施用；配制药物组合物用于口服施用，口腔施用或；舌下施用。配制药物组合物用于静脉内、肌内或皮下施用；配制药物组合物用于局部施用，例如皮肤局部施用、粘膜局部施用。
粘膜制剂以干粉制剂形式施用，例如，包含生物活性剂，其为具有适当粒径或在适当粒径范围内的干燥形式，通常为冻干形式，用于鼻内递送。适于在鼻或肺通道内沉积的最小粒径通常为约0.5微米质量中值等效空气动力学直径(MMEAD)，通常约1微米MMEAD，更通常约2微米MMEAD。适于在鼻腔内沉积的最大粒径通常约10微米MMEAD，通常约8微米MMEAD，更通常约4微米MMEAD。在这些尺寸范围内的鼻内可吸入粉末可通过各种常规技术生产，例如喷射研磨，喷雾干燥，溶剂沉淀，超临界流体冷凝等。这些合适的MMEAD干粉可以通过常规干粉吸入器(DPI)施用至患者，所述干粉吸入器依靠患者的呼吸，在肺或鼻吸入后，将粉末分散成雾化量。或者，干粉可以通过空气辅助装置施用，该装置使用外部电源将粉末分散成雾化量，例如活塞泵。
适用于口服/口腔/舌下施用的药物组合物
用于口服，口腔或舌下施用的制剂可以是胶囊剂、扁囊剂、丸剂、片剂、糖锭(使用调味基质，通常是蔗糖和阿拉伯胶或黄蓍胶)、粉剂、颗粒剂、或作为在水性或非水性液体中的溶液或悬浮液、或作为水包油或油包水液体乳液、或作为酏剂或糖浆、或作为锭剂(使用惰性基质，如明胶和甘油，或蔗糖和阿拉伯胶)、和/或作为漱口剂等，各自含有预定量的主题多肽治疗剂作为活性成分。除活性化合物外，悬浮液还包含助悬剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶以及它们的混合物。
在用于口服、口腔或舌下施用的固体剂型(胶囊剂，片剂，丸剂，糖衣丸，粉末剂，颗粒剂等)中，可以将一种或多种治疗剂与一种或多种药学上可接受的载体混合，例如柠檬酸钠或磷酸二钙，和/或以下中任何一种：(1)填充剂或增量剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和/或硅酸；(2)粘合剂，例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶；(3)保湿剂，如甘油；(4)崩解剂，如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、海藻酸，某些硅酸盐和碳酸钠；(5)溶液缓凝剂，如石蜡；(6)吸收促进剂，如季铵化合物；(7)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(8)吸收剂，如高岭土和膨润土；(9)润滑剂，例如滑石，硬脂酸钙，硬脂酸镁，固体聚乙二醇，十二烷基硫酸钠及它们的混合物；(10)着色剂。在胶囊剂、片剂和丸剂的情况下，药物组合物还可包含缓冲剂。类似类型的固体组合物也可用作软填充和硬填充明胶胶囊中的填充剂，其使用诸如乳糖或乳糖的赋形剂，以及高分子量聚乙二醇等。用于口服施用的液体剂型包括药学上可接受的乳液，微乳液，溶液，悬浮液，糖浆和酏剂。除活性成分外，液体剂型还可含有本领域常用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1、3-丁二醇、油(特别是棉籽油，花生油，玉米油，胚芽油，橄榄油，蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇以及脱水山梨糖醇的脂肪酸酯，以及它们的混合物。除惰性稀释剂外，口服组合物还可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂、着色剂、芳香剂和防腐剂。
适于注射的药物组合物
对于静脉内，肌内或皮下注射，或患处注射，活性成分将是肠胃外可接受的水性溶液的形式，其是无热原的并且具有合适的pH、等渗性和稳定性。本领域相关技术人员能够使用诸如等渗媒介物(如氯化钠注射液，林格氏注射液，乳酸林格氏注射液)制备合适的溶液。根据需要，可以将防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其他添加剂包含在内。
在各种实施方案中，单位剂型是小瓶、安瓿、瓶或预填充注射器。在一些实施方案中，单位剂型含有0.01mg、0.1mg、0.5mg、1mg、2.5mg、5mg、10mg、12.5mg、25mg、50mg、75mg或100mg的阿托伐醌组合物。在一些实施方案中，单位剂型含有125mg、150mg、175mg或200mg的阿托伐醌组合物。在一些实施方案中，单位剂型含有250mg阿托伐醌组合物。
在一些实施方案中，单位剂型中的药物组合物是适于溶解的固体形式，例如冻干物。
适于局部施用的药物组合物,用于局部施用的药物组合物和制剂可包括透皮贴剂、软膏剂、洗剂、乳膏剂、凝胶剂、滴剂、栓剂、喷雾剂、液体剂和粉剂。常规的药物载体，水性、粉状或油性基质，增稠剂等可能是必需的或期望的。
一般剂量范围
可任选地采用体内和/或体外测定来帮助确定使用的最佳剂量范围。制剂中使用的精确剂量还取决于施用途径和病症的严重程度，并应根据医师的判断和每个个体的情况来决定。可根据源自体外或动物模型测试系统的剂量-反应曲线外推有效剂量。
使用方法：治疗肥大细胞介导的炎性疾病的方法
在另一个方面，提供了用于治疗患有免疫系统疾病的个体的方法。在典型的实施方案中，免疫系统疾病是肥大细胞相关的炎性疾病，治疗的疾病包括但不限于：免疫系统疾病是肥大细胞活化综合征(“MCAS”)、物理性和化学性荨麻疹，特发性荨麻疹，克罗恩病，炎性肠病，皮炎和接触性皮炎，关节炎和类风湿性关节炎，对刺痛(sting)或其他过敏性或类过敏性刺激的皮肤、组织或全身反应，犬肥大细胞增多症，牛、猪中的过敏和炎症等。进一步涉及成人或儿童或幼儿的皮肤湿疹，皮炎、特应性皮炎、接触性皮炎、神经性皮炎、荨麻疹等过敏性皮炎或其他过敏性疾病。
本文使用的术语“治疗”等通常意指获得所需的药理学和/或生理学作用。就完全或部分预防疾病、病症或其症状而言，该效果可以是预防性的，和/或就部分或完全治愈疾病或病症和/或可归因于所述疾病或病症的不良反应(例如症状)而言，该效果可以是治疗性的。本文所用的“治疗”包括对哺乳动物，特别是人的疾病或病症的任何治疗，并且包括：(a)在易患所述疾病或病症但尚未被诊断患上所述疾病或病症的个体中预防所述疾病或病症的发生；(b)抑制所述疾病或病症(例如，阻止其进展)；或(c)缓解所述疾病或病症(例如，引起所述疾病或病症的消退，提供一种或多种症状的改善)。可以根据本领域已知的标准方法和技术容易地评估任何病症的改善。通过该方法治疗的个体群包括患有不期望的病症或疾病的个体，以及具有患上病症或疾病的风险的个体。
术语“治疗有效剂量”或“有效量”是指产生所需效果所施用的剂量或量。确切的剂量或量将取决于治疗的目的，并且本领域技术人员可以使用已知技术确定。
在一些实施方案中，药物组合物每天施用一次，每天施用2-4次，每周施用2-4次，每周施用一次或每两周施用一次。
取决于待治疗的病症，组合物可以单独施用或与其他治疗同时或依次组合施用。
本发明提供了包含阿托伐醌的药物组合物。已经证明该组合物具有显著的抗炎作用，因此，它们可以对免疫病症具有治疗作用，所述免疫病症涉及过度炎症反应，例如从肥大细胞释放异常增加的组胺。
实施例
提供以下实施例是为了说明而非限制。
实施例1：阿托伐醌对肥大细胞脱颗粒的抑制研究
β-己糖胺酶测定法实验方法包括如下步骤：
1、预备PNAG/HEPES buffer/0.1％Triton-100/甘氨酸溶液于常温；
2、从37℃孵箱取出LAD2cell读取细胞数并根据实验细胞需要取适量的细胞混悬液(以5000-10000/well估算)；
3、4℃离心机离心LAD2细胞混悬液5min，3000rps后去上清；
4、加入HEPES butffer后混匀细胞至溶液中；
5、将细胞混悬液移至96孔板，每孔80μl；
6、根据实验设计加入待测药物阿托伐醌至相应位置，并预留出阳性对照SP(神经肽P物质)、阴性对照QWF(MRGPRX2受体拮抗剂)及空白对照的位置，每个药物采用三次重复的方式开展；
7、细胞与药物共孵育30min；
8、加入SP至除了空白对照之外的所有平板孔中，后孵育30min；
9、5min，3000rps低温离心后，取上清50μl至预先加入50ul/孔PNAG的上清板，共孵育90min；
10、往取上清后余下的溶液中加入150μl/孔的0.1％Triton-100，后取50ul/孔至预先加入50μl/孔PNAG细胞裂解板，共孵育90min；
11、取出两板后，分别加入50ul/孔甘氨酸溶液；
m.吸光值检测；
12、计算肥大细胞脱颗粒百分比值。
根据公式：脱颗粒百分比＝2×上清板吸光值/(上清板吸光值+4×细胞裂解板吸光值)×100％。
实验结果：
由图1的LAD2肥大细胞脱颗粒百分比图图示可见，在LAD2细胞的SP刺激实验中，当加入Atovaquone和QWF时，LAD2肥大细胞脱颗粒情况明显改善，Atovaquone远远优于QWF。即阿托伐醌能够显著抑制肥大细胞脱颗粒。
实施例2：细胞内钙离子流动实验
孵育缓冲液由0.5μlFluo-3、2μlPluronic F-127和997.5μlCIB(钙成像缓冲液：125mM NaCl，3mM KCl，2.5mM CaCl2、0.6mM MgCl2、10mM HEPES，20mM葡萄糖，1.2mM NaHCO3和20mM蔗糖，pH＝7.4)组成。在孵育缓冲液中制备了不同浓度的阿托伐醌(0、1、10、100nM和1μM)，不含阿托伐醌的孵育缓冲液用作阴性对照。LAD2细胞用CIB洗涤两次，然后添加所需的孵育缓冲液。孵育30分钟后，将细胞用CIB洗涤两次，然后接种到96孔板中以进行钙成像。对于钙成像，将细胞放大200倍，并在蓝光下每秒获得一张照片。注射物质后，如果[Ca2+]上升至少50％，则细胞被确认为有反应。
实验结果见图2和图3：
图2是P物质作用于不同受体时的钙离子变化动态观察图，P物质作用于MrgA1，MrgX2和NK1R的图示(5nM作用于NK1R，50nM作用于MrgX2和10μM作用MrgA1)。该图像集合是自左至右，每隔5秒时拍摄一次,持续120秒。每组图上一列为加入阿托伐醌的细胞，下一列为未加入阿托伐醌的细胞，图示在加入阿托伐醌后对MrgA1和NK1R介导的钙离子流动的影响不如对MrgX2的影响大。
图3是不同浓度下的阿托伐醌导致了钙离子流动性降低，当阿托伐醌为10nM/L及以上时钙离子则开始显示出无明显流动性。
由此可见，阿托伐醌显著减低了肥大细胞的炎性活动。
Claims (3)
1.阿托伐醌在制备治疗或预防肥大细胞介导的炎症疾病的药物中的用途，所述的炎症疾病选自皮炎。
2.如权利要求1所述的用途，其特征在于，所述皮炎包括物理性和化学性荨麻疹，特发性荨麻疹。
3.如权利要求1所述的用途，其特征在于，所述的炎症疾病包括成人或儿童或幼儿的皮炎。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110395403.0A CN115192557B (zh) | 2021-04-13 | 2021-04-13 | 用于治疗肥大细胞介导的炎性疾病的药物组合物 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110395403.0A CN115192557B (zh) | 2021-04-13 | 2021-04-13 | 用于治疗肥大细胞介导的炎性疾病的药物组合物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115192557A CN115192557A (zh) | 2022-10-18 |
| CN115192557B true CN115192557B (zh) | 2023-12-12 |
Family
ID=83570717
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110395403.0A Active CN115192557B (zh) | 2021-04-13 | 2021-04-13 | 用于治疗肥大细胞介导的炎性疾病的药物组合物 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115192557B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024077506A1 (zh) * | 2022-10-12 | 2024-04-18 | 储蕾 | 用于治疗肥大细胞介导的炎性疾病的药物组合物 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018133862A1 (zh) * | 2017-01-22 | 2018-07-26 | 北京蔚蓝之源医药科技有限公司 | 细胞色素bc1复合物抑制剂在制备医药组合物中的用途 |
| CN109640948A (zh) * | 2016-06-16 | 2019-04-16 | 利物浦大学 | 化学组合物 |
| CN110536681A (zh) * | 2017-02-01 | 2019-12-03 | Gbs全球生物制药公司 | 用于治疗肥大细胞相关的或嗜碱性粒细胞介导的炎性疾病的含大麻素复杂混合物 |
-
2021
- 2021-04-13 CN CN202110395403.0A patent/CN115192557B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109640948A (zh) * | 2016-06-16 | 2019-04-16 | 利物浦大学 | 化学组合物 |
| WO2018133862A1 (zh) * | 2017-01-22 | 2018-07-26 | 北京蔚蓝之源医药科技有限公司 | 细胞色素bc1复合物抑制剂在制备医药组合物中的用途 |
| CN110536681A (zh) * | 2017-02-01 | 2019-12-03 | Gbs全球生物制药公司 | 用于治疗肥大细胞相关的或嗜碱性粒细胞介导的炎性疾病的含大麻素复杂混合物 |
Non-Patent Citations (2)
| Title |
|---|
| Atovaquone attenuates experimental colitis by reducing neurtrophil infiltration of colonic mucosa;Laura D. Manzanares et al.;《Front Pharmacol.》;第2022卷(第13期);1011115 * |
| Brigida R. Pinho et al..Modulation of Basophils' Degranulation and Allergy-Related Enzymes by Monomeric and Dimeric Naphthopquinones.《Plos One》.2014,第9卷(第2期),e90122. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115192557A (zh) | 2022-10-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210212961A1 (en) | Cannabinoid-containing complex mixtures for the treatment of mast cell-associated or basophil-mediated inflammatory disorders | |
| EP1307189B1 (en) | Use of hydroxyethylrutosides for treating symptoms of common cold, allergic rhinitis and infections relating to the respiratory tract | |
| US20200323843A1 (en) | Use of levocetirizine and montelukast in the treatment of viral infection caused by coronavirus | |
| WO2018113027A1 (zh) | 白果内酯作为增效剂在制备防治脑神经损伤性疾病药物的应用 | |
| Braido et al. | New therapies for allergic rhinitis | |
| KR20130099140A (ko) | 베포타스틴 조성물 | |
| US20080319087A1 (en) | Use of Ambroxol for the Treatment of Rhinovirus Infections | |
| CN115192557B (zh) | 用于治疗肥大细胞介导的炎性疾病的药物组合物 | |
| CN1838885A (zh) | 治疗皮肤的疮和损害的方法 | |
| Barrow et al. | An appraisal of the efficacy of the antiviral R 61837 in rhinovirus infections in human volunteers | |
| WO2024077506A1 (zh) | 用于治疗肥大细胞介导的炎性疾病的药物组合物 | |
| RU2669942C1 (ru) | Соединение семейства авермектина или семейства мильбемицина для лечения и/или профилактики атопического дерматита | |
| WO2005041984A1 (en) | Compositions and treatments for envelope virus infections | |
| Higgins et al. | Failure to demonstrate synergy between interferon-α and a synthetic antiviral, enviroxime, in rhinovirus infections in volunteers | |
| US11426392B1 (en) | Antiviral and virucidal lung nebulizer compositions and related treatment methods | |
| Yeo et al. | Protective effect of loop diuretics, piretanide and frusemide, against sodium metabisulphite-induced bronchoconstriction in asthma | |
| Liu et al. | Clinical efficacy of vitamin D3 adjuvant therapy in allergic rhinitis: a randomized controlled trial | |
| US20240100047A1 (en) | Composition and method for treating covid-19 | |
| Mochizuki et al. | Suppressive effects of F-1322 on the antigen-induced late asthmatic response and pulmonary eosinophilia in guinea pigs | |
| US20220273594A1 (en) | Compositions and Use of N-Chlorotaurine for Treatment and Prevention of Respiratory Infections | |
| US11583561B2 (en) | Composition for preventing, treating, or alleviating viral infection diseases or respiratory diseases comprising vesicle derived from Lactobacillus paracasei | |
| US20240091153A1 (en) | Composition for use as an antiviral in the form of nasal drops and in nebulisers | |
| Van Cauwenberge et al. | Antihistamines and nasal blockage. | |
| Samoliński et al. | Intranasal combo: fixed-dose combination of mometasone furoate and olopatadine hydrochloride in therapeutic strategies for rhinosinusitis. | |
| CN102949400A (zh) | 用于治疗鼻部炎症的含有糖皮质激素和nos抑制剂的药物组合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |